Structural interrogation of phosphoproteome identified by mass spectrometry reveals allowed and disallowed regions of phosphoconformation

High-throughput mass spectrometric (HT-MS) study is the method of choice for monitoring global changes in proteome. Data derived from these studies are meant for further validation and experimentation to discover novel biological insights. Here we evaluate use of relative solvent accessible surface area (rSASA) and DEPTH as indices to assess experimentally determined phosphorylation events deposited in PhosphoSitePlus. Based on accessibility, we map these identifications on allowed (accessible) or disallowed (inaccessible) regions of phosphoconformation. Surprisingly a striking number of HT- MS/MS derived events (1461/5947 sites or 24.6%) are present in the disallowed region of conformation. By considering protein dynamics, autophosphorylation events and/or the sequence specificity of kinases, 13.8% of these phosphosites can be moved to the allowed region of conformation. We also demonstrate that rSASA values can be used to increase the confidence of identification of phosphorylation sites within an ambiguous MS dataset. While MS is a stand-alone technique for the identification of vast majority of phosphorylation events, identifications within disallowed region of conformation will benefit from techniques that independently probe for phosphorylation and protein dynamics. Our studies also imply that trapping alternate protein conformations may be a viable alternative to the design of inhibitors against mutation prone drug resistance kinases

Predictive-State Decoders: Encoding the Future into Recurrent Networks

Recurrent neural networks (RNNs) are a vital modeling technique that rely on internal states learned indirectly by optimization of a supervised, unsupervised, or reinforcement training loss. RNNs are used to model dynamic processes that are characterized by underlying latent states whose form is often unknown, precluding its analytic representation inside an RNN. In the Predictive-State Representation (PSR) literature, latent state processes are modeled by an internal state representation that directly models the distribution of future observations, and most recent work in this area has relied on explicitly representing and targeting sufficient statistics of this probability distribution. We seek to combine the advantages of RNNs and PSRs by augmenting existing state-of-the-art recurrent neural networks with Predictive-State Decoders (PSDs), which add supervision to the network's internal state representation to target predicting future observations. Predictive-State Decoders are simple to implement and easily incorporated into existing training pipelines via additional loss regularization. We demonstrate the effectiveness of PSDs with experimental results in three different domains: probabilistic filtering, Imitation Learning, and Reinforcement Learning. In each, our method improves statistical performance of state-of-the-art recurrent baselines and does so with fewer iterations and less data.Comment: NIPS 201

Autonomy Infused Teleoperation with Application to BCI Manipulation

Robot teleoperation systems face a common set of challenges including latency, low-dimensional user commands, and asymmetric control inputs. User control with Brain-Computer Interfaces (BCIs) exacerbates these problems through especially noisy and erratic low-dimensional motion commands due to the difficulty in decoding neural activity. We introduce a general framework to address these challenges through a combination of computer vision, user intent inference, and arbitration between the human input and autonomous control schemes. Adjustable levels of assistance allow the system to balance the operator's capabilities and feelings of comfort and control while compensating for a task's difficulty. We present experimental results demonstrating significant performance improvement using the shared-control assistance framework on adapted rehabilitation benchmarks with two subjects implanted with intracortical brain-computer interfaces controlling a seven degree-of-freedom robotic manipulator as a prosthetic. Our results further indicate that shared assistance mitigates perceived user difficulty and even enables successful performance on previously infeasible tasks. We showcase the extensibility of our architecture with applications to quality-of-life tasks such as opening a door, pouring liquids from containers, and manipulation with novel objects in densely cluttered environments

Corrigendum to “Discovery of novel interacting partners of PSMD9, a proteasomal chaperone: Role of an Atypical and versatile PDZ-domain motif interaction and identification of putative functional modules” [FEBS Open Bio 4 (2014) 571–583]

10.1016/j.fob.2015.06.010FEBS Open Bio5731-73

BLOOM: A 176B-Parameter Open-Access Multilingual Language Model

Large language models (LLMs) have been shown to be able to perform new tasks based on a few demonstrations or natural language instructions. While these capabilities have led to widespread adoption, most LLMs are developed by resource-rich organizations and are frequently kept from the public. As a step towards democratizing this powerful technology, we present BLOOM, a 176B-parameter open-access language model designed and built thanks to a collaboration of hundreds of researchers. BLOOM is a decoder-only Transformer language model that was trained on the ROOTS corpus, a dataset comprising hundreds of sources in 46 natural and 13 programming languages (59 in total). We find that BLOOM achieves competitive performance on a wide variety of benchmarks, with stronger results after undergoing multitask prompted finetuning. To facilitate future research and applications using LLMs, we publicly release our models and code under the Responsible AI License

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta