#Superior 6 Str

[vmantras]

BYD eMAX 7: Performance and Features Review

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[yeliuxi]

A silly little stylized mastermind rogue Jing Beiyuan sketch for @mscutellatus! Thanks for your prompt for @danmei-action <3 (Whoops there is a typo but I am ignoring it)

Full text transcription below the cut

Jing Qi. Given a second chance at his first lifetime of fated love, Jing Qi possesses invaluable foreknowledge and insight. He's clever and scheming, but can't afford to let anyone know this secret. Instead, the Prince Nanning is content to laze about when he can, and has earned an indulgent and carefree reputation.

With the obsessions of his previous six lives put behind him, Jing Qi is eager to secure the throne for the Crown Prince. The imperial court of Great Qing is dangerous, but Jing Qi works diligently behind the scenes (when he's not napping), and is determined to succeed.

Stat block.

Armor class: 13 (leather armor) / Hit points: 53 (10d8+10) / Speed: 30 ft.

STR 8 (-1). DEX 14 (-2). CON 10 (+0). INT 17 (+3). WIS 14 (+2). CHA 18 (+4).

Evasion. Oh, you want Jing Qi to make a DEX saving throw for half damage? He'll pass. If he succeeds he takes 0 damage, and half if he fails. Yeah. Serves you right for trying.

Insightful Manipulator. Interact with Jing Qi for 1 minute outside of combat at your own risk. He can learn whether you're his equal, superior, or inferior in any two of your INT, WIS, CHA scores, or class levels (if any).

Sneak Attack. When Jing Qi has advantage, or when Wuxi is within 5 feet of his target, he deals an extra 17 (5d6) damage. How battle couple of them.

Actions. Crossbow. Ranged Weapon Attack: +6 to hit, 80/320 range, one target. Hit: 7 (1d6+2) piercing damage. (Sorry, he meant to hit you, not the other guy…)

Bonus Actions. Cunning Action. On each turn, Jing Qi can take the Dash, Disengage, or Hide action as a bonus action. Hey, he can be efficient when he wants to be…

Master of Tactics. Jing Qi can use the Help action as a bonus action. When using the Help action to aid Wuxi in an attack, the target of the attack can be within 30 feet, instead of 5.

Reactions. Uncanny Dodge. When an attacker Jing Qi can see hits him with an attack, Jing Qi can use his reaction to halve the attack's damage. Don't get the jump on him easily. Once/rest.

[utilitycaster]

Level-Up Post: Mighty Nein: Echoes of the Solstice addendum

This is going to be short and sweet (ish) and covering deviations or clarifications to the pre-show post.

Everyone (except Luc) (and Aggy): level 20!

Fjord: I stand by my opinion that Open Sea Paladin 7's Aura of Liberation is superior to Hexblade 14's Master of Hexes, but both are very solid and the important thing is that Aura of Protection from paladin 6. We don't know his invocation but we do know his L13 Warlock Mystic Arcanum, Crown of Stars, or, more accurately to how he flavored it,

Beau: She DID take the mobile feat, and I'm so happy. 70 ft/round base walking speed. Monks, y'all.

Caleb: has the Wish spell; is using it solely, currently, to replicate lower spells, which is iconic of him. Responsible casting at its finest. One of his at-will 1st level spells is Fortune's Favor, but I don't think we got any of the others, and I believe his feat is also unknown.

Veth: We do not know; truly hilarious of Sam to do this. Don't worry; I'll talk about Luc in a second.

Jester: Her feat is Flash Recall, which is in the TCSR and allows you to replace a prepared spell with another spell of the same level without a long rest. Very good for Jester, whose spell prep is iconic in its eclecticism (complimentary).

Caduceus: much like his careful evasion of any questions from others asking how he was doing during the campaign (also complimentary), his feats - level 19 and level 16 remain a mystery (though we know his INT increased with his level 16 feat). In short:

Yasha: Took barbarian levels and has the CON and STR to prove it; also took Great Weapon Master, which is a solid option.

Our guests:

Rab "Aggy" Agg: Level 5 monk; no subclass we die like Bertrand Bell.

Luc Brenatto: I don't know how by how much the potion increased his level; at least to level 7 rogue (Evasion) from his base Arcane Trickster Rogue 5/War Mage Wizard 3. For a quick refresh on Arcane Trickster and rogue low levels, Luc has expertise, sneak attack, and uncanny dodge as well as the special arcane trickster mage hand abilities. He has 3 cantrips and 4 spells known from his rogue subclass. Meanwhile, as a wizard he has arcane recovery (not used; a long rest but no short ones), can prepare 6 spells from his spellbook, and he is treated as a 4th level spellcaster (1/3rd his rogue level rounded down plus his wizard level), so he can cast up to 2nd level spells. War mage is, on its own, notably a kind of shitty wizard subclass, but it's actually hilarious and pretty great as a multiclass option here. Luc used Arcane Deflection, which lets him use his reaction to grant either an AC bonus or a saving throw bonus, although when used you cannot cast spells other than cantrips until your next turn. This sucks if you are a wizard, but Luc is a rogue with an Aeorian security cannon, so it's fine. He also gets a +3 (INT mod) to his initiative.

[the-whatcherof-89]

Sir CyberKnife Herald of order.

CR 22 LG Medium Humanoid (Orc, Humanoid)

XP 614,400 (if used as npc for encounter)Advanced Half orc Bard(Negotiator)12 Paladin(Scion of peace)8

Lawful Good Medium humanoid (half orc)

Init +7; Senses Perception +39

AC 36, touch 25, flat-footed 29, (+7Natural, +5Deflect, +6Armor, +5Shield, +7Dexterity, +1Intuition) Hp 225 (12d8+8D10+148)

Fort +33, Ref +33, Will +36

Speed 30 ft. Melee Diplomat3+28/23/18/13 1D6+4, Spells. Ranged Bow of Artaphernes+32/27/22/17 1D8+8, Spells.

Racial Speed 30ft, Darkvision 60ft, Human-raised, sacred tattoo, Orc blood.

Traits Noble Savage.

Class features Hard bargain, Bardic performance(Counter-argument, Fast talk, binding contract, Distraction, Fascinate, Inspire competence, Suggestion, Dirge of doom, Soothing performance), Master of rhetoric 2/day, Well-versed, Jack of all trades, Rogue talents(Finesse rogue, Charmer, Ranged disarm, Slippery mind), Scion’s faith, Egalitarian, Aura of good, Detect evil, Smite evil3/day, Bonded eagle, Lay on hands, Aura of courage, Divine health, Channel positive energy, Mercy(Deceived, Riled), Consensus.

Spellcasting CL12(Bard) Daily 8/8/7/6 CL5th(Paladin) Daily 4/4 DC22.

Known(Bard): 0-Read magic, Mage hand, Prestidigitation, Detect magic, Repair, Message. I-Charm person, Hideous laughter, Grease, Cure light wounds, Animate ropes, Alarm. II-Cure moderate wounds, Calm emotions, Mirror image, Enthrall, Hold person. III-Haste, Good hope, Dispel magic, Charm monster. IV-Hold monster, Summon monster IV-Freedom of movement, Illusory terrain.

Prepared(Paladin): I-Bless, Lesser restoration, Build trust, Detect undead. II-Resist energy, Bull’s strength, Shield other, Zone of truth.

Str 12, Dex 24, Con 24, Int 24, Wis 22, Cha 34

Base Atk +17/12/7/2; CMB +13; CMD +20

Feats Scribe scroll, Combat expertise, Precise shot, Improved disarm, Deadly aim, Adept champion, Outflank, Leadership, Point-blank shot, Spell focus(Enchantment), Greater spell focus(Enchantment).

Skills Acrobatics+30, Appraise+11, Bluff+22, Climb+9, Craft(Calligraphy)+30, Diplomacy+46, Disguise+16, Escape artist+30, Fly+11, Handle animal+16, Heal+12, Intimidate+22, Knowledge (Arcana+29, Dungeon+15, Engineering+15, Geography+15, History+15, Local+21, Nature+15, Nobility+15, The planes+15, Religion+15), Linguistics+4, Perception+29, Perform(Oratory)+35, Profession(Ambassador)+15, Ride+11, Sense motive+45, Sleight of hand+15, Spellcraft+28, Stealth+15, Survival+10, Swim+5, Use magic device+33.

Leadership score (40)Cohort lv17th Followers I-135 II-13 III-7 IV-4 V-2  VI-2 (Special modifications due to the Kingstone)

Languages Common, Orcish, Giant, Abyssal, Draconic, Ignan, Aquan, Necril, Alko, Sylvan, Tongues(via the Kingstone).

Combat gear Diplomat3(Disarming blade+Diplomat’s traveling stick+ Defending rapier+4), Bow of Artaphernes(Adaptive Cunning Allying dispelling Longbow+5), 50+3 Arrows, Clod iron longsword, Uniform of Apollonius(Heavy fortification Iadran dress uniform+3), Ring of protection+5, Ring of tactical precision(Outflank), Amulet of natural armor+5, Quick-block buckler, Staff of bolstering, Headband of mental superiority+6(Escape artist), Belt of physical might+6(Dex, Con), Cloak of Diogenes(Cloak of the diplomat+Cloak of resistance+3), Inquisitor’s monocle, Bracers of steadiness, Bag of holding(Type I), Tome of leadership and influence+3(Used), Ioun stones(Lavender and green ellipsoid, Dusty rose prism), Potions of gaseous form(4), Scrolls: Haste(1), Heroism(1), (Summon monster IV(3), Bard’s kit, 373GP, The Kingstone(Artifact).

The Kingstone(Artifact) Aura(Strong enchantment) CL18th Description: 

This artifact looks like a finely-carved marble sphere with runes of gold inscribed in various languages reciting poems of kings and rulers which changes every day. The stone can be carried by anyone but only those who are worthy can use its powers. Those deemed unworthy will have the stone turned into a cursed artifact known as a Loadstone. However, should one work to find a suitable user, the stone will guide the holder toward the “Ideal King” via prophetic dreams and other means granting the power to use Divine Favor upon itself once per day. Once the stone finds the “Ideal King” it will bestow its powers upon him which includes the following: 1)The user is constantly under the effect of of the following spells: Divine Favor, Tongues and Heroism. 2)All effect of auras, inspiration and Charisma-based skills, abilities and spells double the area which they cover normally, their other effects remain unchanged. 3)Finally, if the user manages to become a ruling figure of a kingdom or to be accepted as a king, the stone allows to the user to project an illusory image of the kingdoms and it will automatically know if there are enemies in the land(such as an invading army). This effect functions as the spell Sand Table. 4)All the authority bonuses increases by +3, furthermore, the user can summon an extra Monstrous Cohort of the appropriate level that serves him once per day for 1 hour which can be divided in 1 minute increments at his request(In this case it’s a Young Silver Dragon). If the cohort is killed, it disappears and can be summoned again after 24h. The more the user becomes famous, the more it becomes closer to turn into the “Ideal King” the ruler of all nations and kingdoms whom will unite all the world under a single banner. It is unknown if this is true or just a myth, but if the holder of the stone wishes to pass the torch of rulership it must find a replacement before giving it away. Common people will come flocking under the holder of the Kingstone seeing him as the true king (Regardless, such situation must be discussed by the DM). Destruction: To destroy the Kingstone it must be buried in the ground of the material plane in a land where no kingdom/nation has been established for at least 100 years and it must stay there for 1000 years untouched. When said time has passed, the stone turns into dust. However, the gods will not stay idle and a new Kingstone is sure to reappear somewhere, somehow to find a new candidate “Ideal King”.

Challenge rating modifiers +1 advanced template, Improved stats, PC equipment.

