Distribution of activity across the monkey cerebral cortical surface, thalamus and midbrain during rapid, visually guided saccades

To examine the distribution of visual and oculomotor activity across the macaque brain, we performed functional magnetic resonance imaging (fMRI) on awake, behaving monkeys trained to perform visually guided saccades. Two subjects alternated between periods of making saccades and central fixations while blood oxygen level dependent (BOLD) images were collected [3 T, (1.5 mm)(3) spatial resolution]. BOLD activations from each of four cerebral hemispheres were projected onto the subjects' cortical surfaces and aligned to a surface-based atlas for comparison across hemispheres and subjects. This surface-based analysis revealed patterns of visuo-oculomotor activity across much of the cerebral cortex, including activations in the posterior parietal cortex, superior temporal cortex and frontal lobe. For each cortical domain, we show the anatomical position and extent of visuo-oculomotor activity, including evidence that the dorsolateral frontal activation, which includes the frontal eye field (on the anterior bank of the arcuate sulcus), extends anteriorly into posterior principal sulcus (area 46) and posteriorly into part of dorsal premotor cortex (area 6). Our results also suggest that subcortical BOLD activity in the pulvinar thalamus may be lateralized during voluntary eye movements. These findings provide new neuroanatomical information as to the complex neural substrates that underlie even simple goal-directed behaviors

Essential requirement for JPT2 in NAADP-evoked Ca²⁺ signaling

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger that releases Ca2+ from acidic organelles through the activation of two-pore channels (TPCs) to regulate endolysosomal trafficking events. NAADP action is mediated by NAADP-binding protein(s) of unknown identity that confer NAADP sensitivity to TPCs. Here, we used a “clickable” NAADP-based photoprobe to isolate human NAADP-binding proteins and identified Jupiter microtubule-associated homolog 2 (JPT2) as a TPC accessory protein required for endogenous NAADP-evoked Ca2+ signaling. JPT2 was also required for the translocation of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus through the endolysosomal system. Thus, JPT2 is a component of the NAADP receptor complex that is essential for TPC-dependent Ca2+ signaling and control of coronaviral entry

Loss of neuronal Miro1 disrupts mitophagy and induces hyperactivation of the integrated stress response

Clearance of mitochondria following damage is critical for neuronal homeostasis. Here, we investigate the role of Miro proteins in mitochondrial turnover by the PINK1/Parkin mitochondrial quality control system in vitro and in vivo. We find that upon mitochondrial damage, Miro is promiscuously ubiquitinated on multiple lysine residues. Genetic deletion of Miro or block of Miro1 ubiquitination and subsequent degradation lead to delayed translocation of the E3 ubiquitin ligase Parkin onto damaged mitochondria and reduced mitochondrial clearance in both fibroblasts and cultured neurons. Disrupted mitophagy in vivo, upon post-natal knockout of Miro1 in hippocampus and cortex, leads to a dramatic increase in mitofusin levels, the appearance of enlarged and hyperfused mitochondria and hyperactivation of the integrated stress response (ISR). Altogether, our results provide new insights into the central role of Miro1 in the regulation of mitochondrial homeostasis and further implicate Miro1 dysfunction in the pathogenesis of human neurodegenerative disease

Inactivation of Ppp1r15a minimises weight gain and insulin resistance during caloric excess in female mice.

Phosphorylation of the translation initiation factor eIF2α within the mediobasal hypothalamus is known to suppress food intake, but the role of the eIF2α phosphatases in regulating body weight is poorly understood. Mice deficient in active PPP1R15A, a stress-inducible eIF2α phosphatase, are healthy and more resistant to endoplasmic reticulum stress than wild type controls. We report that when female Ppp1r15a mutant mice are fed a high fat diet they gain less weight than wild type littermates owing to reduced food intake. This results in healthy leaner Ppp1r15a mutant animals with reduced hepatic steatosis and improved insulin sensitivity, albeit with a possible modest defect in insulin secretion. By contrast, no weight differences are observed between wild type and Ppp1r15a deficient mice fed a standard diet. We conclude that female mice lacking the C-terminal PP1-binding domain of PPP1R15A show reduced dietary intake and preserved glucose tolerance. Our data indicate that this results in reduced weight gain and protection from diet-induced obesity.The work was also supported by Diabetes UK and the MRC [G1002610]. VP held an Arthur and Sadie Pethybridge PhD Studentship from Diabetes UK. The CIMR microscopy core facility is supported by a Wellcome Trust Strategic Award [100140] and a Wellcome Trust equipment grant [093026]

