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New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/nobel-prize-physiology-medicine-1994/

The Nobel Prize in Physiology or Medicine 1994

The Nobel Prize in Physiology or Medicine 1994 was awarded jointly to Alfred G. Gilman and Martin Rodbell “for their discovery of G-proteins and the role of these proteins in signal transduction in cells.”

Nobelist Born Died Affiliation at the time of the award Alfred G. Gilman 1 July 1941, New Haven, CT, USA 23 December 2015, Dallas, TX, USA University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA Martin Rodbell 1 December 1925, Baltimore, MD, USA 7 December 1998, Chapel Hill, NC, USA National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

Summary It has been known for some time that cells communicate with each other by means of hormones and other signal substances, which are released from glands, nerves and other tissues. It is only recently that we have begun to understand how the cell handles this information from the outside and converts it into relevant action – i.e. how signals are transduced in cells.

The discoveries of the G-proteins by the Americans Alfred G. Gilman and Martin Rodbell have been of paramount importance in this context, and have opened up a new and rapidly expanding area of knowledge.

G-proteins have been so named because they bind guanosine triphosphate (GTP). Gilman and Rodbell found that G-proteins act as signal transducers, which transmit and modulate signals in cells. G-proteins have the ability to activate different cellular amplifier systems. They receive multiple signals from the exterior, integrate them and thus control fundamental life processes in the cells.

Disturbances in the function of G-proteins – too much or too little of them, or genetically determined alterations in their composition – can lead to disease. The dramatic loss of salt and water in cholera is a direct consequence of the action of cholera toxin on G-proteins. Some hereditary endocrine disorders and tumours are other examples. Furthermore, some of the symptoms of common diseases such as diabetes or alcoholism may depend on altered transduction of signals through G-proteins.

More detailed information at The Nobel Prize in Physiology or Medicine 1994.

[abbkineeu]

New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/nobel-prize-physiology-medicine-1994/

The Nobel Prize in Physiology or Medicine 1994

The Nobel Prize in Physiology or Medicine 1994 was awarded jointly to Alfred G. Gilman and Martin Rodbell “for their discovery of G-proteins and the role of these proteins in signal transduction in cells.”

Nobelist Born Died Affiliation at the time of the award Alfred G. Gilman 1 July 1941, New Haven, CT, USA 23 December 2015, Dallas, TX, USA University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA Martin Rodbell 1 December 1925, Baltimore, MD, USA 7 December 1998, Chapel Hill, NC, USA National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

Summary It has been known for some time that cells communicate with each other by means of hormones and other signal substances, which are released from glands, nerves and other tissues. It is only recently that we have begun to understand how the cell handles this information from the outside and converts it into relevant action – i.e. how signals are transduced in cells.

The discoveries of the G-proteins by the Americans Alfred G. Gilman and Martin Rodbell have been of paramount importance in this context, and have opened up a new and rapidly expanding area of knowledge.

G-proteins have been so named because they bind guanosine triphosphate (GTP). Gilman and Rodbell found that G-proteins act as signal transducers, which transmit and modulate signals in cells. G-proteins have the ability to activate different cellular amplifier systems. They receive multiple signals from the exterior, integrate them and thus control fundamental life processes in the cells.

Disturbances in the function of G-proteins – too much or too little of them, or genetically determined alterations in their composition – can lead to disease. The dramatic loss of salt and water in cholera is a direct consequence of the action of cholera toxin on G-proteins. Some hereditary endocrine disorders and tumours are other examples. Furthermore, some of the symptoms of common diseases such as diabetes or alcoholism may depend on altered transduction of signals through G-proteins.

More detailed information at The Nobel Prize in Physiology or Medicine 1994.

[abbkineeu]

New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/nobel-prize-physiology-medicine-1994/

The Nobel Prize in Physiology or Medicine 1994

The Nobel Prize in Physiology or Medicine 1994 was awarded jointly to Alfred G. Gilman and Martin Rodbell “for their discovery of G-proteins and the role of these proteins in signal transduction in cells.”

Nobelist Born Died Affiliation at the time of the award Alfred G. Gilman 1 July 1941, New Haven, CT, USA 23 December 2015, Dallas, TX, USA University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA Martin Rodbell 1 December 1925, Baltimore, MD, USA 7 December 1998, Chapel Hill, NC, USA National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

Summary It has been known for some time that cells communicate with each other by means of hormones and other signal substances, which are released from glands, nerves and other tissues. It is only recently that we have begun to understand how the cell handles this information from the outside and converts it into relevant action – i.e. how signals are transduced in cells.

The discoveries of the G-proteins by the Americans Alfred G. Gilman and Martin Rodbell have been of paramount importance in this context, and have opened up a new and rapidly expanding area of knowledge.

G-proteins have been so named because they bind guanosine triphosphate (GTP). Gilman and Rodbell found that G-proteins act as signal transducers, which transmit and modulate signals in cells. G-proteins have the ability to activate different cellular amplifier systems. They receive multiple signals from the exterior, integrate them and thus control fundamental life processes in the cells.

Disturbances in the function of G-proteins – too much or too little of them, or genetically determined alterations in their composition – can lead to disease. The dramatic loss of salt and water in cholera is a direct consequence of the action of cholera toxin on G-proteins. Some hereditary endocrine disorders and tumours are other examples. Furthermore, some of the symptoms of common diseases such as diabetes or alcoholism may depend on altered transduction of signals through G-proteins.

More detailed information at The Nobel Prize in Physiology or Medicine 1994.

[abbkineeu]

New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/nobel-prize-physiology-medicine-1994/

The Nobel Prize in Physiology or Medicine 1994

The Nobel Prize in Physiology or Medicine 1994 was awarded jointly to Alfred G. Gilman and Martin Rodbell “for their discovery of G-proteins and the role of these proteins in signal transduction in cells.”

Nobelist Born Died Affiliation at the time of the award Alfred G. Gilman 1 July 1941, New Haven, CT, USA 23 December 2015, Dallas, TX, USA University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA Martin Rodbell 1 December 1925, Baltimore, MD, USA 7 December 1998, Chapel Hill, NC, USA National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

Summary It has been known for some time that cells communicate with each other by means of hormones and other signal substances, which are released from glands, nerves and other tissues. It is only recently that we have begun to understand how the cell handles this information from the outside and converts it into relevant action – i.e. how signals are transduced in cells.

The discoveries of the G-proteins by the Americans Alfred G. Gilman and Martin Rodbell have been of paramount importance in this context, and have opened up a new and rapidly expanding area of knowledge.

G-proteins have been so named because they bind guanosine triphosphate (GTP). Gilman and Rodbell found that G-proteins act as signal transducers, which transmit and modulate signals in cells. G-proteins have the ability to activate different cellular amplifier systems. They receive multiple signals from the exterior, integrate them and thus control fundamental life processes in the cells.

Disturbances in the function of G-proteins – too much or too little of them, or genetically determined alterations in their composition – can lead to disease. The dramatic loss of salt and water in cholera is a direct consequence of the action of cholera toxin on G-proteins. Some hereditary endocrine disorders and tumours are other examples. Furthermore, some of the symptoms of common diseases such as diabetes or alcoholism may depend on altered transduction of signals through G-proteins.

More detailed information at The Nobel Prize in Physiology or Medicine 1994.

[abbkineeu]

New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/reward-behaviour-regulated-strength-hippocampus-nucleus-accumbens-synapses/

Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses

Content introduction:

Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses

Somatic APP gene recombination in Alzheimer’s disease and normal neurons

Distinct activity-gated pathways mediate attraction and aversion to CO2 in Drosophila

Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release

TIC236 links the outer and inner membrane translocons of the chloroplast

1. Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses

Reward drives motivated behaviours and is essential for survival, and therefore there is strong evolutionary pressure to retain contextual information about rewarding stimuli. This drive may be abnormally strong, such as in addiction, or weak, such as in depression, in which anhedonia (loss of pleasure in response to rewarding stimuli) is a prominent symptom. Hippocampal input to the shell of the nucleus accumbens (NAc) is important for driving NAc activity and activity-dependent modulation of the strength of this input may contribute to the proper regulation of goal-directed behaviours. However, there have been few robust descriptions of the mechanisms that underlie the induction or expression of long-term potentiation (LTP) at these synapses, and there is, to our knowledge, no evidence about whether such plasticity contributes to reward-related behaviour. Here Tara A. LeGates at University of Maryland School of Medicine in Baltimore, USA and his colleagues show that high-frequency activity induces LTP at hippocampus–NAc synapses in mice via canonical, but dopamine-independent, mechanisms. The induction of LTP at this synapse in vivo drives conditioned place preference, and activity at this synapse is required for conditioned place preference in response to a natural reward. Conversely, chronic stress, which induces anhedonia, decreases the strength of this synapse and impairs LTP, whereas antidepressant treatment is accompanied by a reversal of these stress-induced changes. They conclude that hippocampus–NAc synapses show activity-dependent plasticity and suggest that their strength may be critical for contextual reward behaviour.

Read more, please click https://www.nature.com/articles/s41586-018-0740-8

2. Somatic APP gene recombination in Alzheimer’s disease and normal neurons

The diversity and complexity of the human brain are widely assumed to be encoded within a constant genome. Somatic gene recombination, which changes germline DNA sequences to increase molecular diversity, could theoretically alter this code but has not been documented in the brain, to our knowledge. Here Ming-Hsiang Lee at Sanford Burnham Prebys Medical Discovery Institute in La Jolla, USA and his colleagues describe recombination of the Alzheimer’s disease-related gene APP, which encodes amyloid precursor protein, in human neurons, occurring mosaically as thousands of variant ‘genomic cDNAs’ (gencDNAs). gencDNAs lacked introns and ranged from full-length cDNA copies of expressed, brain-specific RNA splice variants to myriad smaller forms that contained intra-exonic junctions, insertions, deletions, and/or single nucleotide variations. DNA in situ hybridization identified gencDNAs within single neurons that were distinct from wild-type loci and absent from non-neuronal cells. Mechanistic studies supported neuronal ‘retro-insertion’ of RNA to produce gencDNAs; this process involved transcription, DNA breaks, reverse transcriptase activity, and age. Neurons from individuals with sporadic Alzheimer’s disease showed increased gencDNA diversity, including eleven mutations known to be associated with familial Alzheimer’s disease that were absent from healthy neurons. Neuronal gene recombination may allow ‘recording’ of neural activity for selective ‘playback’ of preferred gene variants whose expression bypasses splicing; this has implications for cellular diversity, learning and memory, plasticity, and diseases of the human brain.