Background: Very little is known about the one known as Cyberknife(if that is his real name). From what  little snippets of knowledge some attained, he was born in the Nether as all Piglins(Orcs) does. However, as it happens very rarely, the pig inhabitants of the red wastes will give birth to a hybrid: a Hal-feh(half-orc). Even more rarely, these hybrids becomes just better than the more run-of-the-mill gold-obsessed creatures. Of course, the leaders of the various clans will see these as “impure” and/or a danger for their leadership and will most likely try to systematically eliminate the threat before it becomes a real one. Cyberknife was one such case, but as he was about to be sacrificed in a ritual for their god, he succeeded at escaping by causing a Hoglin stampede across the bastion and escaping from an obsidian portal. Although, he did heard that if one of their kin does escape the dimension is turned into a zombie, he knew he was born DIFFERENT. As he left, he felt something change but he was fine; He found a vibrant world completely different from the lava-scarred caves he used to live. He walked the land, and although he had a rocky start(not being accepted by the inhabitants of this land) eventually things took a turn when he was accepted in a traveling circus where he discovered his talent for the bardic arts. He then enrolled into a bardic academy where he was the only one of his kind, not a good thing but he did not care for he had bigger plans in mind: He wanted to change the view the world had on the Nether and reestablish a peaceful relationships with the two dimensions. This was not an easy task but he was DETERMINED. After more years, he left the academy to look for fortune as an adventurer; and one day after a long expedition in an ancient tomb he found that stone: the Kingstone. After that day, it took him little to enroll as an advisor in a battlefield and even less to rise in the ranks and become a commander. With the glory of victory he entered the kingdom a champion, then, with the money that he attained, he founded a political campaign to promote the betterment of the kingdom. The opposition attempted to destroy him, but he was always able to thwart their efforts and won in a landslide. Cyberknife became the ruler of a nation at the young age of 22 and had no intention of stopping. After 10 years of turmoil he succeeded to quell the conflict between 3 more kingdoms and unite them under his banner. Now, from his massive palace he plans for the future… but what future?

First image - made with Heroforge.

Second image - Art by the fantastic Goatfella: https://www.tumblr.com/goatfellaa/693602368642809856/cyberknife-design?source=share

[dungeonmalcontent]

How to play a real genuine werewolf in core 5e (so you don't have to resort to blood hunter).

Step 1) warlock. Undead patron.

Hear me out. Form of dread transforms you to reflect your patron. Your patron is a werewolf lord. RAW, werewolves are "humanoids", yes. However, mythologically, they tend to fall under undead as often as they don't. Or if you want a real comparison, Discworld werewolves are undead differently alive.

But the transformation grants you temp hp, a fear effect, and immunity to the frightened condition.

Step 2) invocations - beast speech and anything else you want, I suggest cloak of flies.

Beast speech is pretty obvious. You're being a beast cursed person, you can speak to beasts. Cloak of flies is because you will probably be melee. But also your second invocation will change later.

Step 3) pact of the blade

For this simple reason. Natural weapons available to the player are considered weapons. Therefore, you can summon them as a pact weapon. And you are going to be taking the claws from beast path barbarian form of the beast feature. These claws deal 1d6, but they double up. Every time you use one for an attack action, you can "take one additional claw attack as part of that same action." This will come back later.

And since you've leveled up to 3, you can swap invocations. You can pick up improved pact weapon. This makes your hands a +1 magic weapon.

Step 4) level 4, split paths

At 4th level, you take a feat (hopefully you didn't need the ASI) and it should probably be one of these:

+ slasher (TCE) Dex or Str up, reduce speed on claw attacks, and impose a round of disadvantage on a target you crit on.

+ fighting initiate (TCE) you get a fighter fighting style. I would select unarmed. And this would be a discussion with your GM, but it can potentially make your claws a d8 weapon instead of d6. It also lets you do automatic damage to creatures you grapple. Otherwise you can grab superior technique (but at that point you should be doing martial adept, not fighting initiate) or two weapon fighting which I would argue let's you off-hand with your claws.

+ Tough (PHB) this is self explanatory. You wanna be a brawling warlock? You need hit points.

+ eldritch adept (TCE) which is also self explanatory. You get an extra invocation. Always useful. Especially with pact of the blade.

+ fey touched (TCE) you get a cha +1 and misty step and then either hunter's mark or hex (and you get these spells as learned and as a freebie)

Step 5) level 5 new invocation

Not going to beat around the bush. Thirsting blade. If you were smart, you have fighting initiate and either deal 1d8s or get an extra 1d6 off-hand. With thirsting blade you get to do something cheeky. Remember how I said that additional attack with the claws would be coming back? You get extra attack. But the claws specify an "additional" attack as part of the attack action. That means 3 swipes at a d8 with unarmed style or 3 attacks and an off-hand swipe with two-weapon fighting.

If you picked up eldritch adept at level 4, you can also swap that extra invocation to eldritch smite.

Step 6+) it all works out pretty naturally from here. You can get some fun spells to augment your werewolfishness and damage output (spirit shroud is super good, so are mirror image and armor of agathys), some items like the insignia of claws from hoard of the dragon queen, and you can keep stacking feats as you get ASI (or if you picked variant human/custom lineage and start with a feat you have more options).

But also, at this point if you haven't asked "why not just play path of the beast barbarian?" I'm going to tell you now. You get more hit points, yes. But you don't get spells, you have less versatility and utility, and you scale slower. It's also just so much more fun to do it the weird way.

[helmoftelepathy]

Orc Class for BX/OSE

Orc

Demihuman Class

Requirements: Minimum 9 CON

Prime Requisite: STR

Hit Dice: 1d6

Maximum Level: 12

Armor: Any, including shields

Weapons: Any

Languages: Alignment, Common, Orcish

Orcs are bulky, pig-like demihumans with snouts, fur, and occasionally tusks. Usually weighing around 200 pounds and are between 4’11” and 5’3” in height. Orcs don’t typically associate themselves with adventuring parties, tending to stick to their own kind. Orcs that do work with adventuring parties can be helpful liaisons to other Orc clans, expert trackers, or formidable fighters in their own right.

Combat

Orcs can use all types of weapons and armour.

Enhanced Sense of Smell

Orcs can attempt to use their superior sense of smell to gain more information whilst in a dungeon. Orcs have a 2-in-6 chance of sniffing out the presence of monsters in adjacent rooms. (The referee may determine if any further information can be gathered such as specific monsters or number of monsters). After reaching 9th Level, Orcs have a 3-in-6 chance of sniffing out monsters.

Infravision

Orcs have infravision to 60’ (see Darkness under Hazards and Challenges in Classic Fantasy: Adventures).

Greater Awareness

When rolling for if the party is surprised, a party with an Orc is only surprised on a 1-in-6 chance.

Natural Forager

When foraging in the wilderness, a party with an Orc has a 2-in-6 chance of finding food instead of a 1-in-6.

After Reaching 9th Level

An Orc can create an Orc warband, attracting 1d6x10 orcs. The followers may be used as retainers or mercenaries and do not count for a character’s retainer limit based on their Charisma.

[superthatguy62]

Things Final Fantasy III does not tell you about Final Fantasy III.

When it comes to RPGs, information that the player has is far from a guarantee. Some games will tell players practically everything about their systems and leave it to the player to use that information. Others will leave some mechanics in the background, quietly applying them without the player's knowledge. The Final Fantasy III remake falls into the latter category, as there are some mechanics that the player may not realize even exist unless they look outside of the game. Here are seven of them.

This is based on the Future Press Official Strategy Guide. As far as SGs go, it seems pretty close to the Japanese SE guide (baring at least one case).

Party Member Levels (Life of the Party)

While temporary party aren't directly controllable, they seem to have their own levels and stats. Interestingly the Future Press strategy guide states that they also have stats. Though I should clarify: At this time, I have yet to find these in the Japanese strategy guide, so I am not entirely sure that these are accurate. However, the FP guide in general is close to the Japanese guide in terms of technical information, so I am willing to accept that risk.

These are:

Sara: Lv 5 (Str/Vit/Agi/Min: 6, Int: 7)

Cid: Lv 3 (Str/Agi: 5, Vit/Int/Min: 8)

Desch: Lv 10 (Str: 15, Vit: 10, Agi: 14, Int: 7, Min: 6

Aria: Lv 25 (All: 25)

Alus: Lv 30 (All: 35)

Doga/Unei: Lv 50 (All: 45)

Some observations:

The guide notes that the characters stats are usually significantly higher than the main characters' at the same levels. This is especially noticeable with Alus (The party's base stats, by compare, will be: Str/Agi: 24, Vit/Min/Int: 20)

Cid is the only party member to be weaker than the character before him (Sara), presumably due to how little time the party spends with him. He does have an impressively strong hammer, though.

Despite being portrayed as a White Mage, Sara's Int (7) is slightly higher than her Min (6).

It seems that after Desch, the devs kinda gave up with making varied stats, so Aria, Alus, Doga and Unei have the same number for all their stats.

Coincidence or otherwise, Aria's stat number also matches her level.

Doga and Unei share the same levels and stats as each other, a distinction no other party member has. For extra fun, Xande is also level 50, although his actual stats are unfortunately but understandably different.

Alus, a 10 year old boy is somehow twice as strong as Desch, a grown man.

Mognet Details (Stampin' N Stompin')

Most of Mognet's discussion usually begins and ends with it being connected to the sidequests. Because of this, there are a few features of Mognet that go undernoticed.

One particular aspect is the cards: For meeting the Legendary Smith with a mastered job and defeating the Iron Giant, the party can get cards signifying their mastery.

(I have yet to defeat the Iron Giant. I apologize for being a fraud).

In the PSP and Steam versions, these cards are mostly just rewards. In the DS version, however, they can be used as stamps for Mognet. And while the Iron Giant is purely to flaunt your superiority over the beast, the job mastery cards actually allow players to help out other players: If a player holding a signed letter runs into the Legendary Smith, she will give the player the respective job mastery item without having a level 99 job. While it doesn't break the game, due to how late it is before you can encounter the Smith, it does cut down on the grind you'd need if you wanted those items.

Encounter Frequency (Fights in the A.M. P.M. F.M.)

In Octopath Traveler, a later game by Team Asano, entering a new location will usually show you a danger level, giving you a general idea of how strong the enemies in that area are. While the mechanic is visible in OT, it was actually deployed discreetly in Final Fantasy III: Each area has a level that the guides recommend the player be at. However, the game itself uses a more subtle method: If your party is below the recommended level, the encounter rate will be higher than usual. By contrast, the further above the recommended level that the party is (up to six levels), the lower the encounter rate will be.

For example: The Nepto Shrine has a Danger Level of 10. If the party made it to the Shrine at level 7, then they will likely encounter more enemies than they would at level 10. By contrast, at level 16, they will have a chance at encountering the least amount of enemies.

Attack Types (SMASH! SLASH! STAB!)

In Final Fantasy III, elemental weaknesses are clear and easily implied by the fact that Mages have themed spells. However, the game also has a second, subtle weakness system: Attack Types, the physical counterpart.

The four attack types are

Unhanded: Despite the name, Claws are also included

Blow: Weapons that focus on slamming or bludgeoning the foe

Cut: Weapons that actually cut the foe, like Swords

Stab: Weapons that stab or have a stab-like effect, like Arrows

Interestingly, some weapons aren't mutually exclusive: Axes count for both blows and cuts, Knives count for both stabs and cuts and Unarmed counts for both Unhanded and Blow.

Hands (The Hands of Fate)

The Hand stat is a secret stat that the game silently keeps track of for each character. The hand stat represents how many times a physical attack has been made with a particular hand, the hand getting 3 XP for each use. Much like job levels only one hand level can be gained per battle, regardless of how many points are racked up. Theoretically, if you can have hands of different levels, although given how much III encourages dual-wielding, it's unlikely.

The FP guide recommends using the Ranger's barrage if you want to build up the hand stat, as that is a multi-hit attack that nonetheless counts each hit for the hand.

Weight (The Weight of the World)

Weight is not a new mechanic to Final Fantasy. Final Fantasy V, in particular has the stat help to determine who quickly a character acts (i.e. how fast the ATB bar fills up). However, V is the rare game where the game will actively inform the player of its existence. Other games in the series have it, including III (at least, in the remake).

Weight, along with Agility, determines how soon a character will act during the turn, as well as how many hits a character does (alongside the aforementioned Hand stat). This is why a Warrior with an axe will generally hit less than a Warrior with a sword, despite having higher attack. Interestingly magic also has weight to it with spells having a specific weight/cast time to it.

Boss Scripts (Script Write)

Bosses changing strategy mid-fight has been a Final Fantasy staple since at least Final Fantasy IV (Zeromus, for example, only starts to spam Meteo when he's close to dying), so the FF3 remake isn't particularly new or original for using this. Still, it's something to be aware of in case you make a particular fight harder than it needs to be.

A likely candidate for this is actually the final boss: While the Cloud of Darkness uses Particle Beam (and spams it during the last phase), it actually doesn't use the move until it's down to 80% of its HP, using the less threatening standard attack instead. This means that a player willing to take some turns to lower the danger can focus on the tentacles, which are the more immediate threat.

[pathfinderunlocked]

Vulcadaemon - CR17 Daemon

Burn, miserable little worms!

Artwork by Daniele Mendes on ArtStation.

