#TLR4

[longhaulerbear]

“Taken together, our study presents the highest resolution, multi-cohort and multi-omics analysis to date, providing an important resource to facilitate mechanistic hypotheses of host-microbiome interactions in ME/CFS.”

Highlights:

Spike protein infusion into mouse brain induces late cognitive dysfunction

Spike protein induces late hippocampal microgliosis and synapse loss

Blockage of TLR4 renders mice resistant to Spike-induced cognitive dysfunction

TLR4-2604G>A GG genotype was related to poor cognitive outcomes in COVID-19 patients

Cognitive dysfunction is often reported in patients with post-COVID, but its underlying mechanisms are not completely understood. Evidence suggests that SARS-CoV-2 Spike protein or its fragments are released from the cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA.

Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID syndrome. We also show that neuroinflammation and hippocampal microgliosis mediates Spike-induced memory dysfunction via complement-dependent engulfment of synapses.

Genetic or pharmacological blockage of TLR4 signaling protects animals against synapse elimination and memory dysfunction induced by Spike brain infusion. Accordingly, in a cohort of 86 patients recovered from mild COVID-19, the genotype GG TLR4 -2604G>A (rs10759931) is associated with poor cognitive outcome. These results identify TLR4 as a key target to investigate the long-term cognitive dysfunction after COVID infection both in humans and rodents.

TLRs are activated by different pathogen-associated molecular patterns (PAMPs) and are crucial for evoking the innate immune responses to infection, stress or injury. Studies have predicted that SARS-CoV-2 Spike protein binds to TLR4 with higher affinity than it binds to ACE2, and its aberrant signaling is involved in the hyperinflammatory response of patients with COVID-19. In vitro studies also demonstrated that SARS-CoV-2 Spike protein activates TLR4 in cultured phagocytic cells, stimulating production of proinflammatory mediators.

Although TLR4 has already been implicated in microglial activation and cognitive dysfunction of Alzheimer’s disease, the impact of TLR4 signaling in COVID-related neurological dysfunction is still unknown.

Further indicating that late but not early microgliosis was induced by Spike protein, we found significantly higher TMEM119 immunoreactivity in the DG hippocampal subregion of Spike-infused mice. Notably, the mRNA levels of the inflammatory mediators TNF, IL-1β, IFNα and IFNβ as well as the IFN receptor IFNAR2 were higher in the hippocampus of Spike-infused mice at this late time point.

We also found increased serum levels of TNF only in the late stage of the model, which returned to the control levels at 60 days post-infusion (Supplementary Fig.5T29 V), correlating with the cognitive dysfunction (Fig. 1B-E). Altogether, our results indicate that the cognitive impairment induced by Spike protein is accompanied by microglial activation and neuroinflammation.

SARS-CoV-2 Spike protein induces synaptic phagocytosis by microglia in mice. Remarkably, C1q blockage rescued object recognition memory impairment in Spike protein-infused mice without any effect on locomotion or exploration. Similarly, neutralizing C1q antibody treatment also prevented spatial memory dysfunction induced by Spike protein infusion. We found that the C1q blockage also prevented the late decrease in hippocampal synaptic puncta and reduced microglial synaptic engulfment in mice infused with the Spike protein. Together, these data suggest that C1q-mediated microglial phagocytosis underlie long-term cognitive dysfunction induced by Spike protein, as seen for other viral encephalitis.

Studies have described that Spike protein induces toll-like receptor 4 (TLR4) activation in cultured immune cells. Additionally, TLR4 has been implicated in microglial activation and cognitive dysfunction in degenerative chronic disease of CNS such as Alzheimer’s disease. In agreement with these observations, despite no changes found in TLR4 expression levels at the early time point after Spike protein infusion (Fig. 4A), we found a late upregulation of TLR4 gene in the hippocampus of Spike protein-infused mice that matches the late cognitive dysfunction.

To evaluate the role of TLR4 in Spike-induced cognitive impairment, we used either a pharmacological approach or a TLR4 knockout mouse model (TLR4First, to investigate whether activation of TLR4 is an early event that could impact cognition later on, mice were treated with the TLR4 inhibitor TAK242 1h before Spike protein brain infusion and once a day for 7 days.) Remarkably, early inhibition of TLR4 greatly prevented late memory dysfunction induced by Spike protein.

Together, these data suggest that TLR4 activation mediates cognitive deficit and synaptic pruning induced by Spike protein in mice.