Read more, please click https://www.nature.com/articles/s41586-018-0718-6

3. Distinct activity-gated pathways mediate attraction and aversion to CO2 in Drosophila

Carbon dioxide is produced by many organic processes and is a convenient volatile cue for insects that are searching for blood hosts, flowers, communal nests, fruit and wildfires. Although Drosophila melanogaster feed on yeast that produce CO2 and ethanol during fermentation, laboratory experiments suggest that walking flies avoid CO2. Here Floris van Breugel at California Institute of Technology in Pasadena, USA and his colleagues resolve this paradox by showing that both flying and walking Drosophila find CO2 attractive, but only when they are in an active state associated with foraging. Their aversion to CO2 at low-activity levels may be an adaptation to avoid parasites that seek CO2, or to avoid succumbing to respiratory acidosis in the presence of high concentrations of CO2 that exist in nature. In contrast to CO2, flies are attracted to ethanol in all behavioural states, and invest twice the time searching near ethanol compared to CO2. These behavioural differences reflect the fact that ethanol is a unique signature of yeast fermentation, whereas CO2 is generated by many natural processes. Using genetic tools, they determined that the evolutionarily conserved ionotropic co-receptor IR25a is required for CO2 attraction, and that the receptors necessary for CO2 avoidance are not involved in this attraction. Their study lays the foundation for future research to determine the neural circuits that underlie both state- and odorant-dependent decision-making in Drosophila.

Read more, please click https://www.nature.com/articles/s41586-018-0732-8

4. Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release

Development and routine tissue homeostasis require a high turnover of apoptotic cells. These cells are removed by professional and non-professional phagocytes via efferocytosis. How a phagocyte maintains its homeostasis while coordinating corpse uptake, processing ingested materials and secreting anti-inflammatory mediators is incompletely understood. Here, using RNA sequencing to characterize the transcriptional program of phagocytes actively engulfing apoptotic cells, Sho Morioka at University of Virginia in Charlottesville, USA and his colleagues identify a genetic signature involving 33 members of the solute carrier (SLC) family of membrane transport proteins, in which expression is specifically modulated during efferocytosis, but not during antibody-mediated phagocytosis. They assessed the functional relevance of these SLCs in efferocytic phagocytes and observed a robust induction of an aerobic glycolysis program, initiated by SLC2A1-mediated glucose uptake, with concurrent suppression of the oxidative phosphorylation program. The different steps of phagocytosis—that is, ‘smell’ (‘find-me’ signals or sensing factors released by apoptotic cells), ‘taste’ (phagocyte–apoptotic cell contact) and ‘ingestion’ (corpse internalization)—activated distinct and overlapping sets of genes, including several SLC genes, to promote glycolysis. SLC16A1 was upregulated after corpse uptake, increasing the release of lactate, a natural by-product of aerobic glycolysis. Whereas glycolysis within phagocytes contributed to actin polymerization and the continued uptake of corpses, lactate released via SLC16A1 promoted the establishment of an anti-inflammatory tissue environment. Collectively, these data reveal a SLC program that is activated during efferocytosis, identify a previously unknown reliance on aerobic glycolysis during apoptotic cell uptake and show that glycolytic by-products of efferocytosis can influence surrounding cells.

Read more, please click https://www.nature.com/articles/s41586-018-0735-5

5. TIC236 links the outer and inner membrane translocons of the chloroplast

The two-membrane envelope is a defining feature of chloroplasts. Chloroplasts evolved from a Gram-negative cyanobacterial endosymbiont. During evolution, genes of the endosymbiont have been transferred to the host nuclear genome. Most chloroplast proteins are synthesized in the cytosol as higher-molecular-mass preproteins with an N-terminal transit peptide. Preproteins are transported into chloroplasts by the TOC and TIC (translocons at the outer- and inner-envelope membranes of chloroplasts, respectively) machineries, but how TOC and TIC are assembled together is unknown. Here Yih-Lin Chen at Academia Sinica in Taipei, Taiwan and his colleagues report the identification of the TIC component TIC236; TIC236 is an integral inner-membrane protein that projects a 230-kDa domain into the intermembrane space, which binds directly to the outer-membrane channel TOC75. The knockout mutation of TIC236 is embryonically lethal. In TIC236-knockdown mutants, a smaller amount of the inner-membrane channel TIC20 was associated with TOC75; the amount of TOC–TIC supercomplexes was also reduced. This resulted in a reduced import rate into the stroma, though outer-membrane protein insertion was unaffected. The size and the essential nature of TIC236 indicate that—unlike in mitochondria, in which the outer- and inner-membrane translocons exist as separate complexes and a supercomplex is only transiently assembled during preprotein translocation—a long and stable protein bridge in the intermembrane space is required for protein translocation into chloroplasts. Furthermore, TIC236 and TOC75 are homologues of bacterial inner-membrane TamB5 and outer-membrane BamA, respectively. Their evolutionary analyses show that, similar to TOC75, TIC236 is preserved only in plants and has co-evolved with TOC75 throughout the plant lineage. This suggests that the backbone of the chloroplast protein-import machinery evolved from the bacterial TamB–BamA protein-secretion system.

Read more, please click https://www.nature.com/articles/s41586-018-0713-y

[abbkineeu]

New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/reward-behaviour-regulated-strength-hippocampus-nucleus-accumbens-synapses/

Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses

Content introduction:

Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses

Somatic APP gene recombination in Alzheimer’s disease and normal neurons

Distinct activity-gated pathways mediate attraction and aversion to CO2 in Drosophila

Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release

TIC236 links the outer and inner membrane translocons of the chloroplast

1. Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses

Reward drives motivated behaviours and is essential for survival, and therefore there is strong evolutionary pressure to retain contextual information about rewarding stimuli. This drive may be abnormally strong, such as in addiction, or weak, such as in depression, in which anhedonia (loss of pleasure in response to rewarding stimuli) is a prominent symptom. Hippocampal input to the shell of the nucleus accumbens (NAc) is important for driving NAc activity and activity-dependent modulation of the strength of this input may contribute to the proper regulation of goal-directed behaviours. However, there have been few robust descriptions of the mechanisms that underlie the induction or expression of long-term potentiation (LTP) at these synapses, and there is, to our knowledge, no evidence about whether such plasticity contributes to reward-related behaviour. Here Tara A. LeGates at University of Maryland School of Medicine in Baltimore, USA and his colleagues show that high-frequency activity induces LTP at hippocampus–NAc synapses in mice via canonical, but dopamine-independent, mechanisms. The induction of LTP at this synapse in vivo drives conditioned place preference, and activity at this synapse is required for conditioned place preference in response to a natural reward. Conversely, chronic stress, which induces anhedonia, decreases the strength of this synapse and impairs LTP, whereas antidepressant treatment is accompanied by a reversal of these stress-induced changes. They conclude that hippocampus–NAc synapses show activity-dependent plasticity and suggest that their strength may be critical for contextual reward behaviour.

Read more, please click https://www.nature.com/articles/s41586-018-0740-8

2. Somatic APP gene recombination in Alzheimer’s disease and normal neurons

The diversity and complexity of the human brain are widely assumed to be encoded within a constant genome. Somatic gene recombination, which changes germline DNA sequences to increase molecular diversity, could theoretically alter this code but has not been documented in the brain, to our knowledge. Here Ming-Hsiang Lee at Sanford Burnham Prebys Medical Discovery Institute in La Jolla, USA and his colleagues describe recombination of the Alzheimer’s disease-related gene APP, which encodes amyloid precursor protein, in human neurons, occurring mosaically as thousands of variant ‘genomic cDNAs’ (gencDNAs). gencDNAs lacked introns and ranged from full-length cDNA copies of expressed, brain-specific RNA splice variants to myriad smaller forms that contained intra-exonic junctions, insertions, deletions, and/or single nucleotide variations. DNA in situ hybridization identified gencDNAs within single neurons that were distinct from wild-type loci and absent from non-neuronal cells. Mechanistic studies supported neuronal ‘retro-insertion’ of RNA to produce gencDNAs; this process involved transcription, DNA breaks, reverse transcriptase activity, and age. Neurons from individuals with sporadic Alzheimer’s disease showed increased gencDNA diversity, including eleven mutations known to be associated with familial Alzheimer’s disease that were absent from healthy neurons. Neuronal gene recombination may allow ‘recording’ of neural activity for selective ‘playback’ of preferred gene variants whose expression bypasses splicing; this has implications for cellular diversity, learning and memory, plasticity, and diseases of the human brain.

Read more, please click https://www.nature.com/articles/s41586-018-0718-6

3. Distinct activity-gated pathways mediate attraction and aversion to CO2 in Drosophila

Carbon dioxide is produced by many organic processes and is a convenient volatile cue for insects that are searching for blood hosts, flowers, communal nests, fruit and wildfires. Although Drosophila melanogaster feed on yeast that produce CO2 and ethanol during fermentation, laboratory experiments suggest that walking flies avoid CO2. Here Floris van Breugel at California Institute of Technology in Pasadena, USA and his colleagues resolve this paradox by showing that both flying and walking Drosophila find CO2 attractive, but only when they are in an active state associated with foraging. Their aversion to CO2 at low-activity levels may be an adaptation to avoid parasites that seek CO2, or to avoid succumbing to respiratory acidosis in the presence of high concentrations of CO2 that exist in nature. In contrast to CO2, flies are attracted to ethanol in all behavioural states, and invest twice the time searching near ethanol compared to CO2. These behavioural differences reflect the fact that ethanol is a unique signature of yeast fermentation, whereas CO2 is generated by many natural processes. Using genetic tools, they determined that the evolutionarily conserved ionotropic co-receptor IR25a is required for CO2 attraction, and that the receptors necessary for CO2 avoidance are not involved in this attraction. Their study lays the foundation for future research to determine the neural circuits that underlie both state- and odorant-dependent decision-making in Drosophila.