Daemons in my setting are each associated with a negative emotion that they both create and feed upon. The vulcadaemon is a fiend of arrogance, feeding on those who believe themselves superior to others, and influencing the emotions of those it interacts with to make them look down on lesser beings.

A vulcadaemon's high intelligence is a major source of its sense of superiority, and it studies alchemy and uses it in combat. Vulcadaemons continuously study to find alchemical ways to increase their power and perfect their bodies, and make deals with arrogant mortals who wish to share their knowledge to gain immortality. Rather than taking a mortal's soul in exchange, a vulcadaemon is more likely to ask for a mortal's offspring, infusing the child with magic at a young age or siring a child with the mortal, and taking them as slaves when they reach a useful age. Vulcadaemons have been known to use their magic jar spell to take over a mortal's body in order to sire or bear a child as part of a deal, resulting in a tiefling child with the Pass For Human trait.

Its bombs function like alchemists' bombs but are made from its own fiery feathers, which it plucks from its body, turns into explosive projectiles, and launches at its opponents. Picture Gambit from the X-Men but with feathers instead of playing cards.

This is a multi-phase boss fight. A vulcadaemon starts as a land-based medium creature and can transform into a colossal aerial form, but doing so exacts a significant toll on its body when the effect ends, and also lowers its DR, so it waits to do this until it's in danger and believes flying would be beneficial. I would recommend doing so when it reaches about 150 HP remaining, or when it's suffered some kind of serious debilitating condition.

Sorry for the gigantic text of the Extracts ability. This creature's extracts do actually work somewhat differently than an alchemist's extracts. Notably, it can use extracts of offensive spells, but the range is changed to the ground underneath its reach, instead of the spell's normal range.

It has two things it can do with its swift actions - poison a bomb, or cast wall of fire. Make sure to do one or the other each round.

Vulcadaemon - CR 17

The hunchbacked bird-person has skin that looks like magma. Where its eyes should be are instead pits of dripping liquid flame.

XP 102,400 NE Medium outsider (daemon, evil, extraplanar, fire) Init +11 Senses darkvision 60 ft., detect magic, detect poison, see invisibility; Perception +30

DEFENSE

AC 29, touch 19, flat-footed 20 (+8 Dex, +1 dodge, +10 natural) hp 262 (21d10+147); regeneration 10 (cold) Fort +18, Ref +20, Will +15 DR 15/good or ice Immune acid, death effects, fire, poison Resist electricity 10 Weaknesses vulnerable to cold SR 28

OFFENSE

Speed 30 ft. Melee 2 talons +27 (1d6+5/19–20 plus 1d6 fire) Ranged bomb +29/+24/+19/+14 ranged touch (7d6+9 plus 16 splash) (DC 26 Reflex halves splash) (20 ft. range increment) (24/day) Space 5 ft.; Reach 5 ft. Special Attacks bombs, emerge into flame, smoke form, smoke talons

Spell-Like Abilities (CL 20th; concentration +26)    Constant—detect magic, detect poison, read magic, see invisibility    1/day—summon (level 6, 1 fiendish greater fire elemental 100%)

Extracts Prepared (CL 20th)    1/day—fire storm (x4) (DC 27), magic jar (DC 24), true seeing, quickened wall of fire x3

STATISTICS

Str 21, Dex 26, Con 22, Int 29, Wis 22, Cha 23 Base Atk +21; CMB +27; CMD 45 Feats Blinding Critical (DC 31), Combat Reflexes, Critical Focus, Dodge, Flyby Attack, Improved Critical (talon), Improved Initiative, Iron Will, Mobility, Skill Focus (craft alchemy), Toughness Skills Acrobatics +29, Craft (alchemy) +53, Fly +32, Intimidate +30, Knowledge (arcana, history, local, nature, planes) +33, Knowledge (dungeoneering, engineering, religion) +30, Perception +30, Sense Motive +20, Spellcraft +30, Stealth +21; Racial Modifiers +14 Craft (alchemy) Languages Abyssal, Draconic, Common, Ignan, Infernal, 5 others; telepathy 100 ft. Gear formula book (fire storm, magic jar, true seeing, wall of fire), spell component pouch

SPECIAL ABILITIES

Bombs (Su) A vulcadaemon can throw bombs as a 14th level alchemist with the Fast Bombs discovery. These bombs are typically created from its feathers. It can use a number of bombs per day equal to 15 plus its Intelligence modifier (typically 24 bombs per day). A bomb counts as a thrown splash weapon, and throwing a bomb is a ranged touch attack with a 20 ft. range increment. Each bomb does 7d6 fire damage plus the vulcadaemon's Intelligence modifier (typically +9), increasing to 8d6 plus twice its Intelligence modifier on a critical hit (typically +18). A bomb deals splash damage to adjacent targets equal to the minimum damage of the bomb (typically 16 damage, or 26 damage on a critical hit). A DC 26 Reflex save halves the splash damage. The save DC is Intelligence-based.

A vulcadaemon can prepare and throw multiple bombs as a full-round action, which functions just like a full-attack with a ranged weapon.

Emerge Into Flame (Su) Once per day, a vulcadaemon can transform into a Colossal flying form made of liquid fire for 2 minutes. This does not require an action, and can be done even while helpless. When a vulcadaemon transforms into this form, it heals 80 hit points, and can remove harmful effects on itself as if it had successfully cast both cleanse and greater dispel magic (targeted dispel) at caster level 20, with a natural result of 20 on the d20 for the dispel check.

While in its emerged form, a vulcadaemon has a 30-ft. space and a 20-ft. reach. It gains a 120 ft. fly speed with good maneuverability (typically giving it a total bonus of +28 Fly) while in this form. It takes the standard -4 penalty to attack rolls and AC, and +4 bonus to CMB and CMD, along with the other typical effects of being Colossal-sized. Its damage reduction is reduced from 15 to 10.

After this effect ends, a vulcadaemon is sickened for 8 hours.

Extracts A vulcadaemon can use a number of extracts, which in many ways function similarly to spells in potion or oil form, and as such their effects can be dispelled by effects like dispel magic. It uses Intelligence as its spellcasting ability score with extracts. An extract immediately becomes inert if it leaves the vulcadaemon’s possession, reactivating as soon as it returns to the vulcadaemon's keeping. An extract, once created, remains potent for 1 day before becoming inert, so a vulcadaemon must re-prepare its extracts every day, which takes 1 minute per extract.

A vulcadaemon possesses a formula book, functioning like an alchemist's formula book, although note that several of its spells are not on the alchemist spell list and are therefore not learnable by alchemists.

A vulcadaemon can only prepare a limited number of extracts per day. Its typical extracts are listed in its statistics above, though when preparing extracts in the morning, it can choose to instead prepare any combination of 9 extracts that are in its formula book. Unlike an alchemist, a vulcadaemon's extracts are not tied to different spell levels - it can simply prepare any 9 extracts per day. This amount is based on its Intelligence modifier.

Unlike an alchemist's extracts, a vulcadaemon's extracts are "cast" by picking up an object (usually one of its feathers, which is treated as always being in hand, similar to a material component), infusing it with magic, and dissolving the object into a burning liquid. The liquid casts the spell upon touching a creature or the ground, so a vulcadaemon's spells can only target itself, a creature within its reach, or the ground underneath itself or underneath a space within its reach, instead of the normal range of the spell. A spell with an area of effect (such as fire storm or wall of fire) emanates out from the targeted ground to its normal area.

Using an extract has the same casting time as the spell, except for quickened wall of fire, which a vulcadaemon can use as a swift action.

Quickened Wall of Fire A vulcadaemon can prepare a wall of fire extract as if with the quickened spell metamagic, reducing its casting time to a swift action.

Smoke Form (Su) A vulcadaemon’s form is typically solid. As a free action it can change to a smoky form or back to solid form. It can switch forms once per round as a free action and can spend up to 20 rounds per day in smoke form. In smoke form, a vulcadaemon can fly at a speed of 50 feet (perfect). This ability is otherwise similar to a gaseous form spell (caster level 20th), except that the vulcadaemon can use its Smoke Talons ability while in this form.

Smoke Talons (Ex) A vulcadaemon using its smoke form ability can enter a target’s square as a standard action that does not provoke attacks of opportunity. The target must make a DC 26 Fortitude save or inhale part of the creature. Creatures that do not need to breathe are immune to this attack. The save DC is Constitution-based.

As a swift action while a target has inhaled this smoke, the vulcadaemon can cause the smoke inside the victim to solidify into a talon and attacks the target from within, automatically dealing 3d8 points of damage. If the target moves, the vulcadaemon may automatically move with the target; this movement does not count toward the vulcadaemon's movement, and does not provoke attacks of opportunity against or from the vulcadaemon. Each round, the target can attempt another DC 26 Fortitude save to cough out the vulcadaemon's smoke, which ends the smoke claws attack and forces the vulcadaemon into an adjacent square.

Swift Poisoning (Ex) A vulcadaemon can apply vulcadaemon poison to one of its bombs per round as a swift action, causing that bomb to poison a target struck with a direct hit. This poison becomes inert if the bomb is not thrown immediately. The poison is not applied to the splash damage.

Vulcadaemon Poison (Ex) Type poison (injury); Save Fortitude DC 21; Frequency 1/round for 6 rounds; Cure 2 consecutive saves; Effect 1d4 Con and 1d2 Dex

And I have a second image for phase 2 of this fight.

Artwork by John Pomeroy, from Fantasia 2000, copyright Disney.

[overfedvenison]

So within the Tau meta right now, people are running squads of Crisis Suits with all Cyclic Ion Blasters. This is, mathematically, typically the strongest weapon you have. Cyclic Ion Blasters can Overcharge and get three Str 8, AP-2 shots each, and each suit can get three of these. Since they are Vehicles, they can absorb a decent amount of the self-damage from an Overcharged weapon (Which deals Recoil, basically) but you are still fielding a suicide unit basically. Most people still consider this the most viable choice, to the point of being the only viable choice in many people's eyes. But there are other options. I'm using Flamers with Farsight leading the squad. Flamers, even under normal circumstances, out-pace Cyclics against Guardsmen and other chaff units, and are giving a lot of threat under the new Overwatch rules (Which allow you to shoot whenever someone moves.) Farsight gives a +1 to wound, which is... A lot. It's a different kind of strategy; I really do not see the point in fielding Cyclic Ions on Farsight when almost any other commander would be a superior option in that scenario. But Flamers really just halt an enemy's approach and demand a response in the right scenario, SUPER dominant play when it works. But I saw someone post an interesting comment on a reddit thread: Plunging Fire. If a unit is on top of ruins at least 6" tall, they gain Plunging Fire and increase their AP by 1. So this guy was fielding his Crisis Suits in small squads, high up on terrain, and utilizing that bonus with the longest-range weapons he could - Plasma Rifles (24") and Missile pods (30") A 30" Missile Pod would get two shots each at Str 7, AP-2 in this building, and dealing 2 damage each. That's comparable to Cyclic Ion Blasters, but is far, far more survivable (No threat of recoil, more conservative placement, and cover when on ruins) and especially good against Marine-equivalents. That is a REALLY compelling rogue strat, albeit a little terrain-dependant. The standard rules are that you and an opponent alternate placing terrain, but in practice some boards are pre-made. Still, that is.... Interesting

[justicegundam82]

3.0 to PF1e Conversion: Formian, Winged Warrior

Welcome back!

This new conversion comes from the 3.0 Fiend Folio, which introduced a lot of cool monsters (and some not-so-cool ones, but hey, can't win them all). The book introduced three new castes of Formian: the Armadon, the Observer and the Winged Warrior. The Creature Chronicle blog already converted the Armadon, but the other two were left in the dust. Until now, of course.

I plan on doing the Observer and another new Formian caste soon enough. Until then, I hope you like this.

FORMIAN, WINGED WARRIOR

Image copyright Wizards of the Coast, from Fiend Folio, by LGW

This creature looks like a strange cross between an ant and a garner, with a glossy bluish-black exoskeleton, two pairs of large insectile wings, and a slender tail tipped with sharp spikes. Its legs end in small hands, armed with pointed claws.

