#sdea

Managing safety across diverse global regions requires a specialized tactical approach to ensure no detail is overlooked. This includes specialized Affiliate Management, such as maintaining PV Agreements (SDEAs) and managing vendor and alliance compliance. Robust tactical management—including Drug Safety Coordination and Mailbox Management—ensures that critical safety data is processed efficiently and reported to the correct authorities on time.

Crazy Beat Mixtape 89-93 #oldschool #hiphop #Zaragoza

El domingo 19 de septiembre Aragón Tv emitió en su programa Objetivo un reportaje titulado: La ciudad del Rap. En este reportaje aparece el grupo Crazy Beat, del que forme parte activa durante cuatro años. Nos reunimos 30 años después para salir unos minutos como parte testimonial de los pioneros del hip hop en Zaragoza. Animado por este momento de nostalgia he recopilado una mixtape de la…

Structural basis of ubiquitin modification by the Legionella effector SdeA

Content introduction:

Pyramidal cell regulation of interneuron survival sculpts cortical networks

Cortical direction selectivity emerges at convergence of thalamic synapses

Structural basis of ubiquitin modification by the Legionella effector SdeA

ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase

Structure of a volume-regulated anion channel of the LRRC8 family

1. Pyramidal cell regulation of interneuron survival sculpts cortical networks Complex neuronal circuitries such as those found in the mammalian cerebral cortex have evolved as balanced networks of excitatory and inhibitory neurons. Although the establishment of appropriate numbers of these cells is essential for brain function and behaviour, our understanding of this fundamental process is limited. Here Fong Kuan Wong at King’s College London in London, UK and his colleagues show that the survival of interneurons in mice depends on the activity of pyramidal cells in a critical window of postnatal development, during which excitatory synaptic input to individual interneurons predicts their survival or death. Pyramidal cells regulate interneuron survival through the negative modulation of PTEN signalling, which effectively drives interneuron cell death during this period. Their findings indicate that activity-dependent mechanisms dynamically adjust the number of inhibitory cells in nascent local cortical circuits, ultimately establishing the appropriate proportions of excitatory and inhibitory neurons in the cerebral cortex.

Read more, please click https://www.nature.com/articles/s41586-018-0139-6

2. Cortical direction selectivity emerges at convergence of thalamic synapses Detecting the direction of motion of an object is essential for our representation of the visual environment. The visual cortex is one of the main stages in the mammalian nervous system in which the direction of motion may be computed de novo. Experiments and theories indicate that cortical neurons respond selectively to motion direction by combining inputs that provide information about distinct spatial locations with distinct time delays. Despite the importance of this spatiotemporal offset for direction selectivity, its origin and cellular mechanisms are not fully understood. Anthony D. Lien at University of California San Diego in La Jolla, USA and his colleagues show that approximately 80 ± 10 thalamic neurons, which respond with distinct time courses to stimuli in distinct locations, excite mouse visual cortical neurons during visual stimulation. The integration of thalamic inputs with the appropriate spatiotemporal offset provides cortical neurons with a primordial bias for direction selectivity. These data show how cortical neurons selectively combine the spatiotemporal response diversity of thalamic neurons to extract fundamental features of the visual world.