Read more, please click https://www.nature.com/articles/s41586-018-0732-8

4. Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release

Development and routine tissue homeostasis require a high turnover of apoptotic cells. These cells are removed by professional and non-professional phagocytes via efferocytosis. How a phagocyte maintains its homeostasis while coordinating corpse uptake, processing ingested materials and secreting anti-inflammatory mediators is incompletely understood. Here, using RNA sequencing to characterize the transcriptional program of phagocytes actively engulfing apoptotic cells, Sho Morioka at University of Virginia in Charlottesville, USA and his colleagues identify a genetic signature involving 33 members of the solute carrier (SLC) family of membrane transport proteins, in which expression is specifically modulated during efferocytosis, but not during antibody-mediated phagocytosis. They assessed the functional relevance of these SLCs in efferocytic phagocytes and observed a robust induction of an aerobic glycolysis program, initiated by SLC2A1-mediated glucose uptake, with concurrent suppression of the oxidative phosphorylation program. The different steps of phagocytosis—that is, ‘smell’ (‘find-me’ signals or sensing factors released by apoptotic cells), ‘taste’ (phagocyte–apoptotic cell contact) and ‘ingestion’ (corpse internalization)—activated distinct and overlapping sets of genes, including several SLC genes, to promote glycolysis. SLC16A1 was upregulated after corpse uptake, increasing the release of lactate, a natural by-product of aerobic glycolysis. Whereas glycolysis within phagocytes contributed to actin polymerization and the continued uptake of corpses, lactate released via SLC16A1 promoted the establishment of an anti-inflammatory tissue environment. Collectively, these data reveal a SLC program that is activated during efferocytosis, identify a previously unknown reliance on aerobic glycolysis during apoptotic cell uptake and show that glycolytic by-products of efferocytosis can influence surrounding cells.

Read more, please click https://www.nature.com/articles/s41586-018-0735-5

5. TIC236 links the outer and inner membrane translocons of the chloroplast

The two-membrane envelope is a defining feature of chloroplasts. Chloroplasts evolved from a Gram-negative cyanobacterial endosymbiont. During evolution, genes of the endosymbiont have been transferred to the host nuclear genome. Most chloroplast proteins are synthesized in the cytosol as higher-molecular-mass preproteins with an N-terminal transit peptide. Preproteins are transported into chloroplasts by the TOC and TIC (translocons at the outer- and inner-envelope membranes of chloroplasts, respectively) machineries, but how TOC and TIC are assembled together is unknown. Here Yih-Lin Chen at Academia Sinica in Taipei, Taiwan and his colleagues report the identification of the TIC component TIC236; TIC236 is an integral inner-membrane protein that projects a 230-kDa domain into the intermembrane space, which binds directly to the outer-membrane channel TOC75. The knockout mutation of TIC236 is embryonically lethal. In TIC236-knockdown mutants, a smaller amount of the inner-membrane channel TIC20 was associated with TOC75; the amount of TOC–TIC supercomplexes was also reduced. This resulted in a reduced import rate into the stroma, though outer-membrane protein insertion was unaffected. The size and the essential nature of TIC236 indicate that—unlike in mitochondria, in which the outer- and inner-membrane translocons exist as separate complexes and a supercomplex is only transiently assembled during preprotein translocation—a long and stable protein bridge in the intermembrane space is required for protein translocation into chloroplasts. Furthermore, TIC236 and TOC75 are homologues of bacterial inner-membrane TamB5 and outer-membrane BamA, respectively. Their evolutionary analyses show that, similar to TOC75, TIC236 is preserved only in plants and has co-evolved with TOC75 throughout the plant lineage. This suggests that the backbone of the chloroplast protein-import machinery evolved from the bacterial TamB–BamA protein-secretion system.

Read more, please click https://www.nature.com/articles/s41586-018-0713-y

[abbkineeu]

New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/reward-behaviour-regulated-strength-hippocampus-nucleus-accumbens-synapses/

Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses

Content introduction:

Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses

Somatic APP gene recombination in Alzheimer’s disease and normal neurons

Distinct activity-gated pathways mediate attraction and aversion to CO2 in Drosophila

Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release

TIC236 links the outer and inner membrane translocons of the chloroplast

1. Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses

Reward drives motivated behaviours and is essential for survival, and therefore there is strong evolutionary pressure to retain contextual information about rewarding stimuli. This drive may be abnormally strong, such as in addiction, or weak, such as in depression, in which anhedonia (loss of pleasure in response to rewarding stimuli) is a prominent symptom. Hippocampal input to the shell of the nucleus accumbens (NAc) is important for driving NAc activity and activity-dependent modulation of the strength of this input may contribute to the proper regulation of goal-directed behaviours. However, there have been few robust descriptions of the mechanisms that underlie the induction or expression of long-term potentiation (LTP) at these synapses, and there is, to our knowledge, no evidence about whether such plasticity contributes to reward-related behaviour. Here Tara A. LeGates at University of Maryland School of Medicine in Baltimore, USA and his colleagues show that high-frequency activity induces LTP at hippocampus–NAc synapses in mice via canonical, but dopamine-independent, mechanisms. The induction of LTP at this synapse in vivo drives conditioned place preference, and activity at this synapse is required for conditioned place preference in response to a natural reward. Conversely, chronic stress, which induces anhedonia, decreases the strength of this synapse and impairs LTP, whereas antidepressant treatment is accompanied by a reversal of these stress-induced changes. They conclude that hippocampus–NAc synapses show activity-dependent plasticity and suggest that their strength may be critical for contextual reward behaviour.

Read more, please click https://www.nature.com/articles/s41586-018-0740-8

2. Somatic APP gene recombination in Alzheimer’s disease and normal neurons

The diversity and complexity of the human brain are widely assumed to be encoded within a constant genome. Somatic gene recombination, which changes germline DNA sequences to increase molecular diversity, could theoretically alter this code but has not been documented in the brain, to our knowledge. Here Ming-Hsiang Lee at Sanford Burnham Prebys Medical Discovery Institute in La Jolla, USA and his colleagues describe recombination of the Alzheimer’s disease-related gene APP, which encodes amyloid precursor protein, in human neurons, occurring mosaically as thousands of variant ‘genomic cDNAs’ (gencDNAs). gencDNAs lacked introns and ranged from full-length cDNA copies of expressed, brain-specific RNA splice variants to myriad smaller forms that contained intra-exonic junctions, insertions, deletions, and/or single nucleotide variations. DNA in situ hybridization identified gencDNAs within single neurons that were distinct from wild-type loci and absent from non-neuronal cells. Mechanistic studies supported neuronal ‘retro-insertion’ of RNA to produce gencDNAs; this process involved transcription, DNA breaks, reverse transcriptase activity, and age. Neurons from individuals with sporadic Alzheimer’s disease showed increased gencDNA diversity, including eleven mutations known to be associated with familial Alzheimer’s disease that were absent from healthy neurons. Neuronal gene recombination may allow ‘recording’ of neural activity for selective ‘playback’ of preferred gene variants whose expression bypasses splicing; this has implications for cellular diversity, learning and memory, plasticity, and diseases of the human brain.

Read more, please click https://www.nature.com/articles/s41586-018-0718-6

3. Distinct activity-gated pathways mediate attraction and aversion to CO2 in Drosophila

Carbon dioxide is produced by many organic processes and is a convenient volatile cue for insects that are searching for blood hosts, flowers, communal nests, fruit and wildfires. Although Drosophila melanogaster feed on yeast that produce CO2 and ethanol during fermentation, laboratory experiments suggest that walking flies avoid CO2. Here Floris van Breugel at California Institute of Technology in Pasadena, USA and his colleagues resolve this paradox by showing that both flying and walking Drosophila find CO2 attractive, but only when they are in an active state associated with foraging. Their aversion to CO2 at low-activity levels may be an adaptation to avoid parasites that seek CO2, or to avoid succumbing to respiratory acidosis in the presence of high concentrations of CO2 that exist in nature. In contrast to CO2, flies are attracted to ethanol in all behavioural states, and invest twice the time searching near ethanol compared to CO2. These behavioural differences reflect the fact that ethanol is a unique signature of yeast fermentation, whereas CO2 is generated by many natural processes. Using genetic tools, they determined that the evolutionarily conserved ionotropic co-receptor IR25a is required for CO2 attraction, and that the receptors necessary for CO2 avoidance are not involved in this attraction. Their study lays the foundation for future research to determine the neural circuits that underlie both state- and odorant-dependent decision-making in Drosophila.

Read more, please click https://www.nature.com/articles/s41586-018-0732-8

4. Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release

Development and routine tissue homeostasis require a high turnover of apoptotic cells. These cells are removed by professional and non-professional phagocytes via efferocytosis. How a phagocyte maintains its homeostasis while coordinating corpse uptake, processing ingested materials and secreting anti-inflammatory mediators is incompletely understood. Here, using RNA sequencing to characterize the transcriptional program of phagocytes actively engulfing apoptotic cells, Sho Morioka at University of Virginia in Charlottesville, USA and his colleagues identify a genetic signature involving 33 members of the solute carrier (SLC) family of membrane transport proteins, in which expression is specifically modulated during efferocytosis, but not during antibody-mediated phagocytosis. They assessed the functional relevance of these SLCs in efferocytic phagocytes and observed a robust induction of an aerobic glycolysis program, initiated by SLC2A1-mediated glucose uptake, with concurrent suppression of the oxidative phosphorylation program. The different steps of phagocytosis—that is, ‘smell’ (‘find-me’ signals or sensing factors released by apoptotic cells), ‘taste’ (phagocyte–apoptotic cell contact) and ‘ingestion’ (corpse internalization)—activated distinct and overlapping sets of genes, including several SLC genes, to promote glycolysis. SLC16A1 was upregulated after corpse uptake, increasing the release of lactate, a natural by-product of aerobic glycolysis. Whereas glycolysis within phagocytes contributed to actin polymerization and the continued uptake of corpses, lactate released via SLC16A1 promoted the establishment of an anti-inflammatory tissue environment. Collectively, these data reveal a SLC program that is activated during efferocytosis, identify a previously unknown reliance on aerobic glycolysis during apoptotic cell uptake and show that glycolytic by-products of efferocytosis can influence surrounding cells.