Importantly, the early treatment with TLR4 inhibitor prevented the late neuronal damage, indicating that the TLR4 pathway is central to induce neurodegeneration and long-term cognitive impairment in the present model. Single nucleotide polymorphism within TLR4 gene is associated with increased risk of cognitive dysfunction after COVID-19.

Several lines of evidence have suggested that polymorphisms in TLR4 gene is a risk factor for developing inflammatory diseases, including sporadic Alzheimer's disease.

Considering our clinical findings demonstrating that SNP (rs10759931) is associated with poor cognitive function after COVID-19, we have performed functional analysis aimed to strengthen the link between this genetic variant and the levels of TLR4 mRNA after Spike stimuli.

Spike stimulation of cultured GG genotype cells resulted in increased levels of mRNA TLR4 when compared with GA genotype cells (*p = <0.0001) (Figure 4X). Our findings suggest that polymorphisms in TLR4 gene are associated with altered Spike-induced host immune responses, increasing the risk to develop long-term cognitive deficit in genetically susceptible individuals.

Post-COVID syndrome comprises a myriad of symptoms that emerge after the acute phase of infection, which include psychiatric symptoms, and dementia-like cognitive dysfunction.

Clinical studies have largely mapped the spectrum of neurological symptoms in patients with post-COVID, but do not provide significant advance in describing the molecular mechanisms that trigger this condition or targets for preventive/therapeutic interventions. On the other hand, studies involving COVID-19 preclinical models have focused mostly on the acute impacts of viral infection. Therefore, it is mandatory to develop novel tools to dissect the mechanisms underlying the neurological deficits in post-COVID, especially the direct effect of the virus and/or viral products on the brain.

Synapse damage is a common denominator in a number of memory-related diseases, often preceding neurodegeneration. It has been shown that neuroinvasive viruses, such as West Nile virus (WNV), Borna disease virus (BDV) and Zika virus (ZIKV), are also associated with synapse impairment.

Likewise, we found that the late cognitive dysfunction induced by Spike protein was accompanied by prominent synapse loss in mice hippocampus. Recent data have revealed the upregulation of genes linked to synapse elimination in SARS-CoV-2-infected human brain organoids and in post-mortem brain samples from patients with COVID-19. In line with these observations, we found that infusion of Spike protein into the mouse brain induces a late elevation in plasma levels of NFL, an axonal cytoskeleton protein identified as a component of pre- and postsynaptic terminals. Plasma NFL [Neurofilament light] increase can be employed as a marker of synapse loss and disease progression in neurodegenerative diseases, including Alzheimer's disease.

Collectively, these findings suggest that brain exposure to Spike protein induces the synapse loss and behavioral alterations typical of viral encephalitis, leading to a prolonged neurological dysfunction that can persist long after recovery from the infectious event.

Microglia are the most abundant immune cell type within the CNS and play a critical role in most of the neuroinflammatory diseases. In viral encephalitis, microglial cells have both protective and detrimental activities depending on the phase of infection. Previous studies showed that human coronaviruses can reach the CNS and induce neuroinflammation and/or gliosis both in mature and immature brain tissues. Here we found that microglial cell lineage BV19 2 was impacted by Spike protein, corroborating recent data showing an increase in proinflammatory mediators in S1-stimulated microglia. Since cultured primary cortical neurons were not directly affected by Spike stimulation, our in vitro results indicate that microglia could be seen as the main cell type affected by exposure to SARS-CoV-2 Spike protein.

It is well known that viral infections are often associated with excessive activation of inflammatory and immune responses, which may in turn elicit and/or accelerate brain neurodegeneration. Here, we found that Spike protein-infused mice presented late microglial activation, but not astrocyte reactivity, similar to observed in other animal models of viral encephalitis. Hippocampal and serum increased levels of proinflammatory mediators were found only at late time points after Spike infusion, showing a temporal correlation with synaptic loss and cognitive dysfunctions. Conversely, we found that the downregulation of IFNAR2 gene occurred shortly after Spike injection, similar to what is observed in neuronal cells of post-mortem samples from patients with COVID-19. This finding corroborates recent evidence demonstrating that SARS-CoV-2 may evade innate immune through modulation of type-I IFN responses.

Altogether, our results show that brain exposure to Spike protein induces an early negative modulation of the main receptor involved in type-I IFN response followed by a late proinflammatory process in the hippocampus.

Together, our findings strongly suggest that brain dysfunction in post-COVID is associated with Spike-induced TLR4 signaling in microglial cells.

