A presynaptic phosphosignaling hub for lasting homeostatic plasticity

Stable function of networks requires that synapses adapt their strength to levels of neuronal activity, and failure to do so results in cognitive disorders. How such homeostatic regulation may be implemented in mammalian synapses remains poorly understood. Here we show that the phosphorylation status of several positions of the active-zone (AZ) protein RIM1 are relevant for synaptic glutamate release. Position RIMS1045 is necessary and sufficient for expression of silencing-induced homeostatic plasticity and is kept phosphorylated by serine arginine protein kinase 2 (SRPK2). SRPK2-induced upscaling of synaptic release leads to additional RIM1 nanoclusters and docked vesicles at the AZ and is not observed in the absence of RIM1 and occluded by RIMS1045E. Our data suggest that SRPK2 and RIM1 represent a presynaptic phosphosignaling hub that is involved in the homeostatic balance of synaptic coupling of neuronal networks

A second planet transiting LTT 1445A and a determination of the masses of both worlds

K.H. acknowledges support from STFC grant ST/R000824/1.LTT 1445 is a hierarchical triple M-dwarf star system located at a distance of 6.86 pc. The primary star LTT 1445A (0.257 M⊙) is known to host the transiting planet LTT 1445Ab with an orbital period of 5.36 days, making it the second-closest known transiting exoplanet system, and the closest one for which the host is an M dwarf. Using Transiting Exoplanet Survey Satellite data, we present the discovery of a second planet in the LTT 1445 system, with an orbital period of 3.12 days. We combine radial-velocity measurements obtained from the five spectrographs, Echelle Spectrograph for Rocky Exoplanets and Stable Spectroscopic Observations, High Accuracy Radial Velocity Planet Searcher, High-Resolution Echelle Spectrometer, MAROON-X, and Planet Finder Spectrograph to establish that the new world also orbits LTT 1445A. We determine the mass and radius of LTT 1445Ab to be 2.87 ± 0.25 M⊕ and 1.304-0.060+0.067 R⊕, consistent with an Earth-like composition. For the newly discovered LTT 1445Ac, we measure a mass of 1.54-0.19+0.20 M⊕ and a minimum radius of 1.15 R⊕, but we cannot determine the radius directly as the signal-to-noise ratio of our light curve permits both grazing and nongrazing configurations. Using MEarth photometry and ground-based spectroscopy, we establish that star C (0.161 M⊙) is likely the source of the 1.4 day rotation period, and star B (0.215 M⊙) has a likely rotation period of 6.7 days. We estimate a probable rotation period of 85 days for LTT 1445A. Thus, this triple M-dwarf system appears to be in a special evolutionary stage where the most massive M dwarf has spun down, the intermediate mass M dwarf is in the process of spinning down, while the least massive stellar component has not yet begun to spin down.Publisher PDFPeer reviewe

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Chloride channels of intracellular membranes

Proteins implicated as intracellular chloride channels include the intracellular ClC proteins, the bestrophins, the cystic fibrosis transmembrane conductance regulator, the CLICs, and the recently described Golgi pH regulator. This paper examines current hypotheses regarding roles of intracellular chloride channels and reviews the evidence supporting a role in intracellular chloride transport for each of these proteins

Heavy element production in a compact object merger observed by JWST

The mergers of binary compact objects such as neutron stars and black holes are of central interest to several areas of astrophysics, including as the progenitors of gamma-ray bursts (GRBs) 1, sources of high-frequency gravitational waves (GWs) 2 and likely production sites for heavy-element nucleosynthesis by means of rapid neutron capture (the r-process) 3. Here we present observations of the exceptionally bright GRB 230307A. We show that GRB 230307A belongs to the class of long-duration GRBs associated with compact object mergers 4–6 and contains a kilonova similar to AT2017gfo, associated with the GW merger GW170817 (refs. 7–12). We obtained James Webb Space Telescope (JWST) mid-infrared imaging and spectroscopy 29 and 61 days after the burst. The spectroscopy shows an emission line at 2.15 microns, which we interpret as tellurium (atomic mass A = 130) and a very red source, emitting most of its light in the mid-infrared owing to the production of lanthanides. These observations demonstrate that nucleosynthesis in GRBs can create r-process elements across a broad atomic mass range and play a central role in heavy-element nucleosynthesis across the Universe

Biological Earth observation with animal sensors

Space-based tracking technology using low-cost miniature tags is now delivering data on fine-scale animal movement at near-global scale. Linked with remotely sensed environmental data, this offers a biological lens on habitat integrity and connectivity for conservation and human health; a global network of animal sentinels of environmen-tal change

Binge-Type Eating in Rats is Facilitated by Neuromedin U Receptor 2 in the Nucleus Accumbens and Ventral Tegmental Area

Binge-eating disorder (BED) is the most common eating disorder, characterized by rapid, recurrent overconsumption of highly palatable food in a short time frame. BED shares an overlapping behavioral phenotype with obesity, which is also linked to the overconsumption of highly palatable foods. The reinforcing properties of highly palatable foods are mediated by the nucleus accumbens (NAc) and the ventral tegmental area (VTA), which have been implicated in the overconsumption behavior observed in BED and obesity. A potential regulator of binge-type eating behavior is the G protein-coupled receptor neuromedin U receptor 2 (NMUR2). Previous research demonstrated that NMUR2 knockdown potentiates binge-type consumption of high-fat food. We correlated binge-type consumption across a spectrum of fat and carbohydrate mixtures with synaptosomal NMUR2 protein expression in the NAc and VTA of rats. Synaptosomal NMUR2 protein in the NAc demonstrated a strong positive correlation with binge intake of a “lower„-fat (higher carbohydrate) mixture, whereas synaptosomal NMUR2 protein in the VTA demonstrated a strong negative correlation with binge intake of an “extreme„ high-fat (0% carbohydrate) mixture. Taken together, these data suggest that NMUR2 may differentially regulate binge-type eating within the NAc and the VTA