Read more, please click https://www.nature.com/articles/s41586-018-0148-5

3. Structural basis of ubiquitin modification by the Legionella effector SdeA Protein ubiquitination is a multifaceted post-translational modification that controls almost every process in eukaryotic cells. Recently, the Legionella effector SdeA was reported to mediate a unique phosphoribosyl-linked ubiquitination through successive modifications of the Arg42 of ubiquitin (Ub) by its mono-ADP-ribosyltransferase (mART) and phosphodiesterase (PDE) domains. However, the mechanisms of SdeA-mediated Ub modification and phosphoribosyl-linked ubiquitination remain unknown. Here Yanan Dong at Beijing University of Chemical Technology in Beijing, China and his colleagues report the structures of SdeA in its ligand-free, Ub-bound and Ub–NADH-bound states. The structures reveal that the mART and PDE domains of SdeA form a catalytic domain over its C-terminal region. Upon Ub binding, the canonical ADP-ribosyltransferase toxin turn-turn (ARTT) and phosphate-nicotinamide (PN) loops in the mART domain of SdeA undergo marked conformational changes. The Ub Arg72 might act as a ‘probe’ that interacts with the mART domain first, and then movements may occur in the side chains of Arg72 and Arg42 during the ADP-ribosylation of Ub. Their study reveals the mechanism of SdeA-mediated Ub modification and provides a framework for further investigations into the phosphoribosyl-linked ubiquitination process.

Read more, please click https://www.nature.com/articles/s41586-018-0146-7

4. ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase Editing domains of aminoacyl tRNA synthetases correct tRNA charging errors to maintain translational fidelity. A mutation in the editing domain of alanyl tRNA synthetase (AlaRS) in Aarssti mutant mice results in an increase in the production of serine-mischarged tRNAAla and the degeneration of cerebellar Purkinje cells. Here, using positional cloning, My-Nuong Vo at Scripps Research Institute in La Jolla, USA and his colleagues identified Ankrd16, a gene that acts epistatically with the Aarssti mutation to attenuate neurodegeneration. ANKRD16, a vertebrate-specific protein that contains ankyrin repeats, binds directly to the catalytic domain of AlaRS. Serine that is misactivated by AlaRS is captured by the lysine side chains of ANKRD16, which prevents the charging of serine adenylates to tRNAAla and precludes serine misincorporation in nascent peptides. The deletion of Ankrd16 in the brains of Aarssti/sti mice causes widespread protein aggregation and neuron loss. These results identify an amino-acid-accepting co-regulator of tRNA synthetase editing as a new layer of the machinery that is essential to the prevention of severe pathologies that arise from defects in editing.

Read more, please click https://www.nature.com/articles/s41586-018-0137-8

5. Structure of a volume-regulated anion channel of the LRRC8 family Volume-regulated anion channels are activated in response to hypotonic stress. These channels are composed of closely related paralogues of the leucine-rich repeat-containing protein 8 (LRRC8) family that co-assemble to form hexameric complexes. Here, using cryo-electron microscopy and X-ray crystallography, Dawid Deneka at University of Zurich in Zurich, Switzerland and his colleagues determine the structure of a homomeric channel of the obligatory subunit LRRC8A. This protein conducts ions and has properties in common with endogenous heteromeric channels. Its modular structure consists of a transmembrane pore domain followed by a cytoplasmic leucine-rich repeat domain. The transmembrane domain, which is structurally related to connexin proteins, is wide towards the cytoplasm but constricted on the outside by a structural unit that acts as a selectivity filter. An excess of basic residues in the filter and throughout the pore attracts anions by electrostatic interaction. Their work reveals the previously unknown architecture of volume-regulated anion channels and their mechanism of selective anion conduction.

New Post has been published on http://www.bioadvisers.com/categorybioresearch/

Structural basis of ubiquitin modification by the Legionella effector SdeA

Content introduction:

Pyramidal cell regulation of interneuron survival sculpts cortical networks

Cortical direction selectivity emerges at convergence of thalamic synapses

Structural basis of ubiquitin modification by the Legionella effector SdeA

ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase

Structure of a volume-regulated anion channel of the LRRC8 family

1. Pyramidal cell regulation of interneuron survival sculpts cortical networks Complex neuronal circuitries such as those found in the mammalian cerebral cortex have evolved as balanced networks of excitatory and inhibitory neurons. Although the establishment of appropriate numbers of these cells is essential for brain function and behaviour, our understanding of this fundamental process is limited. Here Fong Kuan Wong at King’s College London in London, UK and his colleagues show that the survival of interneurons in mice depends on the activity of pyramidal cells in a critical window of postnatal development, during which excitatory synaptic input to individual interneurons predicts their survival or death. Pyramidal cells regulate interneuron survival through the negative modulation of PTEN signalling, which effectively drives interneuron cell death during this period. Their findings indicate that activity-dependent mechanisms dynamically adjust the number of inhibitory cells in nascent local cortical circuits, ultimately establishing the appropriate proportions of excitatory and inhibitory neurons in the cerebral cortex.