The engagement of complement and TLRs in signaling crosstalk has been proposed to regulate immune and inflammatory responses in neurodegenerative diseases. Indeed, it was shown that TLR4 activation induces the upregulation of complement components in the mouse hippocampus. Given the role of complement activation in synaptic pruning, we hypothesized that TLR4 is the molecular switch that regulates microglial synaptic engulfment.

Notably, our hypothesis is in agreement with emerging evidence showing a role for TLR4 in Spike-induced microglial responses. Olajide et al. found significant inhibition in TNF and IL-6 release in S1 Spike-stimulated BV-2 microglia using the same pharmacological inhibitor used in our study (TAK-242) or in cells transfected with TLR4 small interfering RNA. Similar results using TLR4 pharmacological or genetic blockade were found in both murine and human macrophages.

Our animal model provides evidence of the ability of SARS-CoV-2 Spike protein to induce synapse dysfunction.

Using brain organoids, Samudyata and colleagues described that SARS-CoV-2 infection is able to increase microglial engulfment of postsynaptic termini 72 hours after virus inoculation. Thus, it is plausible to assume that TLR4 activation can induce either acute or delayed synaptic dysfunction depending on the agonist/proinflammatory insult. In light of this, we speculate that this possible uncommon ability of SARS-CoV-2 Spike protein to induce delayed synapse loss could account for the occurrence of the intriguing delayed-onset post-COVID cognitive impairment.

...longitudinal data indicates that mild SARS‐CoV‐2 infection is associated with persistent cognitive symptoms with delayed symptom onset not only in individuals with pre-existing cognitive risk factors, but also in young individuals in the absence of comorbidities.

[willowreader]

Erin is an amazing person to follow if you have long covid. The link to th article is below.

@doc4care on Twitter also has this to say about mitochondrial damage and drugs

And there are simple, effective ways to quiet TLR4 inflammation (metformin, berberine, curcuminoids, low dose naltrexone, low dose lithium). And for quieting the RAGE pathway low molec wght heparin (or if outside IS, sulodexide - essentially, oral heparin - not approved in U.S.)

[gusty-wind]

Dr. Ryan Cole Explains the COVID Vaccine Interrupts Toll-Like Receptor 4 (TLR4) Which May Cause a Spike in Cancer

[didanawisgi]

Papers Reviewed:

2020 (Jalili et al) - An Overview of Therapeutic Potentials of Taraxacum Officinale (Dandelion): A Traditionally Valuable Herb with a rich historical background

2020 (Xie et al) - Research Progress of Anti-tumor Active Ingredients in Dandelion

2020 (Wu et al) - Dandelion exerts anti-cancer effects in triple negative breast cancer (TNBC) by killing tumour cells via multiple cell death pathways

2021 (Venezuela et al) - Dandelion Root Extract Affects the Proliferation, Survival and Migration of Cervical Cancer Cell Lines

2023 (Liu et al) - Effect of dandelion polysaccharide on migration and invasion of triple-negative breast cancer cells based on PI3K/Akt/GSK-3β pathway

2023 (Stoutjesdyk et al) - In Vitro Anticancer effects of Taraxacum Genus Extracts: A Review

2024 (Kerry Yang et al) - Dandelion root extracts and taraxasterol inhibit LPS‑induced colorectal cancer cell viability by blocking TLR4‑NFκB‑driven ACE2 and TMPRSS2 pathways

2024 June (Hua Gui et al) - Anti-tumor effect of dandelion flavone on multiple myeloma cells and its mechanism

[bpod-bpod]

Brain Bug

Bacterial meningitis is life-threatening. Caused by infection of the brain coverings (meninges) with bacteria, such as E.coli, it's especially deadly in infants. Using mice, researchers investigate how cells in the meninges respond to E.coli infection soon after birth. Upon infection, single nucleus RNA sequencing revealed macrophages, fibroblasts and endothelial cells, which line blood vessels, significantly changed their gene activity. Endothelial cells increased the activity of TLR4, a signalling protein. In mice lacking TLR4, the response to infection was weakened. Next, the team dissected different layers of the meninges – the dura (pictured, top left) and leptomeninges (top right, bottom) – to image cell junction (green, red) and blood-brain barrier proteins (pink). Infection caused proteins normally found at cell junctions in leptomeninges endothelial cells to redistribute elsewhere and leptomeninges capillaries to become disorganised and leaky. This provides insights into how the meninges blood vessel network responds to infection.

