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The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high-resolution transcriptional atlas of rhesus monkey ( Macaca mulatta ) brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical division of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons. Cortical layers and areas acquire adult-like molecular profiles surprisingly late in postnatal development. Disparate cell populations exhibit distinct developmental timing of gene expression, but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, although approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny compared to monkey. A high-resolution gene expression atlas of prenatal and postnatal brain development of rhesus monkey charts global transcriptional dynamics in relation to brain maturation, while comparative analysis reveals human-specific gene trajectories; candidate risk genes associated with human neurodevelopmental disorders tend to be co-expressed in disease-specific patterns in the developing monkey neocortex. Gene expression in the primate brain Following the publication of the mouse and human brain gene expression atlases in recent years, Ed Lein and colleagues now present a high-resolution transcriptional atlas of pre- and post-natal brain development for the rhesus monkey — the dominant non-human primate model for human brain development and disease. The data charts global transcriptional dynamics in relation to brain maturation, while comparative analysis reveals human-specific gene trajectories; candidate risk genes associated with human neurodevelopmental disorders tend to be co-expressed in disease-specific patterns in the developing monkey neocortex.

Cellular force generation and force transmission are of fundamental importance for numerous biological processes and can be studied with the methods of Traction Force Microscopy (TFM) and Monolayer Stress Microscopy. Traction Force Microscopy and Monolayer Stress Microscopy solve the inverse problem of reconstructing cell-matrix tractions and inter- and intra-cellular stresses from the measured cell force-induced deformations of an adhesive substrate with known elasticity. Although several laboratories have developed software for Traction Force Microscopy and Monolayer Stress Microscopy computations, there is currently no software package available that allows non-expert users to perform a full evaluation of such experiments. Here we present pyTFM, a tool to perform Traction Force Microscopy and Monolayer Stress Microscopy on cell patches and cell layers grown in a 2-dimensional environment. pyTFM was optimized for ease-of-use; it is open-source and well documented (hosted at https://pytfm.readthedocs.io/ ) including usage examples and explanations of the theoretical background. pyTFM can be used as a standalone Python package or as an add-on to the image annotation tool ClickPoints . In combination with the ClickPoints environment, pyTFM allows the user to set all necessary analysis parameters, select regions of interest, examine the input data and intermediary results, and calculate a wide range of parameters describing forces, stresses, and their distribution. In this work, we also thoroughly analyze the accuracy and performance of the Traction Force Microscopy and Monolayer Stress Microscopy algorithms of pyTFM using synthetic and experimental data from epithelial cell patches.

Oligodendroglia ensheath axons in the brain with myelin, which provides the insulation that speeds up transmission of neuronal electrical impulses. The process of myelination in the human brain goes on for decades, concurrent with all manner of brain development and cognitive activity. Gibson et al. (p. 10.1126/science.1252304 , published online 10 April; see the Perspective by Bechler and ffrench-Constant ) used optogenetics to study myelination in response to neural activity. Electrical activity in the motor cortex of the brain of awake mice led to proliferation and differentiation of oligodendrocytes and consequently increased myelination and alterations in motor response. Optogenetic stimulation of the mouse motor cortex incites proliferation of myelin-producing cells and axonal myelination. [Also see Perspective by Bechler and ffrench-Constant ] Myelination of the central nervous system requires the generation of functionally mature oligodendrocytes from oligodendrocyte precursor cells (OPCs). Electrically active neurons may influence OPC function and selectively instruct myelination of an active neural circuit. In this work, we use optogenetic stimulation of the premotor cortex in awake, behaving mice to demonstrate that neuronal activity elicits a mitogenic response of neural progenitor cells and OPCs, promotes oligodendrogenesis, and increases myelination within the deep layers of the premotor cortex and subcortical white matter. We further show that this neuronal activity–regulated oligodendrogenesis and myelination is associated with improved motor function of the corresponding limb. Oligodendrogenesis and myelination appear necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement.