Read more, please click https://www.nature.com/articles/s41586-018-0139-6

2. Cortical direction selectivity emerges at convergence of thalamic synapses Detecting the direction of motion of an object is essential for our representation of the visual environment. The visual cortex is one of the main stages in the mammalian nervous system in which the direction of motion may be computed de novo. Experiments and theories indicate that cortical neurons respond selectively to motion direction by combining inputs that provide information about distinct spatial locations with distinct time delays. Despite the importance of this spatiotemporal offset for direction selectivity, its origin and cellular mechanisms are not fully understood. Anthony D. Lien at University of California San Diego in La Jolla, USA and his colleagues show that approximately 80 ± 10 thalamic neurons, which respond with distinct time courses to stimuli in distinct locations, excite mouse visual cortical neurons during visual stimulation. The integration of thalamic inputs with the appropriate spatiotemporal offset provides cortical neurons with a primordial bias for direction selectivity. These data show how cortical neurons selectively combine the spatiotemporal response diversity of thalamic neurons to extract fundamental features of the visual world.

Read more, please click https://www.nature.com/articles/s41586-018-0148-5

3. Structural basis of ubiquitin modification by the Legionella effector SdeA Protein ubiquitination is a multifaceted post-translational modification that controls almost every process in eukaryotic cells. Recently, the Legionella effector SdeA was reported to mediate a unique phosphoribosyl-linked ubiquitination through successive modifications of the Arg42 of ubiquitin (Ub) by its mono-ADP-ribosyltransferase (mART) and phosphodiesterase (PDE) domains. However, the mechanisms of SdeA-mediated Ub modification and phosphoribosyl-linked ubiquitination remain unknown. Here Yanan Dong at Beijing University of Chemical Technology in Beijing, China and his colleagues report the structures of SdeA in its ligand-free, Ub-bound and Ub–NADH-bound states. The structures reveal that the mART and PDE domains of SdeA form a catalytic domain over its C-terminal region. Upon Ub binding, the canonical ADP-ribosyltransferase toxin turn-turn (ARTT) and phosphate-nicotinamide (PN) loops in the mART domain of SdeA undergo marked conformational changes. The Ub Arg72 might act as a ‘probe’ that interacts with the mART domain first, and then movements may occur in the side chains of Arg72 and Arg42 during the ADP-ribosylation of Ub. Their study reveals the mechanism of SdeA-mediated Ub modification and provides a framework for further investigations into the phosphoribosyl-linked ubiquitination process.

Read more, please click https://www.nature.com/articles/s41586-018-0146-7

4. ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase Editing domains of aminoacyl tRNA synthetases correct tRNA charging errors to maintain translational fidelity. A mutation in the editing domain of alanyl tRNA synthetase (AlaRS) in Aarssti mutant mice results in an increase in the production of serine-mischarged tRNAAla and the degeneration of cerebellar Purkinje cells. Here, using positional cloning, My-Nuong Vo at Scripps Research Institute in La Jolla, USA and his colleagues identified Ankrd16, a gene that acts epistatically with the Aarssti mutation to attenuate neurodegeneration. ANKRD16, a vertebrate-specific protein that contains ankyrin repeats, binds directly to the catalytic domain of AlaRS. Serine that is misactivated by AlaRS is captured by the lysine side chains of ANKRD16, which prevents the charging of serine adenylates to tRNAAla and precludes serine misincorporation in nascent peptides. The deletion of Ankrd16 in the brains of Aarssti/sti mice causes widespread protein aggregation and neuron loss. These results identify an amino-acid-accepting co-regulator of tRNA synthetase editing as a new layer of the machinery that is essential to the prevention of severe pathologies that arise from defects in editing.