Written by Lux Fatimathas

Image from work by Jie Wang, Amir Rattner and Jeremy Nathans

Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Image originally published with a Creative Commons Attribution 4.0 International (CC BY 4.0)

Published in eLife, June2023

You can also follow BPoD on Instagram, Twitter and Facebook

[altocat]

Sephiroth,

My sincerest apologies for not responding sooner. I've been...preoccupied with a lot of exciting visits to medical facilities. On that note, while I greatly appreciate your generous offer, I don't believe SOLDIER has any use for someone with a faulty heart.

Did you know that one of the most important aspects of innate immunity in humans is Toll-Like Receptor Four (TLR4)? However, despite its vital function, it plays a major role in causing septic shock which is one of the deadliest and most complex pathologies in modern medicine. In addition, over stimulation of TLR4 is suspected to lead to damage to nervous and cardiac tissue due to an exaggerated immune response?

I heard we were doing book recommendations, and while I don't have much in the way of astronomy, I do have quite a few textbooks on biochem and anatomy&physiology, along with my medical college entrance exam stuff that I've already read through twice if you want them. Biology and human physiology are incredibly vast and fascinating fields. It might just be that it helps when I know what's going on and why when they poke and prod me, but I love it and would definitely recommend.

Dear Datflowrboi115,

Forgive me, I was mistaken earlier. I am writing you a reference for the Shinra Science Department. I feel as if your intelligence and resourcefulness will be put to exceedingly good use there. The Department is in dire need of someone with your talents.

Frankly, I'd very much like to have you onboard in any capacity. You continue to fascinate me. I am grateful for the book donation--As of late, I've been rather intrigued at my own biological configuration. Perhaps this shall clear the air.

I hope to have you here with us soon.

Cordially,

Sephiroth, Soldier First-class

[colinwilson11]

Necrotising Enterocolitis Market Will Grow At Highest Pace Owing To Rising Prevalence Of Preterm Birth Complications

Necrotising enterocolitis (NEC) is a devastating gastrointestinal disease that primarily affects premature infants. It is characterized by inflammation and necrosis of the intestine. The risk factors associated with NEC include prematurity, formula feeding, and bacterial colonization of the intestine. Infants with very low birth weights have the highest risk. NEC treatment involves management of sepsis, support of vital organ function, bowel rest with no oral feeding, and surgery if necessary.

The Necrotising Enterocolitis Market is estimated to be valued at US$ 7.10 Bn in 2024 and is expected to exhibit a CAGR of 5.6% over the forecast period 2024-2031.

Key Takeaways

Key players operating in the Necrotising Enterocolitis market are AbbVie, AstraZeneca, Baxter International, Bristol-Myers Squibb, Fresenius Kabi. Rising prevalence of preterm birth complications globally is expected to drive the growth of the market during the forecast period. According to the World Health Organization, preterm birth complications are the leading cause of death among children under 5 years of age, responsible for approximately 1 million deaths in 2015. Technological advancements in parenteral nutrition and minimal invasive surgery have provided improved treatment outcomes for NEC.

Market Trends

Increasing research on nutraceuticals and probiotics for NEC prevention: Several clinical studies are evaluating the role of pre and probiotics such as Lactobacillus and Bifidobacterium in reducing the risk of NEC in preterm infants. This presents an opportunity for novel prevention strategies.

Rising adoption of minimal invasive surgery: Advancements in minimal invasive surgical techniques such as laparoscopy has resulted in reduced recovery time and complications for NEC patients undergoing surgery. This trend is expected to drive the future demand.

Market Opportunities

Development of novel therapeutics targeting inflammatory pathways: Researchers are investigating potential drug targets such as Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB) signaling pathways to develop novel anti-inflammatory therapies for NEC treatment.

Increasing healthcare expenditure on pediatric care in emerging nations: Emerging countries in Asia Pacific and Latin America are witnessing increased healthcare spending focused on neonatal and pediatric care. This will propel the growth of therapeutics and medical devices market for pediatric gastrointestinal conditions.

Impact Of COVID-19 On Necrotising Enterocolitis Market Growth

The COVID-19 pandemic has adversely impacted the growth of the necrotising enterocolitis market globally. During the peak of pandemic in 2020-2021, the concentration of healthcare resources towards treatment of COVID-19 patients has negatively affected the diagnosis and treatment of other health conditions including necrotising enterocolitis. This led to reduction in number of surgeries and procedures carried out for necrotising enterocolitis management. Moreover, restrictions on non-essential healthcare services along with fear of virus spread stopped patients from visiting hospitals even for emergency cases. This impacted the market growth negatively during the period.