FORMIAN WINGED WARRIOR       CR 6

XP 2’400

LN Medium Monstrous Humanoid

Init+5; Senses blindsense 30 ft., darkvision 60 ft., hive mind; Perception +14 (+18 with hive mind)

------------------

DEFENSE

AC 19, touch 15, flat-footed 14(+5 Dex, +4 natural)

Hp 68 (8d10+24)

Fort +5, Ref +11, Will +8;

Resist sonic 10

Spell Resistance 17

----------------------

OFFENSE

Speed 20 ft., fly 60 ft. (good)

Melee bite +13 (1d6+2), 2 claws +13 (1d4+2)

Ranged tail spike +13 (1d4+2 / 19-20 / x3 plus poison)

Special Attacks augmented critical, poison, tail spikes

----------------------

STATISTICS

Str 15, Dex 20, Con 17, Int 10, Wis 14, Cha 11

Base Atk +8; CMB +10; CMD 25

Feats Flyby Attack, Point Blank Shot, Precise Shot, Shot On The Run (B), Weapon Finesse

Skills Acrobatics +14, Fly +20, Perception +14 (+18 with hive mind), Stealth +15, Survival +12

Languages telepathy 60 ft. (cannot speak)

Special Qualities formian traits

----------------------

ECOLOGY

Environment warm or temperate land or underground

Organization Solitary, team (2-4) or troop (5-10)

Treasure none

----------------------

SPECIAL ABILITIES

Augmented Critical (Ex): A winged warrior’s tail spikes threaten a critical hit on a natural attack roll of 19-20 and inflict triple damage on a confirmed critical hit.

Poison (Ex): Tail spike – injury; save Fort DC 17, frequency 1/round for 6 rounds, effect 1d2 Str damage, cure 1 save.

Tail Spikes (Ex): Six times per day, a winged warrior can release a spike from its tail as a standard action. Tail spikes are considered thrown weapons with a range increment of 20 feet.

----------------------

Winged warriors are specialized members of the formian hives, and the only formian caste capable of flying under their own power. Within the hive’s rigid caste system, winged warriors mostly act as skirmishers and scouts for their superiors, assessing the lands around the hive and reporting on potential enemies. Needless to say, they are agile fliers, but are clumsy and slow on land, and therefore spend most of their time aloft, only landing to rest or report.

In battle, winged warriors mostly rely on providing ranged support to warriors, armadons and taskmasters. As their more robust brethren keep the enemy occupied, a winged warrior shoots sharp spikes from its tail with tremendous accuracy, favoring obvious spellcasters and healers. Each spike is tipped in a narcotic that sap the victim’s strength, making it easier for the hive to capture them alive. Once a winged warrior’s ranged attacks are depleted, they will switch to hit-and-run attacks, trusting their speed and maneuvrability to see them through the fight.

Formian winged warriors stand about 5 feet tall and weigh 120 pounds. While they are capable of communicating via telepathy, they lack the organs needed for vocalization, and therefore cannot speak.

[thecreaturecodex]

Quintessivore

Image © Paizo Publishing

[The quintessivore is a weird monster in a number of ways. For one thing, its PF2e category is "beast", when both its bizarre anatomy and unusual diet would make it seem to be a shoo-in for aberration status. Although maybe that's a result of the art; those proportions and placements of the limbs are truly bizarre, and I'm not sure if that was the original intent. For another thing, the Bestiary 3 entry is mostly taken up with explaining what quintessence is for readers not immersed in PF lore, leaving the actual flavor text for the monster rather thin on the ground. So I had room to expand, and to explain some things that the original entry leaves without comment.]

Quintessivore CR 10 NE Aberration This creature has a head like a deep-sea fish, with pointed teeth and beady eyes. It has four many-jointed limbs—two of them ending in three-fingered claws, and two of them ending in bladed appendages. Its color is a sickly gray, and its body is studded with short spines, ridges and strings of fibrous material.

Quintessivores are strange creatures that feed on quintessence, the raw material of souls and the Outer Planes. They are roughly spider-like in proportion, having long limbs holding up a relatively small body. Their exoskeletons constantly slough off strands of tough fiber, similar in texture to silk but greasier. Quintessivores cannot weave webs as true spiders can, but use their silk as if it were paper, recording their spellbooks and other writings on their secretions. 

A quintessivore on one of the Outer Planes is often docile and talkative, as they have access to effectively infinite food. On the Material Plane, however, they stalk mortal beings in order to strip their souls and consume them slowly. While feeding on a soul, the quintessivore’s blade legs are faintly luminous, and patterns resembling waves, whorls and loops appear and disappear along their length. The process of feeding on a soul empowers their magical abilities, and souls that are more powerful grant longer lasting boons.

Quintessivores are despised by almost all outsiders, as their diet is soul-stuff itself. Psychopomps especially seek to eliminate quintessivores, and these aberrations typically flee from even rumors of psychopomp activity. On the other hand, daemons are rather fond of them, as their feeding reduces the net quintessence in existence, inexorably bringing the end of all things closer. Daemons still by no means respect these mortal creatures, and both the quintessivore and the daemon typically think of themselves as the superior partner in any allegiances unless the power differential between the two is obvious.

Quintessivore      CR 10 XP 9,600 NE Medium aberration Init +6; Senses darkvision 60 ft., Perception +19

Defense AC 25, touch 17, flat-footed 18(+6 Dex, +1 dodge, +8 natural) hp 136 (13d8+78) Fort +10, Ref +10, Will +13

Offense Speed 40 ft., climb 20 ft. Melee 2 claws +15 (1d10+3 plus 1d10 negative energy and ability drain) Special Attacks ability drain (1d3 Con, Fort DC 22), feed, suspend soul Spells CL 10th, concentration +17 (+21 casting defensively) 5th—feeblemind (DC 22), passwall, vampiric shadow shield 4th—arcane eye, black tentacles, contagion (DC 22), enervation  3rd—clairaudience/clairvoyance, fireball (DC 20), protection from energy, ray of exhaustion (DC 20), slow (DC 21) 2nd—cat’s grace (x2), invisibility, scorching ray, see invisibility, web (DC 19) 1st—comprehend languages, expeditious retreat, feather fall, mage armor, magic missile, ray of enfeeblement (DC 19) 0th—detect magic, mage hand, open/close, read magic

Statistics Str 17, Dex 22, Con 23, Int 24, Wis 17, Cha 16 Base Atk +9; CMB +12; CMD 29 (33 vs. trip) Feats Combat Casting, Dodge, Iron Will, Scribe Scroll, Spell Focus (necromancy), Stealthy, Weapon Finesse Skills Acrobatics +22 (+26 jumping),Climb +27, Escape Artist +26, Intimidate +19, Knowledge (arcana) +23, Knowledge (dungeoneering, planes) +20, Perception +19, Spellcraft +23, Stealth +26, Use Magic Device +16 Languages Abyssal, Aklo, Common, Daemonic, Infernal, Undercommon

Ecology Environment underground Organization solitary Treasure standard

Special Abilities Feed (Su) By spending 1 hour with a helpless living creature, or a formerly living creature no more than 2 hours dead, a quintessivore can consume its quintessence, keeping it from reaching the afterlife. A creature fed on in such a way cannot be returned from the dead, unless its soul is freed from the quintessivore by killing the creature. A quintessivore retains the soul bound to it for 1 day per HD of its victim, during which time it gains a +1 on all spell save DCs, and may prepare an additional spell of each spell level. Once this time is elapsed, the victim’s soul is gone forever. A quintessivore can only have one soul bound to it at a time. Spells A quintessivore can prepare and cast spells as a 10th level generalist wizard. It does not gain other benefits of the wizard class, such as a specialty school or arcane bond, unless it takes levels in the wizard class. Suspend Life (Su) As an immediate action, a quintessivore can suspend the life processes of a dying creature within 15 feet. A creature so affected must succeed a DC 21 Fortitude save or be unable to gain or lose hit points for 1 hour. During that time, if the creature receives magical healing, it can attempt another DC 21 Fortitude save to break the effect. The save DC is Charisma based, and includes a +2 racial bonus.

[arganoilsidighanem]

Argan Oil Wholesale: What You Need to Know

Bulk argan oil is a cost-effective solution for businesses in the cosmetics, wellness, and culinary industries. With the increasing demand for natural products, buying wholesale not only reduces costs but also ensures a reliable supply of high-quality oil. This guide highlights the essential factors to consider before purchasing wholesale argan oil.

Introduction: The Benefits of Buying Argan Oil in Bulk

Purchasing argan oil in bulk presents an excellent opportunity for businesses to access premium-quality oil at competitive prices. This article covers everything you need to know before making a wholesale purchase. We will explore product characteristics, key benefits, differences from other oils, pricing, quality, authenticity, customer reviews, and my personal insights. Read on to discover how bulk argan oil can enhance your business.

Why Consider Buying Argan Oil in Bulk?

Bulk argan oil is a cost-effective solution for businesses in the cosmetics, wellness, and culinary industries. With the increasing demand for natural products, buying wholesale not only reduces costs but also ensures a reliable supply of high-quality oil. This guide highlights the essential factors to consider before purchasing wholesale argan oil.

Key Characteristics of Bulk Argan Oil

Composition and Sourcing

100% Pure and Natural – Extracted from the kernels of the Moroccan argan tree, ensuring authenticity and quality.

Cold-Pressed Extraction – Preserves essential nutrients like vitamin E, omega-6, and omega-9 fatty acids, making the oil highly beneficial.

Versatile Applications – Suitable for skincare, haircare, and culinary uses, making it a valuable multi-purpose product.

Production and Sustainability

Ethically Sourced – Many suppliers collaborate with local cooperatives in Morocco, supporting sustainable farming and fair-trade practices.

Traditional Extraction Methods – Maintains the purity and benefits of argan oil while preserving cultural heritage.

Advantages of Purchasing Argan Oil Wholesale

Cost Savings and Business Growth

Economies of Scale – Buying in bulk significantly reduces the cost per unit, increasing profit margins.

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Superior Quality and Multi-Purpose Use

Nutrient-Rich Composition – Cold-pressed oil retains essential vitamins and antioxidants.

Dual-Purpose Functionality – Can be used for both cosmetic and culinary applications, setting it apart from many other oils.

How Bulk Argan Oil Differs from Other Products

Wholesale vs. Retail

Cost Advantage – Wholesale purchases offer better pricing compared to retail, leading to higher profitability.

Direct Supplier Access – Buying in bulk often means working directly with manufacturers or certified distributors, ensuring authenticity and traceability.

Market Advantages

Exclusive Quality – Bulk argan oil is typically of higher quality than mass-produced alternatives.

Ethical Production – Buying wholesale supports Moroccan communities and sustainable harvesting practices, adding a social responsibility aspect to your business.

Pricing Overview: What to Expect When Buying in Bulk

Competitive Mid-Range Pricing – Reflects the premium quality and traditional production methods.

Volume Discounts – The more you buy, the lower the price per unit, making it a smart investment.

Transparent Pricing – Reputable suppliers offer clear pricing structures, including any additional costs for organic certifications or special labels.

Benefits of Wholesale Argan Oil

For Your Business and Customers

Enhanced Product Line – High-quality argan oil adds value to your offerings, increasing customer satisfaction.

Higher Profit Margins – Lower bulk pricing means increased earnings when selling premium products.

Wide Consumer Appeal – Suitable for various applications, from beauty products to nutritional supplements.

Long-Term Business Growth

Reliable Supply Chain – Establishing strong supplier relationships ensures uninterrupted stock availability.

Sustainable Success – Ethically sourced, high-quality products foster customer trust and long-term growth.

Quality and Authenticity: What Sets Bulk Argan Oil Apart?

Strict Quality Control – Reliable suppliers implement rigorous testing to maintain purity and potency.

Authentic Production Methods – Traditional extraction techniques retain the oil’s natural benefits.

Cultural Significance – Argan oil’s deep-rooted Moroccan heritage adds to its authenticity and value.

What Customers Say About Bulk Argan Oil

Jessica M., Skincare Specialist: "The quality of wholesale argan oil is outstanding. It has significantly improved our skincare products and boosted customer satisfaction."

Daniel R., Organic Retailer: "Buying in bulk has allowed us to offer premium argan oil at competitive prices. Our customers appreciate the ethical sourcing and superior quality."

Emily T., Health Enthusiast: "I love the versatility of argan oil. Whether for my beauty routine or in my recipes, the results are always impressive."

My Personal Opinion on Wholesale Argan Oil

Wholesale argan oil is an excellent choice for businesses looking to offer a high-quality, natural product. I highly value its ethical sourcing, traditional extraction methods, and multi-purpose functionality. Whether you aim to expand your product line or maximize profit margins, investing in bulk argan oil is a smart and sustainable decision.

Conclusion: Make an Informed Investment

Buying argan oil in bulk offers numerous advantages, from superior quality and cost savings to ethical sourcing and sustainability. By understanding its characteristics, pricing structures, and market potential, you can make a well-informed decision that benefits both your business and your customers.

Invest in wholesale argan oil today and experience a unique combination of quality, sustainability, and profitability that will help your business grow.