Read more, please click https://www.nature.com/articles/s41586-018-0137-8

5. Structure of a volume-regulated anion channel of the LRRC8 family Volume-regulated anion channels are activated in response to hypotonic stress. These channels are composed of closely related paralogues of the leucine-rich repeat-containing protein 8 (LRRC8) family that co-assemble to form hexameric complexes. Here, using cryo-electron microscopy and X-ray crystallography, Dawid Deneka at University of Zurich in Zurich, Switzerland and his colleagues determine the structure of a homomeric channel of the obligatory subunit LRRC8A. This protein conducts ions and has properties in common with endogenous heteromeric channels. Its modular structure consists of a transmembrane pore domain followed by a cytoplasmic leucine-rich repeat domain. The transmembrane domain, which is structurally related to connexin proteins, is wide towards the cytoplasm but constricted on the outside by a structural unit that acts as a selectivity filter. An excess of basic residues in the filter and throughout the pore attracts anions by electrostatic interaction. Their work reveals the previously unknown architecture of volume-regulated anion channels and their mechanism of selective anion conduction.

Structural basis of ubiquitin modification by the Legionella effector SdeA

Content introduction:

Pyramidal cell regulation of interneuron survival sculpts cortical networks

Cortical direction selectivity emerges at convergence of thalamic synapses

Structural basis of ubiquitin modification by the Legionella effector SdeA

ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase

Structure of a volume-regulated anion channel of the LRRC8 family

1. Pyramidal cell regulation of interneuron survival sculpts cortical networks Complex neuronal circuitries such as those found in the mammalian cerebral cortex have evolved as balanced networks of excitatory and inhibitory neurons. Although the establishment of appropriate numbers of these cells is essential for brain function and behaviour, our understanding of this fundamental process is limited. Here Fong Kuan Wong at King’s College London in London, UK and his colleagues show that the survival of interneurons in mice depends on the activity of pyramidal cells in a critical window of postnatal development, during which excitatory synaptic input to individual interneurons predicts their survival or death. Pyramidal cells regulate interneuron survival through the negative modulation of PTEN signalling, which effectively drives interneuron cell death during this period. Their findings indicate that activity-dependent mechanisms dynamically adjust the number of inhibitory cells in nascent local cortical circuits, ultimately establishing the appropriate proportions of excitatory and inhibitory neurons in the cerebral cortex.

Read more, please click https://www.nature.com/articles/s41586-018-0139-6

2. Cortical direction selectivity emerges at convergence of thalamic synapses Detecting the direction of motion of an object is essential for our representation of the visual environment. The visual cortex is one of the main stages in the mammalian nervous system in which the direction of motion may be computed de novo. Experiments and theories indicate that cortical neurons respond selectively to motion direction by combining inputs that provide information about distinct spatial locations with distinct time delays. Despite the importance of this spatiotemporal offset for direction selectivity, its origin and cellular mechanisms are not fully understood. Anthony D. Lien at University of California San Diego in La Jolla, USA and his colleagues show that approximately 80 ± 10 thalamic neurons, which respond with distinct time courses to stimuli in distinct locations, excite mouse visual cortical neurons during visual stimulation. The integration of thalamic inputs with the appropriate spatiotemporal offset provides cortical neurons with a primordial bias for direction selectivity. These data show how cortical neurons selectively combine the spatiotemporal response diversity of thalamic neurons to extract fundamental features of the visual world.