Despite their importance for sea-level rise, seasonal water availability, and as a source of geohazards, mountain glaciers are one of the few remaining subsystems of the global climate system for which no globally applicable, open source, community-driven model exists. Here we present the Open Global Glacier Model (OGGM), developed to provide a modular and open-source numerical model framework for simulating past and future change of any glacier in the world. The modeling chain comprises data downloading tools (glacier outlines, topography, climate, validation data), a preprocessing module, a mass-balance model, a distributed ice thickness estimation model, and an ice-flow model. The monthly mass balance is obtained from gridded climate data and a temperature index melt model. To our knowledge, OGGM is the first global model to explicitly simulate glacier dynamics: the model relies on the shallow-ice approximation to compute the depth-integrated flux of ice along multiple connected flow lines. In this paper, we describe and illustrate each processing step by applying the model to a selection of glaciers before running global simulations under idealized climate forcings. Even without an in-depth calibration, the model shows very realistic behavior. We are able to reproduce earlier estimates of global glacier volume by varying the ice dynamical parameters within a range of plausible values. At the same time, the increased complexity of OGGM compared to other prevalent global glacier models comes at a reasonable computational cost: several dozen glaciers can be simulated on a personal computer, whereas global simulations realized in a supercomputing environment take up to a few hours per century. Thanks to the modular framework, modules of various complexity can be added to the code base, which allows for new kinds of model intercomparison studies in a controlled environment. Future developments will add new physical processes to the model as well as automated calibration tools. Extensions or alternative parameterizations can be easily added by the community thanks to comprehensive documentation. OGGM spans a wide range of applications, from ice–climate interaction studies at millennial timescales to estimates of the contribution of glaciers to past and future sea-level change. It has the potential to become a self-sustained community-driven model for global and regional glacier evolution.

Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells. ClinicalTrials.gov NCT01365065.

A common feature of glasses is the “boson peak”, observed as an excess in the heat capacity over the crystal or as an additional peak in the terahertz vibrational spectrum. The microscopic origins of this peak are not well understood; the emergence of locally ordered structures has been put forward as a possible candidate. Here, we show that depolarised Raman scattering in liquids consisting of highly symmetric molecules can be used to isolate the boson peak, allowing its detailed observation from the liquid into the glass. The boson peak in the vibrational spectrum matches the excess heat capacity. As the boson peak intensifies on cooling, wide-angle x-ray scattering shows the simultaneous appearance of a pre-peak due to molecular clusters consisting of circa 20 molecules. Atomistic molecular dynamics simulations indicate that these are caused by over-coordinated molecules. These findings represent an essential step toward our understanding of the physics of vitrification. The ‘boson peak’ refers to an extra peak in the terahertz vibrational spectrum of glasses. It is now shown that for liquids of highly symmetric molecules the boson peak can be singled out by means of depolarized Raman scattering; the peak is linked to the formation of clusters of about 20 molecules.