Argan oil, history, business, cosmetic, benefits

Argan oil, composition, potential, export, market

[consultatiiladomiciliu-ro]

Activitatea ingavirinului asupra virusurilor respiratorii umane în experimente in vivo

Citeste articolul pe https://consultatiiladomiciliu.ro/activitatea-ingavirinului-asupra-virusurilor-respiratorii-umane-in-experimente-in-vivo/

Activitatea ingavirinului asupra virusurilor respiratorii umane în experimente in vivo

Am mai scris despre Arbidol si Ingavirin, doua antivirale rusesti (descoperite si produse), fara licenta in alte state care emit astfel de licente, se pot cumpara din statele aflate in sfera de influienta a Rusiei. Profilul lor de siguranta pare a fi mai bun decat al antiviralelor produse de americani si europeni, desi studiile nu sunt cunoscute a fi la fel de riguroase. Din pacate nu putem face o comparatie pertinenta, asa ca luam datele asa cum sunt, tinand cont ca si in Rusia medicii s-au facut medici ca sa faca bine, si de faptul ca si in America, se castiga bani seriosi din dezvoltarea chimicalelor.

STUDIU Activitatea ingavirinului asupra virusurilor respiratorii umane în experimente in vivo

Vladimir V. Zarubaev  1,*,

Angelica V. Garshinina  1,

Nelly A. Kalinina  1,

Anna A. Shtro 1,

Svetlana V. Belyaevskaya 1,

Alexander V. Slita 1,

Vladimir E. Nebolsin 2 and

Oleg I. Kiselev 1

1Influenza Research Institute, 15/17 prof. Popova str., St. Petersburg 197376, Russia

2ValentaPharm, Ltd., 18 block 2, Gen. Dorokhova str., Moscow 119530, Russia*

Author to whom correspondence should be addressed.

Pharmaceuticals 2011, 4(12), 1518-1534; https://doi.org/10.3390/ph4121518

Submission received: 31 August 2011 / Revised: 16 November 2011 / Accepted: 18 November 2011 / Published: 25 November 2011

(This article belongs to the Special Issue Antivirals)

Rezumat

Infecțiile virale respiratorii constituie cel mai frecvent motiv de consultație medicală în lume. Ele pot fi asociate cu o gamă largă de manifestări clinice, de la infecții autolimitate ale tractului respirator superior până la afecțiuni mai devastatoare, cum ar fi pneumonia. În special, în cazurile grave, gripa A duce la pneumonie, care este fatală în special la pacienții cu boli cardiopulmonare, obezitate, copii mici și vârstnici. În studiul de față, arătăm un efect protector al compusului cu greutate moleculară mică Ingavirina (acid 6-[2-(1H-imidazol-4-il)etilamino]-5-oxohexanoic) împotriva virusului gripal A (H1N1), uman virusul parainfluenza și infecțiile cu adenovirus uman la animale. Mortalitatea, pierderea în greutate, titrul infecțios al virusului în țesuturi și morfologia țesuturilor au fost monitorizate în loturile experimentale de animale. Acțiunea protectoare a ingavirinei a fost observată ca o reducere a titrului infecțios al virusului în țesutul pulmonar, prelungirea vieții animalelor infectate, normalizarea dinamicii greutății pe parcursul bolii, scăderea mortalității animalelor tratate în comparație cu un controlul placebo și normalizarea structurii țesuturilor. În cazul infecției cu virusul gripal, activitatea protectoare a Ingavirinei a fost similară cu cea a compusului de referință Tamiflu. Pe baza rezultatelor obținute, ingavirina trebuie considerată o parte importantă a profilaxiei și terapiei antivirale.

Cuvinte cheie: gripă; virus paragripal; adenovirus; pandemic; Ingavirina; antiviral; model animal

1. Introducere Infecțiile virale respiratorii constituie cel mai frecvent motiv de consultație medicală în lume. Ele pot fi asociate cu o gamă largă de manifestări clinice, de la infecții autolimitate ale tractului respirator superior până la afecțiuni mai devastatoare, cum ar fi pneumonia. Prin urmare, prevenirea și controlul acestor infecții rămân obiective clinice majore. În prezent, există aproximativ 200 de viruși respiratori cunoscuți care pot fi grupați într-o familie de virusuri ADN (Adenoviridae) și patru familii de virusuri ARN (Orthomyxoviridae, Paramyxoviridae, Picornaviridae și Coronaviridae).

Virusul gripal A (IAV) este un agent extrem de infecțios care provoacă boli pulmonare acute. Focare de infecții cu virus gripal foarte patogen și apariția în 2009 a unei noi IAV pandemice au declanșat un reînnoit interes pentru cercetarea gripei. În mai 2010, peste 214 de țări și teritorii sau comunități de peste mări au raportat cazuri confirmate de laborator de IAV H1N1 2009, inclusiv peste 18.097 de decese [1]. Medicamentele antivirale ocupă o nișă importantă în managementul acestei boli [2,3]. Acestea vizează componente specifice virusului și sunt un tratament eficient atunci când sunt administrate în stadiul incipient al infecției sau imediat după expunerea la virus [3].

Două clase principale de medicamente antigripală sunt acceptate în prezent pentru chimioterapia IAV. Derivații adamantanului (amantadină și rimantadină) vizează canalul ionic M2 al IAV și nu sunt eficienți împotriva virusului gripal B [4]. Mai mult, apariția rapidă a rezistenței la medicamente în rândul virusurilor gripale de la mijlocul anilor 1990 a compromis mult eficacitatea acestor compuși [5]. Toți virusurile pandemice H1N1 testate până acum par, de asemenea, rezistente la medicamente [6].

Inhibitorii neuraminidazei (NAIs, oseltamivir, zanamivir și peramivir) au un spectru mai larg de activitate care include atât virusurile gripale A cât și virusurile B [7]. Cu toate acestea, din 2007 s-au observat apariția și transmiterea rapidă a virusurilor rezistente la medicamente [5,8,9]. Mai multe tulpini rezistente la NAI au fost, de asemenea, izolate de virusul pandemic H1N1 [10]. Există, prin urmare, o nevoie atât pentru identificarea de antivirale noi și eficiente, cât și pentru monitorizarea susceptibilității virusurilor circulante la compușii antivirali utilizați în clinici.

Paramixovirusurile includ virusuri importante asociate cu infecțiile tractului respirator superior și inferior la om. Printre acestea, trebuie remarcate virusul respirator respirator uman sincicial (RSV) și virusurile paragripale umane (HPIV).

RSV este o cauză majoră a bolii tractului respirator inferior la copiii prematuri (≤ 35 de luni de gestație), sugarii cu vârsta sub 6 luni și subiecții vârstnici instituționalizați. Rezultatul infecției cu RSV implică de obicei infecții ușoare ale tractului respirator superior; totuși, afecțiuni mai severe, cum ar fi pneumonia și bronșiolita, apar la 25-40% dintre copii. Aproximativ 1% dintre sugarii infectați cu RSV necesită spitalizare [11,12].

Au fost descrise patru serotipuri distincte de virusuri paragripale umane [13]. Acești virusuri pot provoca boli ale tractului respirator superior la indivizi de toate grupele de vârstă, deși copiii mici între 6 luni și 3 ani prezintă boli mai severe [13].

Adenovirusurile (AdV) sunt viruși ADN-genom fără anvelopă. În ciuda tropismului multiorganic, unele tipuri de AdV au un tropism preferențial pentru tractul respirator și pot provoca o gamă largă de simptome respiratorii, inclusiv coriza, faringita, amigdalita, bronșita și pneumonia. În general, infecțiile cu AdV sunt ușoare sau autolimitate și se rezolvă în două săptămâni fără complicații pe termen lung. Cu toate acestea, acești virusuri constituie o cauză importantă de mortalitate și morbiditate la pacienții imunocompromiși, inclusiv nou-născuții și primitorii de transplant de măduvă osoasă [11].

Mai mulți compuși pot fi utilizați pentru tratamentul infecției cu RSV, AdV și HPIV. Ribavirina inhibă replicarea virală prin mai multe mecanisme, inclusiv inhibarea polimerazei virale, inhibarea formării capacului 5′ a ARNm și inhibarea IMP dehidrogenazei conducând la o scădere a concentrațiilor intracelulare de GTP [14]. Nu există agenți terapeutici aprobați împotriva infecțiilor cu AdV. Cu toate acestea, unele antivirale cu spectru larg, cum ar fi ribavirina și analogul nucleozidic cidofoir, au fost utilizate în tratamentul infecțiilor severe cu Ad la gazdele imunodeprimate [11]. În plus, în acest scop au fost utilizați inhibitori de fuziune, oligonucleoide antisens și steroizi, niciunul dintre ei nu a fost aprobat pentru aplicare clinică.

Anterior, compusul cu greutate moleculară mică Ingavirina [6-[2-(1H-imidazol-4-il)etilamino]-5-oxohexanoic acid, cunoscut anterior și sub numele de Ingamine] s-a dovedit a avea activitate antigripală împotriva virusurilor gripale A(H3N2), A(H5N1) și B într-un model animal [15,16] și împotriva tulpinilor pandemice ale virusului gripal A/California/04/2009 și A/California/07/2009 [17–19]. În experimentele cu IAV H1N1, ingavirina a scăzut efectul citopatogen indus de virus în cultura celulară cu 50 până la 79% în comparație cu celulele martor. Șoarecii infectați cu IAV H3N2 sau H1N1 (2009) și tratați cu Ingavirină au demonstrat o mortalitate mai scăzută (aproximativ 40%) și o durată medie de viață crescută (aproximativ 4 zile) în comparație cu animalele tratate cu placebo. Luate împreună, aceste date sugerează că Ingavirina este un instrument prospectiv pentru tratamentul infecțiilor cu IAV, în special cele cauzate de virusurile pandemice. Mai mult, ingavirina a demonstrat activitate în experimente in vitro și in vivo împotriva adenovirusului uman și a virusului paragripal [20,21]. Cu toate acestea, mecanismul exact al eficacității sale clinice este departe de a fi înțeles complet.

Aici rezumăm rezultatele studiilor privind activitatea protectoare a Ingavirinei folosind modele de pneumonie gripală letală cauzată de virusul gripal pandemic A(H1N1)2009, pneumonie ușoară cauzată de HPIV și infecție diseminată indusă de adenovirus și prezentăm noi date despre aceasta. activitate antivirală privind virusurile respiratorii umane. Pe baza acestor rezultate se pot face concluzii cu privire la gama sa de activitate și aplicarea ulterioară împotriva bolilor specifice.

2. Materiale și Metode 2.1. Compuși Ingavirina (acid 6-[2-(1H-imidazol-4-il)etilamino]-5-oxohexanoic, Figura 1) a fost furnizată ca substanță pură de către producător (Valenta Pharmaceuticals, Moscova, Rusia). Tamiflu (fosfat de oseltamivir, LaRoche, Elveția), 6-azacitidina (Institutul de Biologie Moleculară și Genetică, Kiev, Ucraina) și ribavirina (ICN Biochemicals, SUA) au fost utilizate în experimente ca medicamente de referință.

Structura INGAVIRIN, un compus asemanator cu Arbidol

2.2. Viruși Virusul gripal A/California/07/09 (H1N1) a fost obținut din colecția de viruși de la Institutul de Cercetare a Gripei. Înainte de experimente, virusul a fost adaptat la șoareci prin trei pasaje în serie în țesutul pulmonar al șoarecilor, urmate de o trecere ulterioară prin cavitatea alantoică a embrionilor de pui de 10-12 zile și o trecere finală prin șoareci [22]. Omogenatul pulmonar în nouă volume de soluție salină sterilă tamponată cu fosfat a fost utilizat ca material infectant în experimente ulterioare.

Virusul paragripal uman (hPIV) de tip 3 (tulpina HA1) și adenovirusul uman (AdV) de tip 5 au fost obținute din colecția de viruși de la Institutul de Cercetare a Gripei și propagate în MA-104 (ATCC CRL-2378) sau HEp-2 (ATCC). celulele CCL-23), în mod corespunzător, la 36 °C în 5% CO2.

2.3. Animale În experimentele cu virusul gripal au fost utilizați femele de șoareci Balb/c, de 16–20 de grame, de la ferma de creștere a animalelor de laborator Rappolovo. Hamsterii sirieni crescuți în Institutul de Cercetare a Gripei au fost utilizați pentru experimente cu hPIV și AdV. Experimentele pe animale au fost planificate în conformitate cu principiile îngrijirii animalelor de laborator (Guide for the Care and Use of Laboratory Animals, National Academy Press: Washington, DC, USA, 1996) și aprobate de Comitetul de etică instituțională.