Read more, please click https://www.nature.com/articles/s41586-018-0735-5

5. TIC236 links the outer and inner membrane translocons of the chloroplast

The two-membrane envelope is a defining feature of chloroplasts. Chloroplasts evolved from a Gram-negative cyanobacterial endosymbiont. During evolution, genes of the endosymbiont have been transferred to the host nuclear genome. Most chloroplast proteins are synthesized in the cytosol as higher-molecular-mass preproteins with an N-terminal transit peptide. Preproteins are transported into chloroplasts by the TOC and TIC (translocons at the outer- and inner-envelope membranes of chloroplasts, respectively) machineries, but how TOC and TIC are assembled together is unknown. Here Yih-Lin Chen at Academia Sinica in Taipei, Taiwan and his colleagues report the identification of the TIC component TIC236; TIC236 is an integral inner-membrane protein that projects a 230-kDa domain into the intermembrane space, which binds directly to the outer-membrane channel TOC75. The knockout mutation of TIC236 is embryonically lethal. In TIC236-knockdown mutants, a smaller amount of the inner-membrane channel TIC20 was associated with TOC75; the amount of TOC–TIC supercomplexes was also reduced. This resulted in a reduced import rate into the stroma, though outer-membrane protein insertion was unaffected. The size and the essential nature of TIC236 indicate that—unlike in mitochondria, in which the outer- and inner-membrane translocons exist as separate complexes and a supercomplex is only transiently assembled during preprotein translocation—a long and stable protein bridge in the intermembrane space is required for protein translocation into chloroplasts. Furthermore, TIC236 and TOC75 are homologues of bacterial inner-membrane TamB5 and outer-membrane BamA, respectively. Their evolutionary analyses show that, similar to TOC75, TIC236 is preserved only in plants and has co-evolved with TOC75 throughout the plant lineage. This suggests that the backbone of the chloroplast protein-import machinery evolved from the bacterial TamB–BamA protein-secretion system.

Read more, please click https://www.nature.com/articles/s41586-018-0713-y

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Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses

Content introduction:

Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses

Somatic APP gene recombination in Alzheimer’s disease and normal neurons

Distinct activity-gated pathways mediate attraction and aversion to CO2 in Drosophila

Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release

TIC236 links the outer and inner membrane translocons of the chloroplast

1. Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses

Reward drives motivated behaviours and is essential for survival, and therefore there is strong evolutionary pressure to retain contextual information about rewarding stimuli. This drive may be abnormally strong, such as in addiction, or weak, such as in depression, in which anhedonia (loss of pleasure in response to rewarding stimuli) is a prominent symptom. Hippocampal input to the shell of the nucleus accumbens (NAc) is important for driving NAc activity and activity-dependent modulation of the strength of this input may contribute to the proper regulation of goal-directed behaviours. However, there have been few robust descriptions of the mechanisms that underlie the induction or expression of long-term potentiation (LTP) at these synapses, and there is, to our knowledge, no evidence about whether such plasticity contributes to reward-related behaviour. Here Tara A. LeGates at University of Maryland School of Medicine in Baltimore, USA and his colleagues show that high-frequency activity induces LTP at hippocampus–NAc synapses in mice via canonical, but dopamine-independent, mechanisms. The induction of LTP at this synapse in vivo drives conditioned place preference, and activity at this synapse is required for conditioned place preference in response to a natural reward. Conversely, chronic stress, which induces anhedonia, decreases the strength of this synapse and impairs LTP, whereas antidepressant treatment is accompanied by a reversal of these stress-induced changes. They conclude that hippocampus–NAc synapses show activity-dependent plasticity and suggest that their strength may be critical for contextual reward behaviour.

Read more, please click https://www.nature.com/articles/s41586-018-0740-8

2. Somatic APP gene recombination in Alzheimer’s disease and normal neurons

The diversity and complexity of the human brain are widely assumed to be encoded within a constant genome. Somatic gene recombination, which changes germline DNA sequences to increase molecular diversity, could theoretically alter this code but has not been documented in the brain, to our knowledge. Here Ming-Hsiang Lee at Sanford Burnham Prebys Medical Discovery Institute in La Jolla, USA and his colleagues describe recombination of the Alzheimer’s disease-related gene APP, which encodes amyloid precursor protein, in human neurons, occurring mosaically as thousands of variant ‘genomic cDNAs’ (gencDNAs). gencDNAs lacked introns and ranged from full-length cDNA copies of expressed, brain-specific RNA splice variants to myriad smaller forms that contained intra-exonic junctions, insertions, deletions, and/or single nucleotide variations. DNA in situ hybridization identified gencDNAs within single neurons that were distinct from wild-type loci and absent from non-neuronal cells. Mechanistic studies supported neuronal ‘retro-insertion’ of RNA to produce gencDNAs; this process involved transcription, DNA breaks, reverse transcriptase activity, and age. Neurons from individuals with sporadic Alzheimer’s disease showed increased gencDNA diversity, including eleven mutations known to be associated with familial Alzheimer’s disease that were absent from healthy neurons. Neuronal gene recombination may allow ‘recording’ of neural activity for selective ‘playback’ of preferred gene variants whose expression bypasses splicing; this has implications for cellular diversity, learning and memory, plasticity, and diseases of the human brain.

Read more, please click https://www.nature.com/articles/s41586-018-0718-6

3. Distinct activity-gated pathways mediate attraction and aversion to CO2 in Drosophila

Carbon dioxide is produced by many organic processes and is a convenient volatile cue for insects that are searching for blood hosts, flowers, communal nests, fruit and wildfires. Although Drosophila melanogaster feed on yeast that produce CO2 and ethanol during fermentation, laboratory experiments suggest that walking flies avoid CO2. Here Floris van Breugel at California Institute of Technology in Pasadena, USA and his colleagues resolve this paradox by showing that both flying and walking Drosophila find CO2 attractive, but only when they are in an active state associated with foraging. Their aversion to CO2 at low-activity levels may be an adaptation to avoid parasites that seek CO2, or to avoid succumbing to respiratory acidosis in the presence of high concentrations of CO2 that exist in nature. In contrast to CO2, flies are attracted to ethanol in all behavioural states, and invest twice the time searching near ethanol compared to CO2. These behavioural differences reflect the fact that ethanol is a unique signature of yeast fermentation, whereas CO2 is generated by many natural processes. Using genetic tools, they determined that the evolutionarily conserved ionotropic co-receptor IR25a is required for CO2 attraction, and that the receptors necessary for CO2 avoidance are not involved in this attraction. Their study lays the foundation for future research to determine the neural circuits that underlie both state- and odorant-dependent decision-making in Drosophila.

Read more, please click https://www.nature.com/articles/s41586-018-0732-8

4. Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release

Development and routine tissue homeostasis require a high turnover of apoptotic cells. These cells are removed by professional and non-professional phagocytes via efferocytosis. How a phagocyte maintains its homeostasis while coordinating corpse uptake, processing ingested materials and secreting anti-inflammatory mediators is incompletely understood. Here, using RNA sequencing to characterize the transcriptional program of phagocytes actively engulfing apoptotic cells, Sho Morioka at University of Virginia in Charlottesville, USA and his colleagues identify a genetic signature involving 33 members of the solute carrier (SLC) family of membrane transport proteins, in which expression is specifically modulated during efferocytosis, but not during antibody-mediated phagocytosis. They assessed the functional relevance of these SLCs in efferocytic phagocytes and observed a robust induction of an aerobic glycolysis program, initiated by SLC2A1-mediated glucose uptake, with concurrent suppression of the oxidative phosphorylation program. The different steps of phagocytosis—that is, ‘smell’ (‘find-me’ signals or sensing factors released by apoptotic cells), ‘taste’ (phagocyte–apoptotic cell contact) and ‘ingestion’ (corpse internalization)—activated distinct and overlapping sets of genes, including several SLC genes, to promote glycolysis. SLC16A1 was upregulated after corpse uptake, increasing the release of lactate, a natural by-product of aerobic glycolysis. Whereas glycolysis within phagocytes contributed to actin polymerization and the continued uptake of corpses, lactate released via SLC16A1 promoted the establishment of an anti-inflammatory tissue environment. Collectively, these data reveal a SLC program that is activated during efferocytosis, identify a previously unknown reliance on aerobic glycolysis during apoptotic cell uptake and show that glycolytic by-products of efferocytosis can influence surrounding cells.

Read more, please click https://www.nature.com/articles/s41586-018-0735-5

5. TIC236 links the outer and inner membrane translocons of the chloroplast

The two-membrane envelope is a defining feature of chloroplasts. Chloroplasts evolved from a Gram-negative cyanobacterial endosymbiont. During evolution, genes of the endosymbiont have been transferred to the host nuclear genome. Most chloroplast proteins are synthesized in the cytosol as higher-molecular-mass preproteins with an N-terminal transit peptide. Preproteins are transported into chloroplasts by the TOC and TIC (translocons at the outer- and inner-envelope membranes of chloroplasts, respectively) machineries, but how TOC and TIC are assembled together is unknown. Here Yih-Lin Chen at Academia Sinica in Taipei, Taiwan and his colleagues report the identification of the TIC component TIC236; TIC236 is an integral inner-membrane protein that projects a 230-kDa domain into the intermembrane space, which binds directly to the outer-membrane channel TOC75. The knockout mutation of TIC236 is embryonically lethal. In TIC236-knockdown mutants, a smaller amount of the inner-membrane channel TIC20 was associated with TOC75; the amount of TOC–TIC supercomplexes was also reduced. This resulted in a reduced import rate into the stroma, though outer-membrane protein insertion was unaffected. The size and the essential nature of TIC236 indicate that—unlike in mitochondria, in which the outer- and inner-membrane translocons exist as separate complexes and a supercomplex is only transiently assembled during preprotein translocation—a long and stable protein bridge in the intermembrane space is required for protein translocation into chloroplasts. Furthermore, TIC236 and TOC75 are homologues of bacterial inner-membrane TamB5 and outer-membrane BamA, respectively. Their evolutionary analyses show that, similar to TOC75, TIC236 is preserved only in plants and has co-evolved with TOC75 throughout the plant lineage. This suggests that the backbone of the chloroplast protein-import machinery evolved from the bacterial TamB–BamA protein-secretion system.

Read more, please click https://www.nature.com/articles/s41586-018-0713-y

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New Post has been published on http://www.bioadvisers.com/nobel-prize-physiology-medicine-1995/

The Nobel Prize in Physiology or Medicine 1995

The Nobel Prize in Physiology or Medicine 1995 was awarded jointly to Edward B. Lewis, Christiane Nüsslein-Volhard and Eric F. Wieschaus “for their discoveries concerning the genetic control of early embryonic development.”