Read more, please click https://www.nature.com/articles/s41586-018-0148-5

3. Structural basis of ubiquitin modification by the Legionella effector SdeA Protein ubiquitination is a multifaceted post-translational modification that controls almost every process in eukaryotic cells. Recently, the Legionella effector SdeA was reported to mediate a unique phosphoribosyl-linked ubiquitination through successive modifications of the Arg42 of ubiquitin (Ub) by its mono-ADP-ribosyltransferase (mART) and phosphodiesterase (PDE) domains. However, the mechanisms of SdeA-mediated Ub modification and phosphoribosyl-linked ubiquitination remain unknown. Here Yanan Dong at Beijing University of Chemical Technology in Beijing, China and his colleagues report the structures of SdeA in its ligand-free, Ub-bound and Ub–NADH-bound states. The structures reveal that the mART and PDE domains of SdeA form a catalytic domain over its C-terminal region. Upon Ub binding, the canonical ADP-ribosyltransferase toxin turn-turn (ARTT) and phosphate-nicotinamide (PN) loops in the mART domain of SdeA undergo marked conformational changes. The Ub Arg72 might act as a ‘probe’ that interacts with the mART domain first, and then movements may occur in the side chains of Arg72 and Arg42 during the ADP-ribosylation of Ub. Their study reveals the mechanism of SdeA-mediated Ub modification and provides a framework for further investigations into the phosphoribosyl-linked ubiquitination process.

Read more, please click https://www.nature.com/articles/s41586-018-0146-7

4. ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase Editing domains of aminoacyl tRNA synthetases correct tRNA charging errors to maintain translational fidelity. A mutation in the editing domain of alanyl tRNA synthetase (AlaRS) in Aarssti mutant mice results in an increase in the production of serine-mischarged tRNAAla and the degeneration of cerebellar Purkinje cells. Here, using positional cloning, My-Nuong Vo at Scripps Research Institute in La Jolla, USA and his colleagues identified Ankrd16, a gene that acts epistatically with the Aarssti mutation to attenuate neurodegeneration. ANKRD16, a vertebrate-specific protein that contains ankyrin repeats, binds directly to the catalytic domain of AlaRS. Serine that is misactivated by AlaRS is captured by the lysine side chains of ANKRD16, which prevents the charging of serine adenylates to tRNAAla and precludes serine misincorporation in nascent peptides. The deletion of Ankrd16 in the brains of Aarssti/sti mice causes widespread protein aggregation and neuron loss. These results identify an amino-acid-accepting co-regulator of tRNA synthetase editing as a new layer of the machinery that is essential to the prevention of severe pathologies that arise from defects in editing.

Read more, please click https://www.nature.com/articles/s41586-018-0137-8

5. Structure of a volume-regulated anion channel of the LRRC8 family Volume-regulated anion channels are activated in response to hypotonic stress. These channels are composed of closely related paralogues of the leucine-rich repeat-containing protein 8 (LRRC8) family that co-assemble to form hexameric complexes. Here, using cryo-electron microscopy and X-ray crystallography, Dawid Deneka at University of Zurich in Zurich, Switzerland and his colleagues determine the structure of a homomeric channel of the obligatory subunit LRRC8A. This protein conducts ions and has properties in common with endogenous heteromeric channels. Its modular structure consists of a transmembrane pore domain followed by a cytoplasmic leucine-rich repeat domain. The transmembrane domain, which is structurally related to connexin proteins, is wide towards the cytoplasm but constricted on the outside by a structural unit that acts as a selectivity filter. An excess of basic residues in the filter and throughout the pore attracts anions by electrostatic interaction. Their work reveals the previously unknown architecture of volume-regulated anion channels and their mechanism of selective anion conduction.

