Protein model quality assessment using rotation-equivariant transformations on point clouds.

Machine learning research concerning protein structure has seen a surge in popularity over the last years with promising advances for basic science and drug discovery. Working with macromolecular structure in a machine learning context requires an adequate numerical representation, and researchers have extensively studied representations such as graphs, discretized 3D grids, and distance maps. As part of CASP14, we explored a new and conceptually simple representation in a blind experiment: atoms as points in 3D, each with associated features.

Assessment of Patient Retention of Inpatient Care Information Post-Hospitalization.

Background: Patient understanding of medical care improves readmission rates and patient satisfaction, yet the literature suggests patients often have poor retention of care information post-hospitalization. Although multiple interventions have been implemented to facilitate this process, the cumulative durability of their benefit remains unclear. The authors conducted this study to more objectively understand how well patients retain care information after hospital discharge and to assess patient perspectives on facilitators of this process (for example, whiteboards and patient portals).

Geometric deep learning of RNA structure.

RNA molecules adopt three-dimensional structures that are critical to their function and of interest in drug discovery. Few RNA structures are known, however, and predicting them computationally has proven challenging. We introduce a machine learning approach that enables identification of accurate structural models without assumptions about their defining characteristics, despite being trained with only 18 known RNA structures.

Gold nanoparticles and tilt pairs to assess protein flexibility by cryo-electron microscopy.

A computational method was developed to recover the three-dimensional coordinates of gold nanoparticles specifically attached to a protein complex from tilt-pair images collected by electron microscopy. The program was tested on a simulated dataset and applied to a real dataset comprising tilt-pair images recorded by cryo electron microscopy of RNA polymerase II in a complex with four gold-labeled single-chain antibody fragments. The positions of the gold nanoparticles were determined, and comparison of the coordinates among the tetrameric particles revealed the range of motion within the protein complexes.

Simple biochemical features underlie transcriptional activation domain diversity and dynamic, fuzzy binding to Mediator.

Gene activator proteins comprise distinct DNA-binding and transcriptional activation domains (ADs). Because few ADs have been described, we tested domains tiling all yeast transcription factors for activation in vivo and identified 150 ADs. By mRNA display, we showed that 73% of ADs bound the Med15 subunit of Mediator, and that binding strength was correlated with activation.

Spatially resolved cell polarity proteomics of a human epiblast model.

Critical early steps in human embryonic development include polarization of the inner cell mass, followed by formation of an expanded lumen that will become the epiblast cavity. Recently described three-dimensional (3D) human pluripotent stem cell-derived cyst (hPSC-cyst) structures can replicate these processes. To gain mechanistic insights into the poorly understood machinery involved in epiblast cavity formation, we interrogated the proteomes of apical and basolateral membrane territories in 3D human hPSC-cysts.

How GPCR Phosphorylation Patterns Orchestrate Arrestin-Mediated Signaling.

Binding of arrestin to phosphorylated G-protein-coupled receptors (GPCRs) controls many aspects of cell signaling. The number and arrangement of phosphates may vary substantially for a given GPCR, and different phosphorylation patterns trigger different arrestin-mediated effects. Here, we determine how GPCR phosphorylation influences arrestin behavior by using atomic-level simulations and site-directed spectroscopy to reveal the effects of phosphorylation patterns on arrestin binding and conformation.

Hierarchical, rotation-equivariant neural networks to select structural models of protein complexes.

Predicting the structure of multi-protein complexes is a grand challenge in biochemistry, with major implications for basic science and drug discovery. Computational structure prediction methods generally leverage predefined structural features to distinguish accurate structural models from less accurate ones. This raises the question of whether it is possible to learn characteristics of accurate models directly from atomic coordinates of protein complexes, with no prior assumptions.

Effect of Cell Spreading on Rosette Formation by Human Pluripotent Stem Cell-Derived Neural Progenitor Cells.

Neural rosettes (NPC rosettes) are radially arranged groups of cells surrounding a central lumen that arise stochastically in monolayer cultures of human pluripotent stem cell (hPSC)-derived neural progenitor cells (NPC). Since NPC rosette formation is thought to mimic cell behavior in the early neural tube, these rosettes represent important models for the study of neural tube morphogenesis. However, using current protocols, NPC rosette formation is not synchronized and results are inconsistent among different hPSC lines, hindering quantitative mechanistic analyses and challenging live cell imaging.

Molecular mechanism of GPCR-mediated arrestin activation.