Nobelist Born Died Affiliation at the time of the award Edward B. Lewis 20 May 1918, Wilkes-Barre, PA, USA 21 July 2004, Pasadena, CA, USA California Institute of Technology (Caltech), Pasadena, CA, USA Christiane Nüsslein-Volhard 20 October 1942, Magdeburg, Germany Max-Planck-Institut für Entwicklungsbiologie, Tübingen, Federal Republic of Germany Eric F. Wieschaus 8 June 1947, South Bend, IN, USA Princeton University, Princeton, NJ, USA

Summary

The 1995 laureates in physiology or medicine are developmental biologists who have discovered important genetic mechanisms which control early embryonic development. They have used the fruit fly, Drosophila melanogaster, as their experimental system. This organism is classical in genetics. The principles found in the fruit fly, apply also to higher organisms including man.

Using Drosophila Nüsslein-Volhard and Wieschaus were able to identify and classify a small number of genes that are of key importance in determining the body plan and the formation of body segments. Lewis investigated how genes could control the further development of individual body segments into specialized organs. He found that the genes were arranged in the same order on the chromosomes as the body segments they controlled. The first genes in a complex of developmental genes controlled the head region, genes in the middle controlled abdominal segments while the last genes controlled the posterior (“tail”) region. Together these three scientists have achieved a breakthrough that will help explain congenital malformations in man.

The fertilized egg is spherical. It divides rapidly to form 2, 4 , 8 cells and so on. Up until the 16-cell stage the early embryo is symmetrical and all cells are equal. Beyond this point, cells begin to specialize and the embryo becomes asymmetrical. Within a week it becomes clear what will form the head and tail regions and what will become the ventral and dorsal sides of the embryo. Somewhat later in development the body of the embryo forms segments and the position of the vertebral column is fixed. The individual segments undergo different development, depending on their position along the “head-tail” axis. Which genes control these events? How many are they? Do they cooperate or do they exert their controlling influence independently of each other? This year’s laureates have answered several of these questions by identifying a series of important genes and how they function to control the formation of the body axis and body segments. They have also discovered genes that determine which organs that will form in individual segments. Although the fruit fly was used as an experimental system, the principles apply also to higher animals and man. Furthermore, genes analogous to those in the fruit fly have been found in man. An important conclusion is that basic genetic mechanisms controlling early development of multicellular organisms have been conserved during evolution for millions of years.

More detailed information at The Nobel Prize in Physiology or Medicine 1995.

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New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/nobel-prize-physiology-medicine-1995/

The Nobel Prize in Physiology or Medicine 1995

The Nobel Prize in Physiology or Medicine 1995 was awarded jointly to Edward B. Lewis, Christiane Nüsslein-Volhard and Eric F. Wieschaus “for their discoveries concerning the genetic control of early embryonic development.”

Nobelist Born Died Affiliation at the time of the award Edward B. Lewis 20 May 1918, Wilkes-Barre, PA, USA 21 July 2004, Pasadena, CA, USA California Institute of Technology (Caltech), Pasadena, CA, USA Christiane Nüsslein-Volhard 20 October 1942, Magdeburg, Germany Max-Planck-Institut für Entwicklungsbiologie, Tübingen, Federal Republic of Germany Eric F. Wieschaus 8 June 1947, South Bend, IN, USA Princeton University, Princeton, NJ, USA

Summary

The 1995 laureates in physiology or medicine are developmental biologists who have discovered important genetic mechanisms which control early embryonic development. They have used the fruit fly, Drosophila melanogaster, as their experimental system. This organism is classical in genetics. The principles found in the fruit fly, apply also to higher organisms including man.

Using Drosophila Nüsslein-Volhard and Wieschaus were able to identify and classify a small number of genes that are of key importance in determining the body plan and the formation of body segments. Lewis investigated how genes could control the further development of individual body segments into specialized organs. He found that the genes were arranged in the same order on the chromosomes as the body segments they controlled. The first genes in a complex of developmental genes controlled the head region, genes in the middle controlled abdominal segments while the last genes controlled the posterior (“tail”) region. Together these three scientists have achieved a breakthrough that will help explain congenital malformations in man.

The fertilized egg is spherical. It divides rapidly to form 2, 4 , 8 cells and so on. Up until the 16-cell stage the early embryo is symmetrical and all cells are equal. Beyond this point, cells begin to specialize and the embryo becomes asymmetrical. Within a week it becomes clear what will form the head and tail regions and what will become the ventral and dorsal sides of the embryo. Somewhat later in development the body of the embryo forms segments and the position of the vertebral column is fixed. The individual segments undergo different development, depending on their position along the “head-tail” axis. Which genes control these events? How many are they? Do they cooperate or do they exert their controlling influence independently of each other? This year’s laureates have answered several of these questions by identifying a series of important genes and how they function to control the formation of the body axis and body segments. They have also discovered genes that determine which organs that will form in individual segments. Although the fruit fly was used as an experimental system, the principles apply also to higher animals and man. Furthermore, genes analogous to those in the fruit fly have been found in man. An important conclusion is that basic genetic mechanisms controlling early development of multicellular organisms have been conserved during evolution for millions of years.

More detailed information at The Nobel Prize in Physiology or Medicine 1995.

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New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/nobel-prize-physiology-medicine-1995/

The Nobel Prize in Physiology or Medicine 1995

The Nobel Prize in Physiology or Medicine 1995 was awarded jointly to Edward B. Lewis, Christiane Nüsslein-Volhard and Eric F. Wieschaus “for their discoveries concerning the genetic control of early embryonic development.”

Nobelist Born Died Affiliation at the time of the award Edward B. Lewis 20 May 1918, Wilkes-Barre, PA, USA 21 July 2004, Pasadena, CA, USA California Institute of Technology (Caltech), Pasadena, CA, USA Christiane Nüsslein-Volhard 20 October 1942, Magdeburg, Germany Max-Planck-Institut für Entwicklungsbiologie, Tübingen, Federal Republic of Germany Eric F. Wieschaus 8 June 1947, South Bend, IN, USA Princeton University, Princeton, NJ, USA

Summary

The 1995 laureates in physiology or medicine are developmental biologists who have discovered important genetic mechanisms which control early embryonic development. They have used the fruit fly, Drosophila melanogaster, as their experimental system. This organism is classical in genetics. The principles found in the fruit fly, apply also to higher organisms including man.

Using Drosophila Nüsslein-Volhard and Wieschaus were able to identify and classify a small number of genes that are of key importance in determining the body plan and the formation of body segments. Lewis investigated how genes could control the further development of individual body segments into specialized organs. He found that the genes were arranged in the same order on the chromosomes as the body segments they controlled. The first genes in a complex of developmental genes controlled the head region, genes in the middle controlled abdominal segments while the last genes controlled the posterior (“tail”) region. Together these three scientists have achieved a breakthrough that will help explain congenital malformations in man.

The fertilized egg is spherical. It divides rapidly to form 2, 4 , 8 cells and so on. Up until the 16-cell stage the early embryo is symmetrical and all cells are equal. Beyond this point, cells begin to specialize and the embryo becomes asymmetrical. Within a week it becomes clear what will form the head and tail regions and what will become the ventral and dorsal sides of the embryo. Somewhat later in development the body of the embryo forms segments and the position of the vertebral column is fixed. The individual segments undergo different development, depending on their position along the “head-tail” axis. Which genes control these events? How many are they? Do they cooperate or do they exert their controlling influence independently of each other? This year’s laureates have answered several of these questions by identifying a series of important genes and how they function to control the formation of the body axis and body segments. They have also discovered genes that determine which organs that will form in individual segments. Although the fruit fly was used as an experimental system, the principles apply also to higher animals and man. Furthermore, genes analogous to those in the fruit fly have been found in man. An important conclusion is that basic genetic mechanisms controlling early development of multicellular organisms have been conserved during evolution for millions of years.

More detailed information at The Nobel Prize in Physiology or Medicine 1995.

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New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/nobel-prize-physiology-medicine-1995/

The Nobel Prize in Physiology or Medicine 1995

The Nobel Prize in Physiology or Medicine 1995 was awarded jointly to Edward B. Lewis, Christiane Nüsslein-Volhard and Eric F. Wieschaus “for their discoveries concerning the genetic control of early embryonic development.”

Nobelist Born Died Affiliation at the time of the award Edward B. Lewis 20 May 1918, Wilkes-Barre, PA, USA 21 July 2004, Pasadena, CA, USA California Institute of Technology (Caltech), Pasadena, CA, USA Christiane Nüsslein-Volhard 20 October 1942, Magdeburg, Germany Max-Planck-Institut für Entwicklungsbiologie, Tübingen, Federal Republic of Germany Eric F. Wieschaus 8 June 1947, South Bend, IN, USA Princeton University, Princeton, NJ, USA

Summary

The 1995 laureates in physiology or medicine are developmental biologists who have discovered important genetic mechanisms which control early embryonic development. They have used the fruit fly, Drosophila melanogaster, as their experimental system. This organism is classical in genetics. The principles found in the fruit fly, apply also to higher organisms including man.

Using Drosophila Nüsslein-Volhard and Wieschaus were able to identify and classify a small number of genes that are of key importance in determining the body plan and the formation of body segments. Lewis investigated how genes could control the further development of individual body segments into specialized organs. He found that the genes were arranged in the same order on the chromosomes as the body segments they controlled. The first genes in a complex of developmental genes controlled the head region, genes in the middle controlled abdominal segments while the last genes controlled the posterior (“tail”) region. Together these three scientists have achieved a breakthrough that will help explain congenital malformations in man.

The fertilized egg is spherical. It divides rapidly to form 2, 4 , 8 cells and so on. Up until the 16-cell stage the early embryo is symmetrical and all cells are equal. Beyond this point, cells begin to specialize and the embryo becomes asymmetrical. Within a week it becomes clear what will form the head and tail regions and what will become the ventral and dorsal sides of the embryo. Somewhat later in development the body of the embryo forms segments and the position of the vertebral column is fixed. The individual segments undergo different development, depending on their position along the “head-tail” axis. Which genes control these events? How many are they? Do they cooperate or do they exert their controlling influence independently of each other? This year’s laureates have answered several of these questions by identifying a series of important genes and how they function to control the formation of the body axis and body segments. They have also discovered genes that determine which organs that will form in individual segments. Although the fruit fly was used as an experimental system, the principles apply also to higher animals and man. Furthermore, genes analogous to those in the fruit fly have been found in man. An important conclusion is that basic genetic mechanisms controlling early development of multicellular organisms have been conserved during evolution for millions of years.