Structural basis of ubiquitin modification by the Legionella effector SdeA

Content introduction:

Pyramidal cell regulation of interneuron survival sculpts cortical networks

Cortical direction selectivity emerges at convergence of thalamic synapses

Structural basis of ubiquitin modification by the Legionella effector SdeA

ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase

Structure of a volume-regulated anion channel of the LRRC8 family

1. Pyramidal cell regulation of interneuron survival sculpts cortical networks Complex neuronal circuitries such as those found in the mammalian cerebral cortex have evolved as balanced networks of excitatory and inhibitory neurons. Although the establishment of appropriate numbers of these cells is essential for brain function and behaviour, our understanding of this fundamental process is limited. Here Fong Kuan Wong at King’s College London in London, UK and his colleagues show that the survival of interneurons in mice depends on the activity of pyramidal cells in a critical window of postnatal development, during which excitatory synaptic input to individual interneurons predicts their survival or death. Pyramidal cells regulate interneuron survival through the negative modulation of PTEN signalling, which effectively drives interneuron cell death during this period. Their findings indicate that activity-dependent mechanisms dynamically adjust the number of inhibitory cells in nascent local cortical circuits, ultimately establishing the appropriate proportions of excitatory and inhibitory neurons in the cerebral cortex.

Read more, please click https://www.nature.com/articles/s41586-018-0139-6

2. Cortical direction selectivity emerges at convergence of thalamic synapses Detecting the direction of motion of an object is essential for our representation of the visual environment. The visual cortex is one of the main stages in the mammalian nervous system in which the direction of motion may be computed de novo. Experiments and theories indicate that cortical neurons respond selectively to motion direction by combining inputs that provide information about distinct spatial locations with distinct time delays. Despite the importance of this spatiotemporal offset for direction selectivity, its origin and cellular mechanisms are not fully understood. Anthony D. Lien at University of California San Diego in La Jolla, USA and his colleagues show that approximately 80 ± 10 thalamic neurons, which respond with distinct time courses to stimuli in distinct locations, excite mouse visual cortical neurons during visual stimulation. The integration of thalamic inputs with the appropriate spatiotemporal offset provides cortical neurons with a primordial bias for direction selectivity. These data show how cortical neurons selectively combine the spatiotemporal response diversity of thalamic neurons to extract fundamental features of the visual world.

Read more, please click https://www.nature.com/articles/s41586-018-0148-5

3. Structural basis of ubiquitin modification by the Legionella effector SdeA Protein ubiquitination is a multifaceted post-translational modification that controls almost every process in eukaryotic cells. Recently, the Legionella effector SdeA was reported to mediate a unique phosphoribosyl-linked ubiquitination through successive modifications of the Arg42 of ubiquitin (Ub) by its mono-ADP-ribosyltransferase (mART) and phosphodiesterase (PDE) domains. However, the mechanisms of SdeA-mediated Ub modification and phosphoribosyl-linked ubiquitination remain unknown. Here Yanan Dong at Beijing University of Chemical Technology in Beijing, China and his colleagues report the structures of SdeA in its ligand-free, Ub-bound and Ub–NADH-bound states. The structures reveal that the mART and PDE domains of SdeA form a catalytic domain over its C-terminal region. Upon Ub binding, the canonical ADP-ribosyltransferase toxin turn-turn (ARTT) and phosphate-nicotinamide (PN) loops in the mART domain of SdeA undergo marked conformational changes. The Ub Arg72 might act as a ‘probe’ that interacts with the mART domain first, and then movements may occur in the side chains of Arg72 and Arg42 during the ADP-ribosylation of Ub. Their study reveals the mechanism of SdeA-mediated Ub modification and provides a framework for further investigations into the phosphoribosyl-linked ubiquitination process.