2.4. Titrarea virusului Înainte de studiile activității protectoare a ingavirinei la animale, virusul gripal adaptat la șoarece a fost titrat pentru efectul său letal. În acest scop, șoarecii (10 în fiecare grup experimental) au fost inoculați intranazal sub anestezie cu 50 μL de diluții zecimale în serie (10-1 până la 10-5) de omogenat pulmonar al șoarecilor infectați cu virus. Diluția care a provocat moartea a 50% dintre animale în 14 zile după infecție (DL50) a fost calculată așa cum a fost descris anterior [23] și utilizată pentru experimentele ulterioare.

2.5. Activitatea protectoare a INGAVIRIN Pentru evaluarea activității antigripală a Ingavirinei in vivo, șoarecii au fost infectați cu cinci LD50 (20 de șoareci) sau un LD50 (30 de șoareci) din virusul titrat anterior (vezi secțiunea „Titrarea virusului”). Ingavirina a fost diluată în ser fiziologic la doze de 15, 20 sau 30 mg/kg greutate corporală/zi și aplicată oral prin gavaj o dată pe zi în ziua unu, două, trei, patru și cinci după infecție (p.i.). Pentru a studia efectul programului de tratament asupra activității de protecție, grupuri separate de animale au fost tratate de două ori (zilele 1 și 2 p.i.) cu 30 mg/kg ingavirină urmate de trei doze de 15 mg/kg (zilele 3, 4 și 5 p.i.) . Cantitatea totală de ingavirină primită de animalele din acest grup a fost egală cu cea din grupul de 20 mg/kg. Medicamentul de referință Tamiflu (doza finală 20 mg/kg greutate corporală) a fost dizolvat în soluție salină și aplicat la 20 de șoareci (cinci DL50) sau 30 de șoareci (o DL50) pe cale orală într-un volum de 200 μL. Animalele martor au fost tratate cu ser fiziologic steril.

Animalele din toate loturile experimentale au fost cântărite zilnic. S-a calculat mortalitatea la fiecare grup de animale. Fiecare grup a fost verificat zilnic pentru animale moarte timp de două săptămâni după inoculare. Pe baza datelor primite, s-au calculat procentul de mortalitate, indicele de protecție (raportul mortalității în grupul de control față de mortalitatea din grupul experimental) și ziua medie a decesului (MDD).

În ziua a treia p.i., zece șoareci din fiecare grup infectat cu un DL50 al virusului au fost sacrificați, pieptul lor deschis și plămânii izolați. Cinci plămâni au fost utilizați pentru titrarea virusului și alți cinci pentru examinarea histologică (vezi secțiunea „Examinare histologică”).

Pentru a determina titrul infecțios al virusului în țesutul pulmonar, plămânii au fost omogenizați în zece volume de soluție salină sterilă tamponată cu fosfat. S-au preparat diluții în serie (10-1-10-7) din fiecare omogenat. Celulele MDCK crescute în plăci cu 96 de godeuri au fost inoculate cu 0,2 mL din fiecare diluție și incubate la 36 °C timp de 48 de ore în 5% CO2. După incubare, supernatantul a fost recoltat și testat pentru prezența virusului gripal prin amestecarea fluidului în godeuri cu fund rotund cu volume egale de suspensie 1% de eritrocite de pui în ser fiziologic. Titrul de virus în plămâni a fost considerat diluția finală atunci când a provocat o reacție de hemaglutinare pozitivă în godeu, iar titrul de virus este exprimat în log10EID50/20 mg țesut. Activitatea compușilor a fost evaluată prin capacitatea lor de a scădea titrul infecțios al virusului în țesutul pulmonar.

Pentru studiul activității anti-hPIV a ingavirinei, hamsterii sirieni în vârstă de patru până la cinci săptămâni au fost infectați cu 0,05 mL (104 TCID50) de virus parainfluenza uman (hPIV) intranazal, așa cum este descris în [24]. Ingavirina a fost utilizată așa cum este descris mai sus. În ziua 3 și 7 p.i. animalele au fost sacrificate, iar plămânii lor au fost utilizați pentru titrarea virusului în celulele MA-104 și, respectiv, analiza histologică (vezi mai jos). Titrul virusului a fost determinat prin ELISA utilizând anticorpi monoclonali anti-hPIV (PPDP Ltd., St. Petersburg, Rusia).

Activitatea anti-AdV a compusului a fost testată așa cum s-a descris anterior [25].

2.6. Examenul histologic Plămânii animalelor au fost fixați în formaldehidă tamponată cu PBS 4%, deshidratați în etanol gradat și încorporați în parafină. Secțiuni de patru micrometri au fost tăiate și colorate cu hemotoxilină-eozină.

În cazul infecției gripale, celulele epiteliului bronșic au fost împărțite în patru categorii distincte morfologic: (i) celule intacte fără semne de replicare a virusului; (ii) celule cu stadii inițiale de formare a incluziunilor specifice virusului; (iii) celule cu incluziuni avansate de virus; și (iv) celule moarte care arătau ca goluri între alte celule cu denudare a membranei bazale. Au fost calculate ratele fiecărei categorii de celule dintre celulele stratului epitelial bronșic. Valorile morfometrice au fost evaluate de doi observatori independenți.

3. Rezultate 3.1. Infecția gripală Inocularea animalelor cu un virus gripal adaptat a dus la dezvoltarea pneumoniei gripale. Semnele clinice ale bolii au fost tipice pentru infecția gripală severă și au inclus ataxie, tremor, respirație scurtă, precum și scăderea consumului de apă și alimente care duce la pierderea în greutate. În ziua 15 p.i. S-a observat moartea a 55–90% dintre animalele infectate, în funcție de doza infectantă a virusului.

Activitatea protectoare a ingavirinei a fost evaluată atunci când este aplicată o dată pe zi timp de cinci zile după inocularea virusului. Nu s-a observat nicio mortalitate nespecifică în grupurile de control de animale neinfectate tratate cu soluție salină și șoareci neinfectați tratați cu Ingavirin. Aplicarea ingavirinei a dus la o scădere a mortalității (la 18–67%), precum și la o creștere a zilei medii de deces (1,2–4,1 zile) comparativ cu animalele martor (în funcție de doza de virus și compus). Șoarecii tratați cu compusul de referință Tamiflu au demonstrat, de asemenea, o mortalitate semnificativ mai scăzută (indicele de protecție 80%) și prelungirea duratei medii de viață (până la 5,4 zile) în comparație cu valorile martor (Tabelul 1). În plus, tratamentul animalelor cu Ingavirina, în mod similar cu compusul de referință Tamiflu, a dus la normalizarea dinamicii greutății animalelor (Figura 2), conducând la profiluri de greutate similare în comparație cu animalele neinfectate.

Figura 2. Dinamica greutății corporale a șoarecilor în cursul pneumoniei cauzate de virusul gripal A/California/7/09 (H1N1)v. Tabelul 1. Activitatea protectoare a Ingavirinei împotriva gripei A (H1N1) 2009. Valorile p < 0,05 sunt indicate cu caractere aldine.

După cum se arată prin titrarea virusului din plămânii șoarecilor, în ziua a treia p.i. virusul s-a replicat în țesutul pulmonar până la 105,1 EID50/20 mg țesut. Aplicarea compusului de referință Tamiflu a scăzut titrul viral de aproximativ 320 de ori (102,6 EID50/20 mg țesut). Tratamentul animalelor cu Ingavirina a dus, de asemenea, la o scădere a titrurilor virusului (aproximativ 103,5 EID50/20 mg), care este statistic identică cu activitatea oseltamivirului (Tabelul 1).

Pentru a evalua efectul ingavirinei asupra structurii țesutului pulmonar, analiza morfologică a fost efectuată în ziua a treia p.i. Plămânii șoarecilor infectați cu virus au fost consolidați și edematoși. Toți șoarecii infectați au prezentat leziuni alveolare difuze exsudative cu edem interstițial, exsudate fibrinoase în alveolele lor, infiltrație inflamatorie, necroză epitelială bronșială și descuamare. Celulele epiteliului bronșic și bronșiolar au conținut incluziuni virale sau au fost absente cu denudarea membranei bazale [Figura 3(a)].

Figura 3. Patologii ale șoarecilor inoculați intranazal cu virusul gripal adaptat la șoarece A/California/7/09 (H1N1)v în ziua 3 p.i. (a) Plămânii unui șoarece tratat cu placebo. Suprafață mare de pneumonie cu exsudate intense în lumenul bronșic, alveolită severă neutrofilă până la histiocitară; (b) Peribronșită limfocitară ușoară cu alveolită ușoară la un șoarece tratat cu 30 mg/kg greutate corporală de ingavirină. Celulele epiteliului bronșic sunt intacte, exsudate ușoare în lumenul bronșic; (c) Peribronșită limfocitară ușoară cu alveolită la un șoarece tratat cu 20 mg/kg oseltamivir; (d) Plămânii șoarecilor intacți. Fără semne de inflamație sau distrugere celulară. Hematoxilin-eozină, ×200. Aplicarea Ingavirinei, similar cu compusul de referință Tamiflu, a dus la normalizarea structurii țesutului pulmonar, în special, la limitarea edemului și a leziunilor alveolare, scăderea cantității de reziduuri în lumenul bronșic și protecția epiteliului bronșic de moarte [Figura 3( b), Tabelul 1].

Pentru a studia mecanismul activității de protecție a ingavirinei, ne-am uitat mai atent la celulele epiteliului bronșic care sunt considerate ținte primare pentru virusul gripal. Analiza morfometrică a celulelor a arătat că aproape 100% din celulele epiteliale ale șoarecilor intacte au fost reprezentate de celule intacte.

Inocularea cu virusul gripal a condus la creșterea ratei celulelor din alte trei grupuri (adică celule cu incluziuni inițiale, incluziuni avansate și celule moarte), sugerând o acțiune citotoxică puternică a virusului. Aplicarea atât a Ingavirinei, cât și a compusului de referință oseltamivir a scăzut puternic numărul de celule moarte și a crescut rata celulelor intacte ale epiteliului bronșic. Din aceste rezultate sugerăm că acest compus este capabil să protejeze celulele împotriva daunelor induse de virus (Figura 4).

Figura 4. Activitatea citoprotectoare a ingavirinei în celulele epiteliului bronșic după infectarea cu virusul gripal adaptat la șoarece A/California/7/09 (H1N1)v (ziua 3 p.i.). 3.2. Infecția cu virusul parainfluenza Infectarea hamsterilor sirieni cu virusul parainfluenza umană (hPIV) are ca rezultat bronșită ușoară, bronșiolită și pneumonie neletale. Virusul poate fi recuperat din plămâni în ziua 3 p.i., iar afectarea specifică a țesuturilor poate fi observată în ziua 7.

După cum se arată prin titrarea virusului, aplicarea atât a ingavirinei, cât și a compusului de referință ribavirină a condus la reducerea titrului infecțios al hPIV în țesutul pulmonar. Ribavirina a demonstrat cea mai mare activitate în scăderea titrului, deși ambele doze de Ingavirina au condus, de asemenea, la o reducere semnificativă statistic (Tabelul 2).

Tabelul 2. Activitatea infecțioasă a hPIV în țesutul pulmonar al hamsterilor sirieni după aplicarea ingavirinei.

Hamsterii infectați cu hPIV nu au prezentat dovezi observabile de boală înainte de sacrificiu, dar din punct de vedere histologic a existat o producție constantă de pneumonie. Leziunile pulmonare constau din exsudate endobronșice împrăștiate compuse din celule mononucleare și polimorfonucleare, infiltrate de celule rotunde peribronșice și perivasculare și zone largi de pneumonie interstițială. Epiteliul bronșic avea un aspect specific care conținea grupuri de celule gigantice înalte care ieșeau în lumenul bronșic [Figurile 5 (a, b)]. Animalele tratate cu ingavirină și ribavirină au demonstrat o arhitectură a țesutului pulmonar aproape normal, cu puține celule infiltrante [Figurile 5 (c, d)].