More detailed information at The Nobel Prize in Physiology or Medicine 1995.

[abbkineeu]

New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/nobel-prize-physiology-medicine-1995/

The Nobel Prize in Physiology or Medicine 1995

The Nobel Prize in Physiology or Medicine 1995 was awarded jointly to Edward B. Lewis, Christiane Nüsslein-Volhard and Eric F. Wieschaus “for their discoveries concerning the genetic control of early embryonic development.”

Nobelist Born Died Affiliation at the time of the award Edward B. Lewis 20 May 1918, Wilkes-Barre, PA, USA 21 July 2004, Pasadena, CA, USA California Institute of Technology (Caltech), Pasadena, CA, USA Christiane Nüsslein-Volhard 20 October 1942, Magdeburg, Germany Max-Planck-Institut für Entwicklungsbiologie, Tübingen, Federal Republic of Germany Eric F. Wieschaus 8 June 1947, South Bend, IN, USA Princeton University, Princeton, NJ, USA

Summary

The 1995 laureates in physiology or medicine are developmental biologists who have discovered important genetic mechanisms which control early embryonic development. They have used the fruit fly, Drosophila melanogaster, as their experimental system. This organism is classical in genetics. The principles found in the fruit fly, apply also to higher organisms including man.

Using Drosophila Nüsslein-Volhard and Wieschaus were able to identify and classify a small number of genes that are of key importance in determining the body plan and the formation of body segments. Lewis investigated how genes could control the further development of individual body segments into specialized organs. He found that the genes were arranged in the same order on the chromosomes as the body segments they controlled. The first genes in a complex of developmental genes controlled the head region, genes in the middle controlled abdominal segments while the last genes controlled the posterior (“tail”) region. Together these three scientists have achieved a breakthrough that will help explain congenital malformations in man.

The fertilized egg is spherical. It divides rapidly to form 2, 4 , 8 cells and so on. Up until the 16-cell stage the early embryo is symmetrical and all cells are equal. Beyond this point, cells begin to specialize and the embryo becomes asymmetrical. Within a week it becomes clear what will form the head and tail regions and what will become the ventral and dorsal sides of the embryo. Somewhat later in development the body of the embryo forms segments and the position of the vertebral column is fixed. The individual segments undergo different development, depending on their position along the “head-tail” axis. Which genes control these events? How many are they? Do they cooperate or do they exert their controlling influence independently of each other? This year’s laureates have answered several of these questions by identifying a series of important genes and how they function to control the formation of the body axis and body segments. They have also discovered genes that determine which organs that will form in individual segments. Although the fruit fly was used as an experimental system, the principles apply also to higher animals and man. Furthermore, genes analogous to those in the fruit fly have been found in man. An important conclusion is that basic genetic mechanisms controlling early development of multicellular organisms have been conserved during evolution for millions of years.

More detailed information at The Nobel Prize in Physiology or Medicine 1995.

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New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/lung-restricted-inhibition-janus-kinase-1-effective-rodent-models-asthma/

Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma

Content introduction:

Two recombinant human monoclonal antibodies that protect against lethal Andes hantavirus infection in vivo

Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis

Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma

IFN-γ–inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5

The HDAC3–SMARCA4–miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma

1. Two recombinant human monoclonal antibodies that protect against lethal Andes hantavirus infection in vivo

Andes hantavirus (ANDV) is an etiologic agent of hantavirus cardiopulmonary syndrome (HCPS), a severe disease characterized by fever, headache, and gastrointestinal symptoms that may progress to hypotension, pulmonary failure, and cardiac shock that results in a 25 to 40% case-fatality rate. Currently, there is no specific treatment or vaccine; however, several studies have shown that the generation of neutralizing antibody (Ab) responses strongly correlates with survival from HCPS in humans. In this study, Jose L. Garrido at Universidad de Concepción in Concepción, Chile and his colleagues screened 27 ANDV convalescent HCPS patient sera for their capacity to bind and neutralize ANDV in vitro. One patient who showed high neutralizing titer was selected to isolate ANDV–glycoprotein (GP) Abs. ANDV-GP–specific memory B cells were single cell sorted, and recombinant immunoglobulin G antibodies were cloned and produced. Two monoclonal Abs (mAbs), JL16 and MIB22, potently recognized ANDV-GPs and neutralized ANDV. They examined the post-exposure efficacy of these two mAbs as a monotherapy or in combination therapy in a Syrian hamster model of ANDV-induced HCPS, and both mAbs protected 100% of animals from a lethal challenge dose. These data suggest that monotherapy with mAb JL16 or MIB22, or a cocktail of both, could be an effective post-exposure treatment for patients infected with ANDV-induced HCPS.

Read more, please click http://stm.sciencemag.org/content/10/468/eaat6420

2. Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis

Fibrosis is the major determinant of morbidity and mortality in patients with nonalcoholic steatohepatitis (NASH) but has no approved pharmacotherapy in part because of incomplete understanding of its pathogenic mechanisms. Here, Changyu Zhu at Columbia University in New York, USA and his colleagues report that hepatocyte Notch activity tracks with disease severity and treatment response in patients with NASH and is similarly increased in a mouse model of diet-induced NASH and liver fibrosis. Hepatocyte-specific Notch loss-of-function mouse models showed attenuated NASH-associated liver fibrosis, demonstrating causality to obesity-induced liver pathology. Conversely, forced activation of hepatocyte Notch induced fibrosis in both chow- and NASH diet–fed mice by increasing Sox9-dependent Osteopontin (Opn) expression and secretion from hepatocytes, which activate resident hepatic stellate cells. In a cross-sectional study, they found that OPN explains the positive correlation between liver Notch activity and fibrosis stage in patients. Further, they developed a Notch inhibitor [Nicastrin antisense oligonucleotide (Ncst ASO)] that reduced fibrosis in NASH diet–fed mice. In summary, these studies demonstrate the pathological role and therapeutic accessibility of the maladaptive hepatocyte Notch response in NASH-associated liver fibrosis.

Read more, please click http://stm.sciencemag.org/content/10/468/eaat0344

3. Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma

Preclinical and clinical evidence indicates that a subset of asthma is driven by type 2 cytokines such as interleukin-4 (IL-4), IL-5, IL-9, and IL-13. Additional evidence predicts pathogenic roles for IL-6 and type I and type II interferons. Because each of these cytokines depends on Janus kinase 1 (JAK1) for signal transduction, and because many of the asthma-related effects of these cytokines manifest in the lung, Hart S. Dengler at Genentech in South San Francisco, USA and his colleagues hypothesized that lung-restricted JAK1 inhibition may confer therapeutic benefit. To test this idea, they synthesized iJak-381, an inhalable small molecule specifically designed for local JAK1 inhibition in the lung. In pharmacodynamic models, iJak-381 suppressed signal transducer and activator of transcription 6 activation by IL-13. Furthermore, iJak-381 suppressed ovalbumin-induced lung inflammation in both murine and guinea pig asthma models and improved allergen-induced airway hyperresponsiveness in mice. In a model driven by human allergens, iJak-381 had a more potent suppressive effect on neutrophil-driven inflammation compared to systemic corticosteroid administration. The inhibitor iJak-381 reduced lung pathology, without affecting systemic Jak1 activity in rodents. Their data show that local inhibition of Jak1 in the lung can suppress lung inflammation without systemic Jak inhibition in rodents, suggesting that this strategy might be effective for treating asthma.

Read more, please click http://stm.sciencemag.org/content/10/468/eaao2151

4. IFN-γ–inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5

It is well established that activation of the transcription factor signal transducer and activator of transcription 1 (STAT1) is required for the interferon-γ (IFN-γ)–mediated antiviral response. Here, Diana Saleiro at Northwestern University in Chicago, USA and her colleagues found that IFN-γ receptor stimulation also activated Unc-51–like kinase 1 (ULK1), an initiator of Beclin-1–mediated autophagy. Furthermore, the interaction between ULK1 and the mitogen-activated protein kinase kinase kinase MLK3 (mixed lineage kinase 3) was necessary for MLK3 phosphorylation and downstream activation of the kinase ERK5. This autophagy-independent activity of ULK1 promoted the transcription of key antiviral IFN-stimulated genes (ISGs) and was essential for IFN-γ–dependent antiviral effects. These findings define a previously unknown IFN-γ pathway that appears to be a key element of the antiviral response.

Read more, please click http://stke.sciencemag.org/content/11/557/eaap9921

5. The HDAC3–SMARCA4–miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood with an unmet clinical need for decades. A single oncogenic fusion gene is associated with treatment resistance and a 40 to 45% decrease in overall survival. Narendra Bharathy at Children’s Cancer Therapy Development Institute in Beaverton, USA and his colleagues previously showed that expression of this PAX3:FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemotherapy and radiotherapy and that the class I–specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3:FOXO1 protein abundance. Here, they established the antitumor efficacy of entinostat with chemotherapy in various preclinical cell and mouse models and found that HDAC3 inhibition was the primary mechanism of entinostat-induced suppression of PAX3:FOXO1 abundance. HDAC3 inhibition by entinostat decreased the activity of the chromatin remodeling enzyme SMARCA4, which, in turn, derepressed the microRNA miR-27a. This reexpression of miR-27a led to PAX3:FOXO1 mRNA destabilization and chemotherapy sensitization in aRMS cells in culture and in vivo. Furthermore, a phase 1 clinical trial (ADVL1513) has shown that entinostat is tolerable in children with relapsed or refractory solid tumors and is planned for phase 1B cohort expansion or phase 2 clinical trials. Together, these results implicate an HDAC3–SMARCA4–miR-27a–PAX3:FOXO1 circuit as a driver of chemoresistant aRMS and suggest that targeting this pathway with entinostat may be therapeutically effective in patients.