Despite intense interest in discovering drugs that cause G-protein-coupled receptors (GPCRs) to selectively stimulate or block arrestin signalling, the structural mechanism of receptor-mediated arrestin activation remains unclear. Here we reveal this mechanism through extensive atomic-level simulations of arrestin. We find that the receptor's transmembrane core and cytoplasmic tail-which bind distinct surfaces on arrestin-can each independently stimulate arrestin activation.

An apicosome initiates self-organizing morphogenesis of human pluripotent stem cells.

Human pluripotent stem cells (hPSCs) self-organize into apicobasally polarized cysts, reminiscent of the lumenal epiblast stage, providing a model to explore key morphogenic processes in early human embryos. Here, we show that apical polarization begins on the interior of single hPSCs through the dynamic formation of a highly organized perinuclear apicosome structure. The membrane surrounding the apicosome is enriched in apical markers and displays microvilli and a primary cilium; its lumenal space is rich in Ca Time-lapse imaging of isolated hPSCs reveals that the apicosome forms de novo in interphase, retains its structure during mitosis, is asymmetrically inherited after mitosis, and relocates to the recently formed cytokinetic plane, where it establishes a fully polarized lumen.

A pluripotent stem cell-based model for post-implantation human amniotic sac development.

Development of the asymmetric amniotic sac-with the embryonic disc and amniotic ectoderm occupying opposite poles-is a vital milestone during human embryo implantation. Although essential to embryogenesis and pregnancy, amniotic sac development in humans remains poorly understood. Here, we report a human pluripotent stem cell (hPSC)-based model, termed the post-implantation amniotic sac embryoid (PASE), that recapitulates multiple post-implantation embryogenic events centered around amniotic sac development.

Self-organized amniogenesis by human pluripotent stem cells in a biomimetic implantation-like niche.

Amniogenesis-the development of amnion-is a critical developmental milestone for early human embryogenesis and successful pregnancy. However, human amniogenesis is poorly understood due to limited accessibility to peri-implantation embryos and a lack of in vitro models. Here we report an efficient biomaterial system to generate human amnion-like tissue in vitro through self-organized development of human pluripotent stem cells (hPSCs) in a bioengineered niche mimicking the in vivo implantation environment.

Lumen Formation Is an Intrinsic Property of Isolated Human Pluripotent Stem Cells.

We demonstrate that dissociated human pluripotent stem cells (PSCs) are intrinsically programmed to form lumens. PSCs form two-cell cysts with a shared apical domain within 20 hr of plating; these cysts collapse to form monolayers after 5 days. Expression of pluripotency markers is maintained throughout this time.

"Schizoid" personality in childhood: auditory P300 and eye tracking responses at follow-up in adult life.

The auditory P300 response and smooth pursuit eye tracking were recorded from a group of 23 male adult subjects who had been diagnosed in childhood as having schizoid personality. No differences were found in these physiological measures between the study group, their matched controls of other child psychiatric patients, and a group of population controls. The essentially negative findings are discussed in the light of abnormalities of these psychophysiological responses previously found in schizophrenic patients, in some of their biological relatives, and in other groups of psychiatric patients, including autistic children and adults with a diagnosis of borderline and schizotypal personality disorder.

'Schizoid' personality in childhood and adult life. II: Adult adjustment and the continuity with schizotypal personality disorder.

In a controlled follow-up study into adulthood of 32 children diagnosed 'schizoid', three-quarters fulfilled DSM-III criteria for schizotypal personality disorder and two developed schizophrenia. Overall their psychosocial adjustment was somewhat, but not markedly, worse than that of other attenders at a child psychiatry clinic, although as a group they remained more solitary, lacking in empathy, oversensitive, with odd styles of communicating, and often with circumscribed interests.

Aspiration needle biopsy for solitary, peripheral lung lesions: a review of 50 examinations.

Percutaneous aspiration needle biopsy forms a simple method of obtaining histological material from solitary peripheral lung lesions. A new method for separating and preparing the material for histological examination is described. The results in 50 cases are recorded with a positive diagnosis in 46.

Transbronchial lung biopsy: A review of 85 cases.

Transbronchial lung biopsy using the fibreoptic bronchoscope was carried out in 85 patients. There were no serious complications; two patients had a 10% pneumothorax and 17 had slight haemoptysis lasting less than 24 hours. The problems of interpreting small biopsy specimens are considered.

Pulmonary lesions due to opportunist mycobacteria. (Review includes 30 cases of M. kansasii infections).

The apparent increase in the incidence of opportunist mycobacterial pulmonary infection is assessed. The clinical, bacteriological and radiological characteristics of 34 cases of such infections seen over a period of ten years in Sheffield are reviewed. The typical radiological appearances consisting of cavities, fibrosis and opacities are described and illustrated.