However, with gradual lift of restrictions in 2022 and availability of COVID-19 vaccines, the market is recovering slowly. The healthcare facilities are focusing on clearing backlog of non-COVID cases and regaining lost momentum in treatment of other diseases. The manufacturers are expanding supply chain capabilities and ramping up production to meet the increasing demand. Various initiatives are being taken by governments and healthcare organizations to raise awareness about timely management of necrotising enterocolitis. This will potentially boost the market in the coming years.

The United States holds the major share of necrotising enterocolitis market in terms of value, owing to large patient population, high treatment cost and adequate reimbursement framework. The region accounted for over 35% revenue share of global market in 2024.

Asia Pacific region is poised to witness fastest growth during the forecast period. Factors such as increasing healthcare expenditure, rising medical tourism, growing birth rate and expanding private hospital infrastructure will aid the market growth in Asia Pacific. China, India and Japan are emerging as profitable markets for necrotising enterocolitis treatment.

Get more insights on this topic: https://www.trendingwebwire.com/necrotising-enterocolitis-market-is-estimated-to-witness-high-growth-owing-to-advancements-in-parenteral-nutrition-solutions-and-devices/

About Author:

Ravina Pandya, Content Writer, has a strong foothold in the market research industry. She specializes in writing well-researched articles from different industries, including food and beverages, information and technology, healthcare, chemical and materials, etc. (https://www.linkedin.com/in/ravina-pandya-1a3984191)

What Are The Key Data Covered In This Necrotising Enterocolitis Market Report?

:- Market CAGR throughout the predicted period

:- Comprehensive information on the aspects that will drive the Necrotising Enterocolitis Market's growth between 2024 and 2031.

:- Accurate calculation of the size of the Necrotising Enterocolitis Market and its contribution to the market, with emphasis on the parent market

:- Realistic forecasts of future trends and changes in consumer behaviour

:- Necrotising Enterocolitis Market Industry Growth in North America, APAC, Europe, South America, the Middle East, and Africa

:- A complete examination of the market's competitive landscape, as well as extensive information on vendors

:- Detailed examination of the factors that will impede the expansion of Necrotising Enterocolitis Market vendors

FAQ’s

Q.1 What are the main factors influencing the Necrotising Enterocolitis Market?

Q.2 Which companies are the major sources in this industry?

Q.3 What are the market’s opportunities, risks, and general structure?

Q.4 Which of the top Necrotising Enterocolitis Market companies compare in terms of sales, revenue, and prices?

Q.5 Which businesses serve as the Necrotising Enterocolitis Market’s distributors, traders, and dealers?

Q.6 How are market types and applications and deals, revenue, and value explored?

Q.7 What does a business area’s assessment of agreements, income, and value implicate?

*Note: 1. Source: Coherent Market Insights, Public sources, Desk research 2. We have leveraged AI tools to mine information and compile it

[edgarsghost]

It would probably be a good idea to take some biofilm dissolvers (Kirkman or Interphase) before doing the test, so you can "break out" as much bacteria as possible so it will show up on the test. It is possible to have a negative result if your bacteria are still embedded in a biofilm.

_____________________________

My understanding is that cirrus actually test your urine against antibiotics. Microgen look for DNA which should tell what you are resistant to. Pathnostics go one step further and rate antibiotics on what should work best. Use them only as a guide, I’ve had both say R and actually I’m S.

I like cirrus bc they test with abx. Microgen goes by the Sanford guide mostly with picking up some resistance - But due to individual resistance I have found it to only e helpful in terms of identifying bugs but not necessarily treating. Plus my insurance covers cirrus abd I love their support.

—————

Dr Ryan heer - Ruth kritz testing. Recommended on uti website for curing via biofilm disruptors.

_________

The study, by researchers at Washington University School of Medicine in St. Louis and the Broad Institute of MIT and Harvard, showed that a round of antibiotics eliminates disease-causing bacteria from the bladder but not from the intestines. Surviving bacteria in the gut can multiply and spread to the bladder again, causing another UTI.

At the same time, repeated cycles of antibiotics wreak havoc on the community of helpful bacteria that normally live in the intestines, the so-called gut microbiome.