Figura 5. Structura țesutului pulmonar al hamsterilor sirieni în ziua 7 după inocularea cu hPIV-3 cu (c,d) sau fără (a,b) tratament cu Ingavirină. a, c—Alveole, b, d—Epiteliu bronșic. Hematoxilină-eozină, ×100 (a), ×400 (b,c,d). 3.3. Infecția cu adenovirus uman Întrucât adenovirusurile umane nu provoacă infecții respiratorii în aer la animale, am studiat activitatea antivirală a ingavirinei folosind modelul dezvoltat anterior de infecție adenovirală diseminată a hamsterilor sirieni nou-născuți cauzată de adenovirusul uman de tip 5 [25]. Similar cu infecția cu hPIV, activitatea de protecție a fost evaluată prin titrarea virusului în organele țintă și analiza histologică a arhitecturii țesuturilor.

Infectarea subcutanată a hamsterilor sirieni nou-născuți a dus la replicarea virusului în plămânii și ficatul animalelor. Rezultatele titrarii virusului în celulele HEp-2 în ziua a treia p.i. sunt rezumate în tabelul 3.

Tabelul 3. Activitatea infecțioasă a AdV în ficat și plămâni la hamsterii sirieni după aplicarea ingavirinei.

După cum se poate observa, tratamentul infecției cu AdV cu compusul de referință 6-AC a dus la restricția replicării virusului atât în ​​ficat, cât și în plămânii animalelor, ceea ce este în acord cu rezultatele noastre anterioare [25]. Aplicarea ingavirinei a condus la o reducere moderată (aproximativ o zecimală), dar semnificativă statistic, a titrului virusului atât în ​​ficat, cât și în plămânii animalelor.

Investigarea histologică a ficatului animalelor infectate a evidențiat focare de necroză. Din punct de vedere morfologic, au fost zonele de distrugere a parenchimului cauzate de leziunea specifică a hepatocitelor și distrugerea nespecifică a țesutului din cauza unei reacții inflamatorii locale. Leziunile specifice celulelor hepatice s-au manifestat în creșterea nucleelor ​​celulare, deformarea acestora și apariția corpurilor de incluziune nucleară eozinofili și bazofili specifici virusului. Alterările reactive ale țesutului s-au datorat distrugerii inflamatorii a hepatocitelor și infiltrației tisulare cu leucocite. Animalele infectate tratate cu ingavirina au avut focare mai mici de inflamație și hepatocite cu aspect intacte, spre deosebire de hepatocitele foarte vacuolizate la animalele de control (Figura 6).

Figura 6. Patologia hepatitei induse de AdV în ficatul hamsterilor sirieni nou-născuți în ziua 3 p.i. Focalizare mare de inflamație cu numeroase celule infectate cu AdV (vârfuri de săgeată), vacuolizarea hepatocitelor (a, b) la animalele de control, focar mic de inflamație și parenchim intact (c) la animalele tratate cu Ingavirina. Hematoxilin-eozină, ×400. Pentru a cuantifica efectul protector al ingavirinei, am măsurat dimensiunea focarelor de necroză în ficat și am numărat numărul de celule infectate cu AdV în fiecare focar (Tabelul 4).

Tabelul 4. Efectul ingavirinei asupra evoluției hepatitei induse de AdV la hamsterii sirieni nou-născuți. Masă După cum arată analiza morfometrică, aplicarea Ingavirinei a scăzut dimensiunea medie a focarelor de inflamație indusă de virus și a redus puternic numărul de celule infectate. Interesant, efectul unei doze mai mari de medicament (45 mg/kg/zi) a fost mai mic decât cel al dozei mai mici (30 mg/kg/zi), sugerând un mod specific de activitate a acestui compus.

4. Discuție În studiul de față, am arătat un efect protector al compusului cu greutate moleculară mică Ingavirina împotriva infecției letale cu virusul gripal cauzat de virusul gripal pandemic A (H1N1) la șoareci și a patologiilor nefatale ale hamsterilor sirieni cauzate de virusul paragripal uman și uman. adenovirus. Au fost investigate efectele dozei asupra activității de protecție a compusului și a replicării virusului în țesut. Acțiunea protectoare a ingavirinei a fost demonstrată ca o reducere a titrului infecțios al virusului în țesutul pulmonar, prelungirea vieții animalelor infectate, normalizarea dinamicii greutății în cursul bolii, scăderea mortalității animalelor tratate în comparație cu un control placebo și normalizarea structurii țesutului pulmonar și hepatic. În cazul infecției gripale, activitatea protectoare a Ingavirinei a apărut similară cu cea a compusului de referință Tamiflu.

În experimentele noastre, Ingavirina a demonstrat activitatea de protecție împotriva pneumoniei gripale letale la șoareci. La unele doze, efectul protector a fost egal cu activitatea oseltamivirului, care este un medicament acceptat la nivel internațional, dovedit a fi eficient împotriva acestui IAV. În general, rezultatele noastre sunt în acord cu datele obținute anterior [15-19] în care s-a demonstrat că Ingavirina are un efect protector împotriva virusurilor gripale A și B.

Krug și Aramini [26] au sugerat că două domenii posibile ale nucleoproteinei virusului gripal (NP), unul situat într-o buclă de coadă și altul într-un canal de legare a ARN găsit între domeniile capului și corpului la suprafața exterioară a trimerului NP, reprezintă potențialele ținte antivirale. Domeniul localizat în bucla de coadă este crucial pentru oligomerizarea NP care este, la rândul său, necesară pentru transcripția și replicarea eficientă a genomului viral. Prin urmare, inactivarea acestui domeniu ar putea fi eficientă pentru suprimarea replicării virusului. Într-adevăr, unele experimente sugerează că Ingavirina vizează nucleoproteina gripei (NP). Într-un studiu recent [27] s-a demonstrat că ingavirina interacționează cu virusul gripal NP, prevenind astfel oligomerizarea NP necesară pentru replicarea virală. În al treilea studiu, mai mulți analogi ai micalamidei A au fost identificați ca inhibitori direcționați de NP ai replicării virusului gripal [28]. S-a demonstrat că acești compuși se leagă de coada N-terminală de 13 aminoacizi, care mediază transportul nuclear al NP și legarea acestuia de ARN viral. Mai mult, Kao et al. [29] au raportat identificarea unui compus cu molecule mici, nucleozina, care declanșează agregarea NP și inhibă acumularea sa nucleară. Nucleozina a împiedicat replicarea virusului gripal A in vitro cu o concentrație nanomolară și a protejat șoarecii provocați cu doze letale de gripă aviară A H5N1. Aceste date sugerează că legarea compusului la această țintă poate inhiba replicarea virală prin inhibarea funcțiilor NP. Nici analogii micalamidei A și nici nucleozina nu demonstrează nicio asemănare structurală cu Ingavirina, ceea ce ne face să presupunem că alte domenii ale NP virale pot fi implicate în interacțiunea cu Ingavirina.

Dintr-o altă parte, s-a demonstrat că aplicarea Ingavirinei are ca rezultat modificarea morfologiei virionilor detectați în lavajul bronhoalveolar al șoarecilor infectați [30]. Animalele de control au produs în cea mai mare parte virioni sferici, în timp ce la animalele tratate cu ingavirină s-au format probabil particule filamentoase cu infectivitate redusă. Aceste rezultate sugerează că ingavirina ar putea interfera cu procesul de asamblare și/sau înmugurire a virusului, conducând la reducerea încărcăturii virale.

În studiul nostru, activitatea oseltamivirului a apărut mai mică decât în ​​experimentele similare ale lui Smee și colab. [31]. Acest lucru ar putea fi legat de o doză mai mare de virus, virus diferit utilizat în experimentele noastre și program diferit de aplicare a medicamentului (o dată pe zi în loc de două ori pe zi în [31]). În același timp, efectele antivirale directe ale ingavirinei detectat printr-o scădere a titrului infecțios al virusului în țesutul pulmonar a apărut de zece ori mai puțin decât cel al Tamiflu, în ciuda nivelului similar de protecție împotriva letalității (Tabelul 1). Această contradicție ar putea indica faptul că alte mecanisme, în plus față de o activitate antivirală directă, ar putea contribui la protecția rezultată a animalelor împotriva letalității cauzate de IAV.

Infecția cu virusul gripal variază în severitate de la o infecție asimptomatică la o boală gravă cu caracteristici sistemice. Gripa severă se manifestă prin reacții specifice virusului cu dezvoltarea ulterioară a proceselor reactive. Aceste procese sunt induse de virusul care se replica în celulele țintă și realizate prin mecanisme gazdă, inclusiv reacții imune, stres oxidativ și alte procese de radicali liberi, activitate proteolitică îmbunătățită, creșterea bruscă a nivelului de citokine proinflamatorii și multe altele [32].

În clinici, unul dintre principalele motive pentru pneumonia gripală severă și complicată, inclusiv cazurile fatale, este tratamentul tardiv și/sau inadecvat [33,34]. În aceste cazuri, evoluția bolii este determinată de mecanisme care sunt inițial induse de virus, dar în cele din urmă realizate de gazdă, inclusiv, în special, inflamația severă („furtuna de citokine”) [35-37]. Experimentele folosind șoareci knockout infectați cu virusul gripal cu gene inactivate în căile inflamatorii, cum ar fi interleukina 1α/β, receptorii de chemokine macrofagice CCR5 și CCR2, ciclooxigenaza 1 și 2 [38–40] au demonstrat clar că, în plus față de nivelul de virus ‘ replicare în plămâni, intensitatea reacțiilor gazdei contribuie în mod semnificativ la cursul și rezultatul bolii. Prin urmare, în cazurile severe de gripă, atât medicamentele antivirale directe, cât și cele patogenetice ar trebui incluse în terapia complexă, în special acei compuși care limitează furtuna de citokine, edemele pulmonare, inflamația și afectarea țesuturilor [41]. De exemplu, recent a fost demonstrată activitatea de protecție ridicată a 7-hidroxicumarinei (7-HC) [42]. S-a demonstrat că 7-HC posedă proprietăți antivirale datorită capacității sale de a scădea nivelul de citokine proinflamatorii la animalele infectate, atenuând astfel infecția gripală severă. În același timp, 7-HC nu a redus nivelul de replicare a virusului în testele de reducere a plăcii, ceea ce sugerează că activitatea sa de protecție, inclusiv scăderea replicării virusului în plămânii de șoarece, este de natură complexă și poate fi mediată de semnalizarea celulară și căile reactive. S-ar putea sugera că, pe lângă capacitatea de a scădea în mod direct nivelul de replicare a virusului în plămâni (Tabelul 1), ingavirina ar putea avea proprietăți similare pe baza rezultatelor examinărilor de morfologie pulmonară la șoarece, care arată că tratamentul cu Ingavirina a redus semnificativ gradul de leziuni tisulare, inflamație și edem (Figura 3, Tabelul 1). Studii suplimentare asupra efectelor ingavirinei asupra diferitelor căi patogenetice ar fi utile pentru înțelegerea mecanismului său de activitate. Ingavirina trebuie considerată o parte importantă a profilaxiei și terapiei antigripală, în special în cazurile severe ale bolii.

În experimentele noastre, Ingavirina a demonstrat, de asemenea, activitate anti-virală împotriva altor două viruși utilizați, hPIV și AdV [19,20]. Deoarece acești viruși sunt filogenetic distincti unul de celălalt și nu există componente virale comune tuturor celor trei viruși utilizați în studiu, se poate concluziona că acest medicament vizează componentele și căile responsabile pentru dezvoltarea patologiei celulare și tisulare în timpul infecției virale. Într-adevăr, în toate cele trei cazuri a demonstrat un grad ridicat de citoprotecție și capacitatea de a normaliza arhitectura țesutului. Aplicarea sa a prevenit moartea celulelor epiteliului bronșic infectate cu virusul gripal, citopatologia indusă de hPIV în plămâni și vacuolizarea indusă de virus a hepatocitelor în timpul infecției cu AdV la hamsteri. Mai mult, în experimentele noastre anterioare [21] am demonstrat capacitatea ingavirinei de a preveni deteriorarea celulară indusă de AdV în cultură. În ciuda formării de incluziuni specifice virusului intranuclear tipic, celulele tratate cu Ingavirina nu au dezvoltat vacuole în citoplasmă și alte semne morfologice de citopatogenitate. Prin urmare, în plus față de alte mecanisme(e) de acțiune antiviră, Ingavirina posedă o activitate citoprotectoare care previne distrugerea celulelor infectate și menține funcția organului țintă minimizând astfel deteriorarea tisulară indusă de virus și simptomele de toxicitate în cursul bolii.