Read more, please click https://www.nature.com/articles/s41586-018-0146-7

4. ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase Editing domains of aminoacyl tRNA synthetases correct tRNA charging errors to maintain translational fidelity. A mutation in the editing domain of alanyl tRNA synthetase (AlaRS) in Aarssti mutant mice results in an increase in the production of serine-mischarged tRNAAla and the degeneration of cerebellar Purkinje cells. Here, using positional cloning, My-Nuong Vo at Scripps Research Institute in La Jolla, USA and his colleagues identified Ankrd16, a gene that acts epistatically with the Aarssti mutation to attenuate neurodegeneration. ANKRD16, a vertebrate-specific protein that contains ankyrin repeats, binds directly to the catalytic domain of AlaRS. Serine that is misactivated by AlaRS is captured by the lysine side chains of ANKRD16, which prevents the charging of serine adenylates to tRNAAla and precludes serine misincorporation in nascent peptides. The deletion of Ankrd16 in the brains of Aarssti/sti mice causes widespread protein aggregation and neuron loss. These results identify an amino-acid-accepting co-regulator of tRNA synthetase editing as a new layer of the machinery that is essential to the prevention of severe pathologies that arise from defects in editing.

Read more, please click https://www.nature.com/articles/s41586-018-0137-8

5. Structure of a volume-regulated anion channel of the LRRC8 family Volume-regulated anion channels are activated in response to hypotonic stress. These channels are composed of closely related paralogues of the leucine-rich repeat-containing protein 8 (LRRC8) family that co-assemble to form hexameric complexes. Here, using cryo-electron microscopy and X-ray crystallography, Dawid Deneka at University of Zurich in Zurich, Switzerland and his colleagues determine the structure of a homomeric channel of the obligatory subunit LRRC8A. This protein conducts ions and has properties in common with endogenous heteromeric channels. Its modular structure consists of a transmembrane pore domain followed by a cytoplasmic leucine-rich repeat domain. The transmembrane domain, which is structurally related to connexin proteins, is wide towards the cytoplasm but constricted on the outside by a structural unit that acts as a selectivity filter. An excess of basic residues in the filter and throughout the pore attracts anions by electrostatic interaction. Their work reveals the previously unknown architecture of volume-regulated anion channels and their mechanism of selective anion conduction.

Structural basis of ubiquitin modification by the Legionella effector SdeA

Content introduction:

Pyramidal cell regulation of interneuron survival sculpts cortical networks

Cortical direction selectivity emerges at convergence of thalamic synapses

Structural basis of ubiquitin modification by the Legionella effector SdeA

ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase

Structure of a volume-regulated anion channel of the LRRC8 family

1. Pyramidal cell regulation of interneuron survival sculpts cortical networks Complex neuronal circuitries such as those found in the mammalian cerebral cortex have evolved as balanced networks of excitatory and inhibitory neurons. Although the establishment of appropriate numbers of these cells is essential for brain function and behaviour, our understanding of this fundamental process is limited. Here Fong Kuan Wong at King’s College London in London, UK and his colleagues show that the survival of interneurons in mice depends on the activity of pyramidal cells in a critical window of postnatal development, during which excitatory synaptic input to individual interneurons predicts their survival or death. Pyramidal cells regulate interneuron survival through the negative modulation of PTEN signalling, which effectively drives interneuron cell death during this period. Their findings indicate that activity-dependent mechanisms dynamically adjust the number of inhibitory cells in nascent local cortical circuits, ultimately establishing the appropriate proportions of excitatory and inhibitory neurons in the cerebral cortex.

Read more, please click https://www.nature.com/articles/s41586-018-0139-6

2. Cortical direction selectivity emerges at convergence of thalamic synapses Detecting the direction of motion of an object is essential for our representation of the visual environment. The visual cortex is one of the main stages in the mammalian nervous system in which the direction of motion may be computed de novo. Experiments and theories indicate that cortical neurons respond selectively to motion direction by combining inputs that provide information about distinct spatial locations with distinct time delays. Despite the importance of this spatiotemporal offset for direction selectivity, its origin and cellular mechanisms are not fully understood. Anthony D. Lien at University of California San Diego in La Jolla, USA and his colleagues show that approximately 80 ± 10 thalamic neurons, which respond with distinct time courses to stimuli in distinct locations, excite mouse visual cortical neurons during visual stimulation. The integration of thalamic inputs with the appropriate spatiotemporal offset provides cortical neurons with a primordial bias for direction selectivity. These data show how cortical neurons selectively combine the spatiotemporal response diversity of thalamic neurons to extract fundamental features of the visual world.