Notably, the microbiomes of women with recurrent UTIs were particularly scarce in bacteria that produce butyrate, a short-chain fatty acid with anti-inflammatory effects.

__________

Can be prescribed pyridium for pain

__________________

My understanding is that cirrus actually test your urine against antibiotics. Microgen look for DNA which should tell what you are resistant to. Pathnostics go one step further and rate antibiotics on what should work best. Use them only as a guide, I’ve had both say R and actually I’m S.

_______

Urinary tract infections (UTIs) typically begin to show symptoms within 2-3 days after the initial bacteria enters the urinary tract. However, the exact timeline can vary:

* Symptoms like a burning sensation during urination, increased urination frequency, and pelvic discomfort often manifest within 1-2 days after the infection starts.

* More severe symptoms like pain, fever, back/abdominal pain, and bloody or cloudy urine may take 2-3 days to develop, as the infection progresses.

* Some individuals may be asymptomatic initially, with the infection only causing noticeable symptoms after a few days.

Frequent or recent sexual activity is the most important risk factor for UTIs in young women. Nearly 80% of all UTIs in premenopausal women occur within 24 hours of intercourse or up to 2 days

_____________________

a frequent and strong urge to urinate even after you empty your bladder, which is called frequency and urgency. a painful or burning sensation when urinating, which is called dysuria.

_____________________

Acute cystitis is an infection of your bladder. “Acute” means that the infection develops suddenly and rises sharply

_____________________

Tumeric:

Curcumin can significantly improve the symptoms of chronic urinary tract infections, protect renal tubular function, and also decline inflammatory responses by influencing the expressions of TLR2 mRNA and TLR4 mRNA so as to exert its curative effect on chronic urinary tract infections

____________

believe Methylene Blue (MB) is safe (and as effective from what I’ve read). And it works for me. I’m not comfortable considering taking Methenamine (Hiprex) because it turns to formaldehyde in the body. Methylene Blue can be gotten on line without an Rx, something I am very grateful for. My urologist dismissed MB when I brought up the idea of taking it to her. She shrugged her shoulders and said “nah, it’s just like pyridium.” Well that simply isn’t true so she lost credibility with me. MB is a treatment that docs apparently don’t want to offer up. Hmm. I wonder why? It’s not because it’s not effective and not safe.

______________________________

https://pharmaceutical-journal.com/article/feature/stuck-in-the-1950s-why-uti-diagnosis-badly-needs-an-update?fbclid=IwZXh0bgNhZW0CMTEAAR1GFwL9LGBBrcSMu3DdXzlj4rQTp3mvj8P2zOGVwCFmpcUh9rJgdQKGEqs_aem_ZUCzdoo6Qa4C7ujVHqWfSQ

Urine culture testing is based on work carried out in 1957 by the scientist Edward Kass, who gathered urine samples from a small group of pregnant women who had pyelonephritis, meaning his work was not representative of patients with acute cystitis.

The subsequent microbiological threshold that was developed based on Kass’ work, and that is still used to diagnose UTIs, looks for the presence of at least 100,000 colony-forming units of bacteria per millilitre of urine (CFU/ml) of a single species of a known pathogen to confirm an infection[4].

Further work in patients with classic symptoms of acute cystitis has demonstrated that a 100,000 CFU/ml threshold missed nearly 50% of genuine infections[5],[6]. In such patients, a threshold of 100 CFU/ml of a known urinary pathogen was proposed as more appropriate.

If your testing is inaccurate then you’ll unintentionally misdiagnose. It’s no surprise that if someone presents with symptoms that sound like a UTI on several occasions, but each time the urine result is negative, they get led down the IC path.”

___________

You will find reading professor Malone-Lee's book very informative. The sex isn't necessarily giving you the uti. If you have embedded infection and sex aggravates my shaking loose the infection therefore causing a rise in your symptoms, that is normally interrupted incorrectly as a new infection. Some may be, but not likely if you consistently get uti symptoms. It's more likely you have Chronic UTI (embedded) and the activity is stirring up and releasing the infection into your urine causing the symptoms. In a few cases sex can be the issue if your partner is carrying infection, obviously tests need to be done to prove this.

———-

Oil of oregano - Any brand is good if it has carvacrol level of 60% or greater.

____________

* Keep the urine's pH at or slightly below 7 during the course of your D-Mannose regimen. Bacteria thrive in an acidic environment doubling in numbers every 20 - 40 minutes. Conversely, bacterial growth is inhibited in a more alkaline environment.