Trebuie remarcat faptul că nu a fost observată nicio toxicitate a ingavirinei la doze de până la doze de 3000 mg/kg. De asemenea, nu au fost observate semne de embriotoxicitate în studiile anterioare [43]. Pentru comparație, DL50 pentru Tamiflu a fost estimată la 100–250 mg/kg, în funcție de calea și programul de inoculare și speciile de animale [44]. Mai mult, în studiile clinice, ingavirina nu a demonstrat efecte secundare atunci când a fost aplicată la pacienții infectați cu gripă [45]. Prin urmare, ingavirina poate fi considerată un compus netoxic cu risc scăzut de supradozaj.

5. Concluzii Luate împreună, datele noastre sugerează că Ingavirina este un antiviral netoxic cu spectru larg, cu mecanism complex de acțiune. Studiul suplimentar al mecanismului fin al activității sale protectoare ar permite optimizarea structurii medicamentului și probabil dezvoltarea unei noi clase de compuși pentru profilaxia și tratamentul infecțiilor virale.

Mulțumiri Mulțumim Tatianei D. Smirnova de la Institutul de Cercetare a Gripei pentru furnizarea de linii celulare. De asemenea, mulțumim Lidiya Nosach de la Institutul de Microbiologie și Virologie, Kiev, Ucraina, și Innei Alexeeva de la Institutul de Biologie Moleculară și Genetică, Kiev, Ucraina, pentru că au furnizat cu amabilitate 6-azacitidină pentru experimente.

Conflict de interese Nu a fost detectat niciun conflict de interese în legătură cu această publicație.

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[the-whatcherof-89]

Tangotek aka Mr Decked out the tangler.

CR 20 N Humanoid Native Outsider

XP 307,200 (if used as npc for encounter)Ifrit (Sun Soul) Sorcerer 20 (Cross-blooded: Harrow-Mechanical)

Neutral Medium humanoid Init +4; Senses Perception +23

AC 32, touch26, flat-footed28 (+4Dex, +6Armor, +6Natural, +5Deflect) HP 175 (20d6+100)

Fort +15, Ref +15, Will +26

Speed 30 ft. Melee Flaming scimitar+13 +1d6 fire Ranged Light Crossbow+16 1d8+2

Racial Native outsider, Darkvision 60ft, Fire in the blood, Fire resistance 5, Sun metal 1/day.

Traits Fiery gaze, overprotective.

Class features Eschew materials, Bloodline powers(Launch gears, See it coming, Invoke the harrow, Harrowed home, Clockwork masterpiece), Bloodline arcana, Bonus feats: Toughness, Iron guts, Harrower, Skill focus Engineering, Craft wondrous times, Extend spells), Bonus spells: Analyze device, Shocking grasp, Harrowing, Shadow conjuration, Rapid repair, Repulsion, Greater Harrowing, Moment of prescience, Weird).

Spellcasting CL20 DC21 spells per day 9/9/9/8/8/8/8/7/7 

Spells known:

9-Wish, Time stop, Meteor swarm.

8-Discern location, Polymorph any object, Sun burst.

7-Limited wish, Symbol of stunning, Spell turning.

6-Dispel magic (Greater), Geas/quest, Anti-magic field.

5-Secret chest, Telekinesis, Cloudkill, Teleport, Fabricate.

4-Wall of fire, Superior invisibility, Stoneskin, Dimension door.

3-Fly, Dispel magic, Haste, Fireball, Phantom mount .

2-Glitterdust, See invisibility, Fog cloud, Resist energy, Molten orb.

1-Shield, Mage armor, Magic missile, Burning hands, Grease.

0-Read magic, Detect magic, Mage hand, Mending, Acid splash, Resistance, Flare, Prestidigitation.

Str 14Dex 18 Con 18 Int 14 Wis 10 Cha 32

Base Atk +10/5; CMB +12; CMD +16

Feats Quicken spells, Strong personality, Eldritch heritage(Mechanical emphaty), Improved Eldritch heritage(The rebuild), Greater eldritch heritage(Warmachine).

Skills Appraise+7, Bluff+16, Craft(Metal and stone)+15, Disable device+9, Fly+9, Intimidate+16, Knowledge (Arcana)+15, (History)+7, (Engineering)+15, Profession(Architect)+13, Perception+13, Spellcraft+15, Use magic device +24. 

Languages Common, Ignan, Draconic.

Combat gear Ampoule of false blood, Staff of metals[allows the use of the following spells: Major creation(1 charge only metal objects), Wall of iron(1Charge), Wand of cure critical wounds, Rod of absorption, Rod of empower metamagic, Ghost touch light crossbow+1, 50+1 seeking Bolts, Flaming scimitar+1, Shoes of the firewalker, Bracers of armor+6, Trapspringer’s gloves, Crimson robes  of Tek(Glamered robe of the Arcane heritage-Harrowed combined with Sorcerer’s robes), Headband of alluring charisma+6, Eyes of the eagle, Ring of protection+5, Belt of physical might+4 (Con Dex), Ioun stones (Scarlet blue and blue sphere, Incandescent blue sphere), Ring of spell knowledge IV(Sculpt stone), Pearl of power III, Tome of leadership and influence+4 (used), Bag of holding (type I), Potions: (2)Cure critical wounds, (2)Gaseous form, (2)Haste, (2)Displacement, Fly(2), Alchemist kit, Sorcerer’s kit, Spell components worth 2000gp, Harrow deck, 442gp. 

Background Cordial, polite, vibrant and cheerful the red eyed Tangotek is one of the many inhabitants of the land of hermits where many buildings are made, defying the very laws of physics reaching an unseen level of wonder. Tango is famous especially for the creations of various games made to entertain the various hermits(sometimes in hilarious ways) and various iron farms that support the local economy. Appreciated and used by all, once you enter the circle of friends of Tango it is certain that he will protect you fiercely like a male alpha lion defends his pride. It was one day like the others and Tango was supervising his creation called Decked out to see if all the mechanical parts were in working order. He was about to finish when he noticed an area that wasn’t there before. “When- when did i make this? Did i make this?” He peeked inside to find a strange hallway with many dioramas displaying different miniature buildings that he made in the past and a very large iron door at the end. “I didn't make this. Grian? Is this yours? Are you trolling me?” As he was looking around someone spoke to him: “I tried your game, very inspiring. Do you want to try mine?” Tango looked around but saw no one, he was alone. “Where are you? Did you build this? You are not Grian, aren’t you?” The voice smirked “No, but he accepted my challenge, as well as the others… ALL OF THEM.” Tango suddenly became worried: “What did you do?!” His yelling was filled with frustration. “Why don’t you find out? Come in.” The large iron door opened, slightly. Tango approached cautiously but when he placed his hand on the handle the world around him shifted and found himself in another room full of traps with new equipments on him: spikes from the ceiling, buzzsaws, wall flamethrowers and so on. “The rules are simple: to whoever finds me first i will realize that person most deep wish. Ready? Set… GO!” Tango, still bamboozled took a deep breath: “It’s READY… SET… NINER! You…!” Realizing that the voice wasn’t there anymore, he just clenched his teeth and pushed forward.

[yenasmatik-tabletops]

FROSTLING (5E)

Warnings: vague mention of death via freezing. Written for a request on r/DungeonsAndDragons. (Mod of the DnD 5E pixie, and inspired by the version of the pixie of angrygolem-games.)

Frostlings look like tiny-sized human children, but with literally snow-white skin, and a blue tint where you'd see rosy cheeks or fingers. Their hair ranges from light blue to white to light silver. Their faces are round, and they're almost always grinning. They wear clothes that appear to be made of ice and snow, and help them blend in the natural landscape where they live. They are native to the snowy and icy lands in the Feywild, and use portals that open in the Material Plane area in similar cold lands, in remote corners or areas. The portals in these places shimmer in all sorts of colors, Auroras are rumored to be the largest of these portals; you can indeed see a lot of frostlings hanging around during this phenomenon. They aren't evil, per se, but they are very much creatures of the frost: their sense of humor is harsh, often callous, they have a habit of stalking people or interesting creatures, and the winter fey's ability to bear a grudge is legendary, even among the fey. Those who try to harm or bully frostlings tend to end up frozen dead at the bottom of a crevasse. Frostlings are fascinated by fire, but won't come near it - they like how it looks, but the heat is uncomfortable for them. Like all fey, they can be bargained with - if you can find something that will keep their attention long enough. Or if they have some reason to seek the help of a mortal - expect trouble if they do. ...

Interests: 1. Their latest prank has offended a winter eladrin, they are in dire need of a negotiator to avoid punishment of the potentially lethal variety. 2. Some of their friends have been caught by a frost giant, they need help mounting a rescue. 3. One (or all) of them has a crush on an evergreen dryad. They need a present to gain the lady's favor. 4. They want to prank a blue cap, and they need accomplices. 5. Someone in the nearest village sings herding calls beautifully, they want you to catch a song in this glowing crystal. 6. They've seen children play with sleds, and they want to try one.

Frostling

Tiny fey, chaotic neutral

Armor Class 15 Hit Points 1 (1d4 - 1) Speed 30 ft. (60 ft. on snowy or icy ground), ice glide.

STR DEX CON 2 (-4) 20 (+5) 8 (-1) INT WIS CHA 10 (+0) 14 (+2) 15 (+2)

Skills Perception +4, Stealth +7 Damage Resistances cold Senses passive Perception 14 Languages Sylvan Challenge 1/4 (50 XP) (?)

Magic Resistance. The frostling has advantage on saving throws against spells and other magical effects.

Ice Glide. The frostling can burrow through nonmagical ice. While doing so, the frostling doesn’t disturb the material it is moving through.

Master Of Snowballs. The frostling has advantage on attacks made with snowballs (see below).

Innate Spellcasting. The frostling's innate spellcasting ability is Charisma (spell save DC 12). It can innately cast the following spells, requiring only snow as a component: At will: gust 1/day each: dancing lights, detect magic, silent image, sleep, pass without trace, calm emotions, fear, slow, freedom of movement, hallucinatory terrain

ACTIONS Snowball. Ranged Weapon Attack: +7 to hit, range 30/120 ft., one target. Hit: 2 (1d4) cold damage. Snowball (magical). Ranged Weapon Attack: +7 to hit, range 30/120 ft., one target. Hit: 2 (1d4) piercing damage. The target must make a DC 10 Constitution saving throw or suffer the effect of either a sleep or a fear spell (choose which before rolling the attack).

Superior Invisibility. The frostling magically turns invisible until its concentration ends (as if concentrating on a spell). Any equipment the frostling wears or carries is invisible with it.

[tsukai22]

3DS online shutting down.

It's supposed to shut down Monday, but it already is Monday in Australia and it hasn't closed down yet. I wonder if it'll shut down at the same time worldwide or if it's a set time for each region (e.g. 6pm in each timezone). Either way I'm using this opportunity to visit some recently updated castles in FE Fates for the last time.

I don't have too many specific memories in Fates though since the vast majority of my online use was for getting Seals or food/ore. There was a player whose Corrin was called DarthVader in his who seemed to update their Death Star castle non-stop - whenever I replayed the game they would always show up a few times in the Recently Updated section at least a couple of times.

I wish I could send out multiple of my save files' castles for people to check out but I can only send one at a time. I could've sent my all-Soleil one, my P5-themed one, my SMT4(A)-themed one or my Horse Emblem one but I chose my "Meme Builds" one which has:

Corrin with the Quixotic + Hoshidan Unity combo (+25% chance to trigger skills) with Dragon Fang, Aether and Luna.

Rhajat with Seal Str/Mag/Spd/Def/Res.

Effie with HP+5 and Def/Res/Spd/Skl+2.

Azama with no weapon, Counter and Countermagic (and HP+5, Renewal and Miracle as a bonus which all help this build a lot). If attacked by most weapons the attacker takes 1.5x damage. [This is my personal favourite]

Velouria with Poison Strike, Savage Blow, Grisly Wound and Toxic Brew. If she initiates the target takes 60% damage after combat and might get 0 movement.

Soleil with Tome/Bow/Axe/Shuriken/Swordbreaker.

Sakura with Charm/Demoiselle/Inspiration. Including her personal skill allies within 2 spaces take -6 damage and deal +6 damage if male, -4 and +4 respectively if female.

Kiragi with Quick Draw, Death Blow, Certain Blow, Darting Blow and Aggressor. He gets +11 damage, Crit+20, Hit+40 and Spd+5 when initiating combat.

Ophelia with Death Blow and Gamble using a Great Club. Combined with her personal skill this gives the weapon a 115% Crit chance. She also has Heartseeker to offset the low accuracy.

And Caeldori with Underdog, Duelist's Blow, Air Superiority, Lucky Seven and Awakening. If all of these are in effect she gets Avoid+125(!). Admittedly only 2 or 3 will probably be active at any given time.