Read more, please click https://www.nature.com/articles/s41586-018-0148-5

3. Structural basis of ubiquitin modification by the Legionella effector SdeA Protein ubiquitination is a multifaceted post-translational modification that controls almost every process in eukaryotic cells. Recently, the Legionella effector SdeA was reported to mediate a unique phosphoribosyl-linked ubiquitination through successive modifications of the Arg42 of ubiquitin (Ub) by its mono-ADP-ribosyltransferase (mART) and phosphodiesterase (PDE) domains. However, the mechanisms of SdeA-mediated Ub modification and phosphoribosyl-linked ubiquitination remain unknown. Here Yanan Dong at Beijing University of Chemical Technology in Beijing, China and his colleagues report the structures of SdeA in its ligand-free, Ub-bound and Ub–NADH-bound states. The structures reveal that the mART and PDE domains of SdeA form a catalytic domain over its C-terminal region. Upon Ub binding, the canonical ADP-ribosyltransferase toxin turn-turn (ARTT) and phosphate-nicotinamide (PN) loops in the mART domain of SdeA undergo marked conformational changes. The Ub Arg72 might act as a ‘probe’ that interacts with the mART domain first, and then movements may occur in the side chains of Arg72 and Arg42 during the ADP-ribosylation of Ub. Their study reveals the mechanism of SdeA-mediated Ub modification and provides a framework for further investigations into the phosphoribosyl-linked ubiquitination process.

Read more, please click https://www.nature.com/articles/s41586-018-0146-7

4. ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase Editing domains of aminoacyl tRNA synthetases correct tRNA charging errors to maintain translational fidelity. A mutation in the editing domain of alanyl tRNA synthetase (AlaRS) in Aarssti mutant mice results in an increase in the production of serine-mischarged tRNAAla and the degeneration of cerebellar Purkinje cells. Here, using positional cloning, My-Nuong Vo at Scripps Research Institute in La Jolla, USA and his colleagues identified Ankrd16, a gene that acts epistatically with the Aarssti mutation to attenuate neurodegeneration. ANKRD16, a vertebrate-specific protein that contains ankyrin repeats, binds directly to the catalytic domain of AlaRS. Serine that is misactivated by AlaRS is captured by the lysine side chains of ANKRD16, which prevents the charging of serine adenylates to tRNAAla and precludes serine misincorporation in nascent peptides. The deletion of Ankrd16 in the brains of Aarssti/sti mice causes widespread protein aggregation and neuron loss. These results identify an amino-acid-accepting co-regulator of tRNA synthetase editing as a new layer of the machinery that is essential to the prevention of severe pathologies that arise from defects in editing.

Read more, please click https://www.nature.com/articles/s41586-018-0137-8

5. Structure of a volume-regulated anion channel of the LRRC8 family Volume-regulated anion channels are activated in response to hypotonic stress. These channels are composed of closely related paralogues of the leucine-rich repeat-containing protein 8 (LRRC8) family that co-assemble to form hexameric complexes. Here, using cryo-electron microscopy and X-ray crystallography, Dawid Deneka at University of Zurich in Zurich, Switzerland and his colleagues determine the structure of a homomeric channel of the obligatory subunit LRRC8A. This protein conducts ions and has properties in common with endogenous heteromeric channels. Its modular structure consists of a transmembrane pore domain followed by a cytoplasmic leucine-rich repeat domain. The transmembrane domain, which is structurally related to connexin proteins, is wide towards the cytoplasm but constricted on the outside by a structural unit that acts as a selectivity filter. An excess of basic residues in the filter and throughout the pore attracts anions by electrostatic interaction. Their work reveals the previously unknown architecture of volume-regulated anion channels and their mechanism of selective anion conduction.