_______________

https://liveutifree.com/uro-vaxom/amp/

Research team at Duke - Dr. Soman Abraham - creating a new treatment:

The immune system’s response is to shed the bladder lining entirely, taking bacteria with it. However, there is a problem with this. The underlying tissue is now exposed to urine and the ammonia, salts, etc, therein, which can cause a great deal of pain. 

Continuing on heroically, the immune system then sends in two types of T-cells to kill off any remaining bacteria (TH1 T-cells) and repair the bladder lining (TH2 T-cells). But in order to save the body from further pain, the repair bit tends to occur faster than the bacteria-killing bit. This can mean that some residual bacteria are left to hide, safe and snug, within the urinary tissues. Multiplying within these tissues, the result is often recurrent UTIs. 

[twinkl22004]

Margaret O. Dayhoff, “Computer Analysis of Protein Evolution”, Scientific American, 1969.

Here I present: Margaret O. Dayhoff (1925-1983), “Computer Analysis of Protein Evolution”, Scientific American, volume 221, July 1969, pages 86-95. The Covid-19 used protein evolution of the morbidity and comorbidity to cause death during the pandemic.  The list of the eleven (11) protein genes of comorbidity is: ACE, AGT, CCR5, CX3CR1, F2, IL1B, IL1RN, IL6, MBL2, NRP3, TLR4. These eleven (11)…

[y2fear]

Ginseng-derived nanoparticles alleviate inflammatory bowel disease via the TLR4/MAPK and p62/Nrf2/Keap1 pathways | Journal of Nanobiotechnology

[leedsomics]

Proximity labeling proteomics reveals Kv1.3 potassium channel immune interactors in microglia.

Microglia are the resident immune cells of the brain and regulate the brain's inflammatory state. In neurodegenerative diseases, microglia transition from a homeostatic state to a state referred to as disease associated microglia (DAM). DAM express higher levels of proinflammatory signaling, like STAT1 and TLR2, and show transitions in mitochondrial activity toward a more glycolytic response. Inhibition of Kv1.3 decreases the proinflammatory signature of DAM, though how Kv1.3 influences the response is unknown. Our goal was to establish the potential proteins interacting with Kv1.3 during the TLR4-mendiated transition to DAM. We utilized TurboID, a biotin ligase, fused to Kv1.3 to evaluate the potential interacting proteins with Kv1.3 via mass spectrometry in BV-2 microglia during an immune response. Electrophysiology, western blots, and flow cytometry were used to evaluate Kv1.3 channel presence and TurboID biotinylation activity. We hypothesized that Kv1.3 contains domain-specific interactors that vary during an TLR4-induced inflammatory response, some of which are dependent on the PDZ-binding domain on the C-terminus. We determined that the N-terminus of Kv1.3 is responsible for trafficking Kv1.3 to the cell surface and mitochondria (i.e. NUNDC, TIMM50). The C-terminus interacts with immune signaling proteins in an LPS-induced inflammatory response (i.e. STAT1, TLR2, and C3). There are 70 proteins that rely on the c-terminal PDZ-binding domain to interact with Kv1.3 (i.e. ND3, Snx3, and Sun1). Overall, we highlight that the Kv1.3 potassium channel functions beyond outward flux of potassium in an inflammatory context and contributes to activity of key immune signaling proteins, such as STAT1 and C3. http://dlvr.it/T255lg

[tumimmtxpapers]

Corrigendum: Tilianin extracted from Dracocephalum moldavica L. induces intrinsic apoptosis and drives inflammatory microenvironment response on pharyngeal squamous carcinoma cells via regulating TLR4 signaling pathways

[This corrects the article DOI: 10.3389/fphar.2020.00205.]. http://dlvr.it/T0HpWK

[rnomics]

Long noncoding #RNA SNHG16 regulates TLR4-mediated autophagy and NETosis formation in alveolar hemorrhage associated with systemic lupus erythematosus

CONCLUSIONS: Our results demonstrate that l#ncRNA SNHG16 regulates TLR4-mediated autophagy and NETosis formation in the human and mouse AH lungs, and provide a therapeutic potential of intra-pulmonary delivery of sh#RNA targeting SNHG16 in this SLE-related lethal manifestation. https://pubmed.ncbi.nlm.nih.gov/37700342/?utm_source=dlvr.it&utm_medium=tumblr&utm_campaign=None&utm_content=1RYYbE7j9SUSBe_aHniaI_J1MQIFIBbfLuFxoWdLNMNDzVVIWF&fc=None&ff=20230916100529&v=2.17.9.post6%2086293ac

[ribosome-papers]

Bazi Bushen maintains intestinal homeostasis through inhibiting TLR4/NFκB signaling pathway and regulating gut microbiota in SAMP6 mice

Pubmed: http://dlvr.it/SsByXS

[kayvanh123]

The perception of pain differs in individuals with Alzheimer’s Disease.