Read more, please click http://stke.sciencemag.org/content/11/557/eaau7632

[abbkineeu]

New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/lung-restricted-inhibition-janus-kinase-1-effective-rodent-models-asthma/

Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma

Content introduction:

Two recombinant human monoclonal antibodies that protect against lethal Andes hantavirus infection in vivo

Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis

Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma

IFN-γ–inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5

The HDAC3–SMARCA4–miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma

1. Two recombinant human monoclonal antibodies that protect against lethal Andes hantavirus infection in vivo

Andes hantavirus (ANDV) is an etiologic agent of hantavirus cardiopulmonary syndrome (HCPS), a severe disease characterized by fever, headache, and gastrointestinal symptoms that may progress to hypotension, pulmonary failure, and cardiac shock that results in a 25 to 40% case-fatality rate. Currently, there is no specific treatment or vaccine; however, several studies have shown that the generation of neutralizing antibody (Ab) responses strongly correlates with survival from HCPS in humans. In this study, Jose L. Garrido at Universidad de Concepción in Concepción, Chile and his colleagues screened 27 ANDV convalescent HCPS patient sera for their capacity to bind and neutralize ANDV in vitro. One patient who showed high neutralizing titer was selected to isolate ANDV–glycoprotein (GP) Abs. ANDV-GP–specific memory B cells were single cell sorted, and recombinant immunoglobulin G antibodies were cloned and produced. Two monoclonal Abs (mAbs), JL16 and MIB22, potently recognized ANDV-GPs and neutralized ANDV. They examined the post-exposure efficacy of these two mAbs as a monotherapy or in combination therapy in a Syrian hamster model of ANDV-induced HCPS, and both mAbs protected 100% of animals from a lethal challenge dose. These data suggest that monotherapy with mAb JL16 or MIB22, or a cocktail of both, could be an effective post-exposure treatment for patients infected with ANDV-induced HCPS.

Read more, please click http://stm.sciencemag.org/content/10/468/eaat6420

2. Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis

Fibrosis is the major determinant of morbidity and mortality in patients with nonalcoholic steatohepatitis (NASH) but has no approved pharmacotherapy in part because of incomplete understanding of its pathogenic mechanisms. Here, Changyu Zhu at Columbia University in New York, USA and his colleagues report that hepatocyte Notch activity tracks with disease severity and treatment response in patients with NASH and is similarly increased in a mouse model of diet-induced NASH and liver fibrosis. Hepatocyte-specific Notch loss-of-function mouse models showed attenuated NASH-associated liver fibrosis, demonstrating causality to obesity-induced liver pathology. Conversely, forced activation of hepatocyte Notch induced fibrosis in both chow- and NASH diet–fed mice by increasing Sox9-dependent Osteopontin (Opn) expression and secretion from hepatocytes, which activate resident hepatic stellate cells. In a cross-sectional study, they found that OPN explains the positive correlation between liver Notch activity and fibrosis stage in patients. Further, they developed a Notch inhibitor [Nicastrin antisense oligonucleotide (Ncst ASO)] that reduced fibrosis in NASH diet–fed mice. In summary, these studies demonstrate the pathological role and therapeutic accessibility of the maladaptive hepatocyte Notch response in NASH-associated liver fibrosis.

Read more, please click http://stm.sciencemag.org/content/10/468/eaat0344

3. Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma

Preclinical and clinical evidence indicates that a subset of asthma is driven by type 2 cytokines such as interleukin-4 (IL-4), IL-5, IL-9, and IL-13. Additional evidence predicts pathogenic roles for IL-6 and type I and type II interferons. Because each of these cytokines depends on Janus kinase 1 (JAK1) for signal transduction, and because many of the asthma-related effects of these cytokines manifest in the lung, Hart S. Dengler at Genentech in South San Francisco, USA and his colleagues hypothesized that lung-restricted JAK1 inhibition may confer therapeutic benefit. To test this idea, they synthesized iJak-381, an inhalable small molecule specifically designed for local JAK1 inhibition in the lung. In pharmacodynamic models, iJak-381 suppressed signal transducer and activator of transcription 6 activation by IL-13. Furthermore, iJak-381 suppressed ovalbumin-induced lung inflammation in both murine and guinea pig asthma models and improved allergen-induced airway hyperresponsiveness in mice. In a model driven by human allergens, iJak-381 had a more potent suppressive effect on neutrophil-driven inflammation compared to systemic corticosteroid administration. The inhibitor iJak-381 reduced lung pathology, without affecting systemic Jak1 activity in rodents. Their data show that local inhibition of Jak1 in the lung can suppress lung inflammation without systemic Jak inhibition in rodents, suggesting that this strategy might be effective for treating asthma.

Read more, please click http://stm.sciencemag.org/content/10/468/eaao2151

4. IFN-γ–inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5

It is well established that activation of the transcription factor signal transducer and activator of transcription 1 (STAT1) is required for the interferon-γ (IFN-γ)–mediated antiviral response. Here, Diana Saleiro at Northwestern University in Chicago, USA and her colleagues found that IFN-γ receptor stimulation also activated Unc-51–like kinase 1 (ULK1), an initiator of Beclin-1–mediated autophagy. Furthermore, the interaction between ULK1 and the mitogen-activated protein kinase kinase kinase MLK3 (mixed lineage kinase 3) was necessary for MLK3 phosphorylation and downstream activation of the kinase ERK5. This autophagy-independent activity of ULK1 promoted the transcription of key antiviral IFN-stimulated genes (ISGs) and was essential for IFN-γ–dependent antiviral effects. These findings define a previously unknown IFN-γ pathway that appears to be a key element of the antiviral response.

Read more, please click http://stke.sciencemag.org/content/11/557/eaap9921

5. The HDAC3–SMARCA4–miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood with an unmet clinical need for decades. A single oncogenic fusion gene is associated with treatment resistance and a 40 to 45% decrease in overall survival. Narendra Bharathy at Children’s Cancer Therapy Development Institute in Beaverton, USA and his colleagues previously showed that expression of this PAX3:FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemotherapy and radiotherapy and that the class I–specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3:FOXO1 protein abundance. Here, they established the antitumor efficacy of entinostat with chemotherapy in various preclinical cell and mouse models and found that HDAC3 inhibition was the primary mechanism of entinostat-induced suppression of PAX3:FOXO1 abundance. HDAC3 inhibition by entinostat decreased the activity of the chromatin remodeling enzyme SMARCA4, which, in turn, derepressed the microRNA miR-27a. This reexpression of miR-27a led to PAX3:FOXO1 mRNA destabilization and chemotherapy sensitization in aRMS cells in culture and in vivo. Furthermore, a phase 1 clinical trial (ADVL1513) has shown that entinostat is tolerable in children with relapsed or refractory solid tumors and is planned for phase 1B cohort expansion or phase 2 clinical trials. Together, these results implicate an HDAC3–SMARCA4–miR-27a–PAX3:FOXO1 circuit as a driver of chemoresistant aRMS and suggest that targeting this pathway with entinostat may be therapeutically effective in patients.

Read more, please click http://stke.sciencemag.org/content/11/557/eaau7632

[abbkineeu]

New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/lung-restricted-inhibition-janus-kinase-1-effective-rodent-models-asthma/

Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma

Content introduction:

Two recombinant human monoclonal antibodies that protect against lethal Andes hantavirus infection in vivo

Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis

Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma

IFN-γ–inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5

The HDAC3–SMARCA4–miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma

1. Two recombinant human monoclonal antibodies that protect against lethal Andes hantavirus infection in vivo

Andes hantavirus (ANDV) is an etiologic agent of hantavirus cardiopulmonary syndrome (HCPS), a severe disease characterized by fever, headache, and gastrointestinal symptoms that may progress to hypotension, pulmonary failure, and cardiac shock that results in a 25 to 40% case-fatality rate. Currently, there is no specific treatment or vaccine; however, several studies have shown that the generation of neutralizing antibody (Ab) responses strongly correlates with survival from HCPS in humans. In this study, Jose L. Garrido at Universidad de Concepción in Concepción, Chile and his colleagues screened 27 ANDV convalescent HCPS patient sera for their capacity to bind and neutralize ANDV in vitro. One patient who showed high neutralizing titer was selected to isolate ANDV–glycoprotein (GP) Abs. ANDV-GP–specific memory B cells were single cell sorted, and recombinant immunoglobulin G antibodies were cloned and produced. Two monoclonal Abs (mAbs), JL16 and MIB22, potently recognized ANDV-GPs and neutralized ANDV. They examined the post-exposure efficacy of these two mAbs as a monotherapy or in combination therapy in a Syrian hamster model of ANDV-induced HCPS, and both mAbs protected 100% of animals from a lethal challenge dose. These data suggest that monotherapy with mAb JL16 or MIB22, or a cocktail of both, could be an effective post-exposure treatment for patients infected with ANDV-induced HCPS.

Read more, please click http://stm.sciencemag.org/content/10/468/eaat6420

2. Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis

Fibrosis is the major determinant of morbidity and mortality in patients with nonalcoholic steatohepatitis (NASH) but has no approved pharmacotherapy in part because of incomplete understanding of its pathogenic mechanisms. Here, Changyu Zhu at Columbia University in New York, USA and his colleagues report that hepatocyte Notch activity tracks with disease severity and treatment response in patients with NASH and is similarly increased in a mouse model of diet-induced NASH and liver fibrosis. Hepatocyte-specific Notch loss-of-function mouse models showed attenuated NASH-associated liver fibrosis, demonstrating causality to obesity-induced liver pathology. Conversely, forced activation of hepatocyte Notch induced fibrosis in both chow- and NASH diet–fed mice by increasing Sox9-dependent Osteopontin (Opn) expression and secretion from hepatocytes, which activate resident hepatic stellate cells. In a cross-sectional study, they found that OPN explains the positive correlation between liver Notch activity and fibrosis stage in patients. Further, they developed a Notch inhibitor [Nicastrin antisense oligonucleotide (Ncst ASO)] that reduced fibrosis in NASH diet–fed mice. In summary, these studies demonstrate the pathological role and therapeutic accessibility of the maladaptive hepatocyte Notch response in NASH-associated liver fibrosis.

