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.

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

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.

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