Branching on multi-aggregated variables

open5siopenGamrath, Gerald; Melchiori, Anna; Berthold, Timo; Gleixner, Ambros M.; Salvagnin, DomenicoGamrath, Gerald; Melchiori, Anna; Berthold, Timo; Gleixner, Ambros M.; Salvagnin, Domenic

Speech rhythm: a metaphor?

Is speech rhythmic? In the absence of evidence for a traditional view that languages strive to coordinate either syllables or stress-feet with regular time intervals, we consider the alternative that languages exhibit contrastive rhythm subsisting merely in the alternation of stronger and weaker elements. This is initially plausible, particularly for languages with a steep ‘prominence gradient’, i.e. a large disparity between stronger and weaker elements; but we point out that alternation is poorly achieved even by a ‘stress-timed’ language such as English, and, historically, languages have conspicuously failed to adopt simple phonological remedies that would ensure alternation. Languages seem more concerned to allow ‘syntagmatic contrast’ between successive units and to use durational effects to support linguistic functions than to facilitate rhythm. Furthermore, some languages (e.g. Tamil, Korean) lack the lexical prominence which would most straightforwardly underpin prominence alternation. We conclude that speech is not incontestibly rhythmic, and may even be antirhythmic. However, its linguistic structure and patterning allow the metaphorical extension of rhythm in varying degrees and in different ways depending on the language, and that it is this analogical process which allows speech to be matched to external rhythms

Bone Marrow Stem Cell Treatment for Ischemic Heart Disease in Patients with No Option of Revascularization: A Systematic Review and Meta-Analysis

PMCID: PMC3686792This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Characterization of human platelet binding of recombinant T cell receptor ligand

<p>Abstract</p> <p>Background</p> <p>Recombinant T cell receptor ligands (RTLs) are bio-engineered molecules that may serve as novel therapeutic agents for the treatment of neuroinflammatory conditions such as multiple sclerosis (MS). RTLs contain membrane distal α1 plus β1 domains of class II major histocompatibility complex linked covalently to specific peptides that can be used to regulate T cell responses and inhibit experimental autoimmune encephalomyelitis (EAE). The mechanisms by which RTLs impede local recruitment and retention of inflammatory cells in the CNS, however, are not completely understood.</p> <p>Methods</p> <p>We have recently shown that RTLs bind strongly to B cells, macrophages, and dendritic cells, but not to T cells, in an antigenic-independent manner, raising the question whether peripheral blood cells express a distinct RTL-receptor. Our study was designed to characterize the molecular mechanisms by which RTLs bind human blood platelets, and the ability of RTL to modulate platelet function.</p> <p>Results</p> <p>Our data demonstrate that human blood platelets support binding of RTL. Immobilized RTL initiated platelet intracellular calcium mobilization and lamellipodia formation through a pathway dependent upon Src and PI3 kinases signaling. The presence of RTL in solution reduced platelet aggregation by collagen, while treatment of whole blood with RTL prolonged occlusive thrombus formation on collagen.</p> <p>Conclusions</p> <p>Platelets, well-known regulators of hemostasis and thrombosis, have been implicated in playing a major role in inflammation and immunity. This study provides the first evidence that blood platelets express a functional RTL-receptor with a putative role in modulating pathways of neuroinflammation.</p

Deep generative modeling for single-cell transcriptomics.

Single-cell transcriptome measurements can reveal unexplored biological diversity, but they suffer from technical noise and bias that must be modeled to account for the resulting uncertainty in downstream analyses. Here we introduce single-cell variational inference (scVI), a ready-to-use scalable framework for the probabilistic representation and analysis of gene expression in single cells ( https://github.com/YosefLab/scVI ). scVI uses stochastic optimization and deep neural networks to aggregate information across similar cells and genes and to approximate the distributions that underlie observed expression values, while accounting for batch effects and limited sensitivity. We used scVI for a range of fundamental analysis tasks including batch correction, visualization, clustering, and differential expression, and achieved high accuracy for each task