Read more, please click http://stm.sciencemag.org/content/10/468/eaat0344

3. Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma

Preclinical and clinical evidence indicates that a subset of asthma is driven by type 2 cytokines such as interleukin-4 (IL-4), IL-5, IL-9, and IL-13. Additional evidence predicts pathogenic roles for IL-6 and type I and type II interferons. Because each of these cytokines depends on Janus kinase 1 (JAK1) for signal transduction, and because many of the asthma-related effects of these cytokines manifest in the lung, Hart S. Dengler at Genentech in South San Francisco, USA and his colleagues hypothesized that lung-restricted JAK1 inhibition may confer therapeutic benefit. To test this idea, they synthesized iJak-381, an inhalable small molecule specifically designed for local JAK1 inhibition in the lung. In pharmacodynamic models, iJak-381 suppressed signal transducer and activator of transcription 6 activation by IL-13. Furthermore, iJak-381 suppressed ovalbumin-induced lung inflammation in both murine and guinea pig asthma models and improved allergen-induced airway hyperresponsiveness in mice. In a model driven by human allergens, iJak-381 had a more potent suppressive effect on neutrophil-driven inflammation compared to systemic corticosteroid administration. The inhibitor iJak-381 reduced lung pathology, without affecting systemic Jak1 activity in rodents. Their data show that local inhibition of Jak1 in the lung can suppress lung inflammation without systemic Jak inhibition in rodents, suggesting that this strategy might be effective for treating asthma.

Read more, please click http://stm.sciencemag.org/content/10/468/eaao2151

4. IFN-γ–inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5

It is well established that activation of the transcription factor signal transducer and activator of transcription 1 (STAT1) is required for the interferon-γ (IFN-γ)–mediated antiviral response. Here, Diana Saleiro at Northwestern University in Chicago, USA and her colleagues found that IFN-γ receptor stimulation also activated Unc-51–like kinase 1 (ULK1), an initiator of Beclin-1–mediated autophagy. Furthermore, the interaction between ULK1 and the mitogen-activated protein kinase kinase kinase MLK3 (mixed lineage kinase 3) was necessary for MLK3 phosphorylation and downstream activation of the kinase ERK5. This autophagy-independent activity of ULK1 promoted the transcription of key antiviral IFN-stimulated genes (ISGs) and was essential for IFN-γ–dependent antiviral effects. These findings define a previously unknown IFN-γ pathway that appears to be a key element of the antiviral response.

Read more, please click http://stke.sciencemag.org/content/11/557/eaap9921

5. The HDAC3–SMARCA4–miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood with an unmet clinical need for decades. A single oncogenic fusion gene is associated with treatment resistance and a 40 to 45% decrease in overall survival. Narendra Bharathy at Children’s Cancer Therapy Development Institute in Beaverton, USA and his colleagues previously showed that expression of this PAX3:FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemotherapy and radiotherapy and that the class I–specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3:FOXO1 protein abundance. Here, they established the antitumor efficacy of entinostat with chemotherapy in various preclinical cell and mouse models and found that HDAC3 inhibition was the primary mechanism of entinostat-induced suppression of PAX3:FOXO1 abundance. HDAC3 inhibition by entinostat decreased the activity of the chromatin remodeling enzyme SMARCA4, which, in turn, derepressed the microRNA miR-27a. This reexpression of miR-27a led to PAX3:FOXO1 mRNA destabilization and chemotherapy sensitization in aRMS cells in culture and in vivo. Furthermore, a phase 1 clinical trial (ADVL1513) has shown that entinostat is tolerable in children with relapsed or refractory solid tumors and is planned for phase 1B cohort expansion or phase 2 clinical trials. Together, these results implicate an HDAC3–SMARCA4–miR-27a–PAX3:FOXO1 circuit as a driver of chemoresistant aRMS and suggest that targeting this pathway with entinostat may be therapeutically effective in patients.

Read more, please click http://stke.sciencemag.org/content/11/557/eaau7632

[abbkineeu]

New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/lung-restricted-inhibition-janus-kinase-1-effective-rodent-models-asthma/

Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma

Content introduction:

Two recombinant human monoclonal antibodies that protect against lethal Andes hantavirus infection in vivo

Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis

Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma

IFN-γ–inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5

The HDAC3–SMARCA4–miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma

1. Two recombinant human monoclonal antibodies that protect against lethal Andes hantavirus infection in vivo

Andes hantavirus (ANDV) is an etiologic agent of hantavirus cardiopulmonary syndrome (HCPS), a severe disease characterized by fever, headache, and gastrointestinal symptoms that may progress to hypotension, pulmonary failure, and cardiac shock that results in a 25 to 40% case-fatality rate. Currently, there is no specific treatment or vaccine; however, several studies have shown that the generation of neutralizing antibody (Ab) responses strongly correlates with survival from HCPS in humans. In this study, Jose L. Garrido at Universidad de Concepción in Concepción, Chile and his colleagues screened 27 ANDV convalescent HCPS patient sera for their capacity to bind and neutralize ANDV in vitro. One patient who showed high neutralizing titer was selected to isolate ANDV–glycoprotein (GP) Abs. ANDV-GP–specific memory B cells were single cell sorted, and recombinant immunoglobulin G antibodies were cloned and produced. Two monoclonal Abs (mAbs), JL16 and MIB22, potently recognized ANDV-GPs and neutralized ANDV. They examined the post-exposure efficacy of these two mAbs as a monotherapy or in combination therapy in a Syrian hamster model of ANDV-induced HCPS, and both mAbs protected 100% of animals from a lethal challenge dose. These data suggest that monotherapy with mAb JL16 or MIB22, or a cocktail of both, could be an effective post-exposure treatment for patients infected with ANDV-induced HCPS.

Read more, please click http://stm.sciencemag.org/content/10/468/eaat6420

2. Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis

Fibrosis is the major determinant of morbidity and mortality in patients with nonalcoholic steatohepatitis (NASH) but has no approved pharmacotherapy in part because of incomplete understanding of its pathogenic mechanisms. Here, Changyu Zhu at Columbia University in New York, USA and his colleagues report that hepatocyte Notch activity tracks with disease severity and treatment response in patients with NASH and is similarly increased in a mouse model of diet-induced NASH and liver fibrosis. Hepatocyte-specific Notch loss-of-function mouse models showed attenuated NASH-associated liver fibrosis, demonstrating causality to obesity-induced liver pathology. Conversely, forced activation of hepatocyte Notch induced fibrosis in both chow- and NASH diet–fed mice by increasing Sox9-dependent Osteopontin (Opn) expression and secretion from hepatocytes, which activate resident hepatic stellate cells. In a cross-sectional study, they found that OPN explains the positive correlation between liver Notch activity and fibrosis stage in patients. Further, they developed a Notch inhibitor [Nicastrin antisense oligonucleotide (Ncst ASO)] that reduced fibrosis in NASH diet–fed mice. In summary, these studies demonstrate the pathological role and therapeutic accessibility of the maladaptive hepatocyte Notch response in NASH-associated liver fibrosis.

Read more, please click http://stm.sciencemag.org/content/10/468/eaat0344

3. Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma

Preclinical and clinical evidence indicates that a subset of asthma is driven by type 2 cytokines such as interleukin-4 (IL-4), IL-5, IL-9, and IL-13. Additional evidence predicts pathogenic roles for IL-6 and type I and type II interferons. Because each of these cytokines depends on Janus kinase 1 (JAK1) for signal transduction, and because many of the asthma-related effects of these cytokines manifest in the lung, Hart S. Dengler at Genentech in South San Francisco, USA and his colleagues hypothesized that lung-restricted JAK1 inhibition may confer therapeutic benefit. To test this idea, they synthesized iJak-381, an inhalable small molecule specifically designed for local JAK1 inhibition in the lung. In pharmacodynamic models, iJak-381 suppressed signal transducer and activator of transcription 6 activation by IL-13. Furthermore, iJak-381 suppressed ovalbumin-induced lung inflammation in both murine and guinea pig asthma models and improved allergen-induced airway hyperresponsiveness in mice. In a model driven by human allergens, iJak-381 had a more potent suppressive effect on neutrophil-driven inflammation compared to systemic corticosteroid administration. The inhibitor iJak-381 reduced lung pathology, without affecting systemic Jak1 activity in rodents. Their data show that local inhibition of Jak1 in the lung can suppress lung inflammation without systemic Jak inhibition in rodents, suggesting that this strategy might be effective for treating asthma.

Read more, please click http://stm.sciencemag.org/content/10/468/eaao2151

4. IFN-γ–inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5

It is well established that activation of the transcription factor signal transducer and activator of transcription 1 (STAT1) is required for the interferon-γ (IFN-γ)–mediated antiviral response. Here, Diana Saleiro at Northwestern University in Chicago, USA and her colleagues found that IFN-γ receptor stimulation also activated Unc-51–like kinase 1 (ULK1), an initiator of Beclin-1–mediated autophagy. Furthermore, the interaction between ULK1 and the mitogen-activated protein kinase kinase kinase MLK3 (mixed lineage kinase 3) was necessary for MLK3 phosphorylation and downstream activation of the kinase ERK5. This autophagy-independent activity of ULK1 promoted the transcription of key antiviral IFN-stimulated genes (ISGs) and was essential for IFN-γ–dependent antiviral effects. These findings define a previously unknown IFN-γ pathway that appears to be a key element of the antiviral response.

Read more, please click http://stke.sciencemag.org/content/11/557/eaap9921

5. The HDAC3–SMARCA4–miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood with an unmet clinical need for decades. A single oncogenic fusion gene is associated with treatment resistance and a 40 to 45% decrease in overall survival. Narendra Bharathy at Children’s Cancer Therapy Development Institute in Beaverton, USA and his colleagues previously showed that expression of this PAX3:FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemotherapy and radiotherapy and that the class I–specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3:FOXO1 protein abundance. Here, they established the antitumor efficacy of entinostat with chemotherapy in various preclinical cell and mouse models and found that HDAC3 inhibition was the primary mechanism of entinostat-induced suppression of PAX3:FOXO1 abundance. HDAC3 inhibition by entinostat decreased the activity of the chromatin remodeling enzyme SMARCA4, which, in turn, derepressed the microRNA miR-27a. This reexpression of miR-27a led to PAX3:FOXO1 mRNA destabilization and chemotherapy sensitization in aRMS cells in culture and in vivo. Furthermore, a phase 1 clinical trial (ADVL1513) has shown that entinostat is tolerable in children with relapsed or refractory solid tumors and is planned for phase 1B cohort expansion or phase 2 clinical trials. Together, these results implicate an HDAC3–SMARCA4–miR-27a–PAX3:FOXO1 circuit as a driver of chemoresistant aRMS and suggest that targeting this pathway with entinostat may be therapeutically effective in patients.

Read more, please click http://stke.sciencemag.org/content/11/557/eaau7632