What is Alzheimer’s Disease?

Alzheimer’s Disease is a progressive neurodegenerative disorder that affects the brain, primarily causing memory loss and cognitive decline. It is the most common form of dementia, accounting for around 60-80% of all cases.

The disease typically develops slowly and worsens over time, leading to difficulties with memory, thinking, and behavior. In the early stages, individuals may experience mild forgetfulness and confusion, which gradually progresses to more severe memory impairment, disorientation, and language difficulties. As the disease advances, individuals may have difficulty recognizing loved ones, performing daily tasks, and maintaining conversations.

Research:

According to recent research conducted at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, individuals with Alzheimer’s Disease (AD) may experience altered processing of pain signals compared to healthy individuals. This study, published in Nature Communications, raises questions about the potential for improving the quality of life for people with AD through changes in pain management strategies.

While chronic musculoskeletal pain is prevalent among individuals with AD, it often goes untreated due to cognitive deficits associated with the disease, making it challenging to report the pain accurately. The researchers aimed to investigate whether there are changes in the nervous system’s response to pain in individuals with AD.

In a mouse model mimicking AD, pain signals were found to be processed differently compared to healthy mice. The protein Galectin-3, responsible for transmitting pain signals to the spinal cord, exhibited altered functionality. The study also observed an increased activation of microglia, immune cells within the spinal cord, in response to pain signals. Interestingly, mice with AD lacked a protein called TLR4 in their central nervous system’s immune cells, which impaired their ability to perceive pain signals in the typical manner.

These findings suggest that individuals with AD may experience altered pain perception due to the absence of TLR4, potentially leading to underreported and untreated pain. Professor Marzia Malcangio, the senior author of the study, highlights the significance of understanding this area, as untreated pain can contribute to the psychiatric symptoms associated with AD. Further research in this field could pave the way for more effective treatments, ultimately enhancing the quality of life for individuals with AD.

George Sideris-Lampretsas, the first author of the study and a PhD student at King’s IoPPN, emphasizes the study’s potential impact in identifying Galectin-3/TLR4 as a potential therapeutic target for chronic pain. Additionally, raising awareness about the underreported and untreated pain experienced by AD patients is crucial for addressing their needs effectively.

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Gut microbiota influence host immunity and metabolism during obesity. Bacterial sensors of the innate immune system relay signals from specific bacterial components (i.e., postbiotics) that can have opposing outcomes on host metabolic inflammation. NOD-like receptors (NLRs) such as Nod1 and Nod2 both recruit receptor-interacting protein kinase 2 (RIPK2) but have opposite effects on blood glucose control. Nod1 connects bacterial cell wall-derived signals to metabolic inflammation and insulin resistance, whereas Nod2 can promote immune tolerance, insulin sensitivity, and better blood glucose control during obesity. NLR family pyrin domain containing (NLRP) inflammasomes can also generate divergent metabolic outcomes. NLRP1 protects against obesity and metabolic inflammation potentially because of a bias toward IL-18 regulation, whereas NLRP3 appears to have a bias toward IL-1β-mediated metabolic inflammation and insulin resistance. Targeting specific postbiotics that improve immunometabolism is a key goal. The Nod2 ligand, muramyl dipeptide (MDP) is a short-acting insulin sensitizer during obesity or during inflammatory lipopolysaccharide (LPS) stress. LPS with underacylated lipid-A antagonizes TLR4 and counteracts the metabolic effects of inflammatory LPS. Providing underacylated LPS derived from Rhodobacter sphaeroides improved insulin sensitivity in obese mice. Therefore, certain types of LPS can generate metabolically beneficial metabolic endotoxemia. Engaging protective adaptive immunoglobulin immune responses can also improve blood glucose during obesity. A bacterial vaccine approach using an extract of the entire bacterial community in the upper gut promotes protective adaptive immune response and long-lasting improvements in blood glucose control. A key future goal is to identify and combine postbiotics that cooperate to improve blood glucose control.