Mouse and human tumour-associated macrophages express PD-1, which increases with cancer stage and induces decreased phagocytosis by macrophages; by contrast, PD-L1 removal increases phagocytosis in vivo , decreases tumour burden and increases survival of mice. Blocking tumour immunity Therapeutic antibodies that inhibit the interaction of programmed cell death protein (PD-1) with its ligand (PD-L1) are known to activate cytotoxic T cells. Here Irv Weissmann and colleagues study the role for PD-1 on tumour-infiltrating macrophages in mice. The study shows that PD-1-expressing macrophages have limited phagocytic capabilities and that blocking PD-1/PD-L1 enhances phagocytosis and correlates with reduced tumour growth. This finding suggests a T-cell-independent mechanism of therapeutic activity of PD-1/PD-L1 inhibitors which may be clinically relevant. Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells for the induction of immune tolerance 1 , 2 . Tumour cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system 3 , 4 . Monoclonal antibodies that block the interaction between PD-1 and PD-L1, by binding to either the ligand or receptor, have shown notable clinical efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small-cell lung cancer and Hodgkin’s lymphoma 5 , 6 , 7 , 8 , 9 . Although it is well established that PD-1–PD-L1 blockade activates T cells, little is known about the role that this pathway may have in tumour-associated macrophages (TAMs). Here we show that both mouse and human TAMs express PD-1. TAM PD-1 expression increases over time in mouse models of cancer and with increasing disease stage in primary human cancers. TAM PD-1 expression correlates negatively with phagocytic potency against tumour cells, and blockade of PD-1–PD-L1 in vivo increases macrophage phagocytosis, reduces tumour growth and lengthens the survival of mice in mouse models of cancer in a macrophage-dependent fashion. This suggests that PD-1–PD-L1 therapies may also function through a direct effect on macrophages, with substantial implications for the treatment of cancer with these agents.

Plectin, a highly versatile cytolinker protein, provides tissues with mechanical stability through the integration of intermediate filaments (IFs) with cell junctions. Here, we hypothesize that plectin-controlled cytoarchitecture is a critical determinant of the intestinal barrier function and homeostasis. Mice lacking plectin in an intestinal epithelial cell (IEC; PleΔIEC) spontaneously developed colitis characterized by extensive detachment of IECs from the basement membrane (BM), increased intestinal permeability, and inflammatory lesions. Moreover, plectin expression was reduced in the colons of ulcerative colitis (UC) patients and negatively correlated with the severity of colitis. Mechanistically, plectin deficiency in IECs led to aberrant keratin filament (KF) network organization and the formation of dysfunctional hemidesmosomes (HDs) and intercellular junctions. In addition, the hemidesmosomal α6β4 integrin (Itg) receptor showed attenuated association with KFs, and protein profiling revealed prominent downregulation of junctional constituents. Consistent with the effects of plectin loss in the intestinal epithelium, plectin-deficient IECs exhibited remarkably reduced mechanical stability and limited adhesion capacity in vitro. Feeding mice with a low-residue liquid diet that reduced mechanical stress and antibiotic treatment successfully mitigated epithelial damage in the PleΔIEC colon.

Background Rare diseases present a substantial patient burden, but the impact on non-professional caregivers is poorly understood. We explored the health-related quality of life (HRQoL) and productivity burden on caregivers of adults with rare diseases. Methods We analysed physician- and caregiver-reported real-world data from France, Germany, Italy, Spain, the United Kingdom, and the United States of America collected July 2017–March 2021 via Adelphi Disease Specific Programmes™ in amyotrophic lateral sclerosis (ALS), eosinophilic esophagitis (EoE), graft versus host disease (GvHD), Huntington’s disease (HD), myasthenia gravis (MG), and progressive supranuclear palsy (PSP). Non-professional caregivers completed the EQ-5D-5L and Work Productivity and Activity Impairment questionnaire. Multivariate regression analysis modelled the relationship of care recipient/caregiver characteristics with caregiver HRQoL and productivity. Results Data were provided by 365 caregivers; 114, 89, 75, 32, 29 and 26 in GvHD, PSP, ALS, MG, EoE and HD, respectively. Care recipients’ mean (standard deviation [SD]) age was 58.7 (15.6) years, 59% were male and 23% had both professional and non-professional caregivers. Patients’ mean (SD) EuroQol visual analogue scale (EQ VAS) score was 50.9 (23.3) and mean EQ-5D utility was 0.460 (0.350). Caregivers’ mean age was 55.8 (13.8) years, 66% were female. Caregivers’ EQ-5D-5L indicated their greatest problems in anxiety/depression. Overall, 45% of caregivers were employed, mostly part-time. In the past 7 days, mean (SD) caregiver absenteeism was 5.2% (13.1%), presenteeism was 28.0% (23.7%), and activity impairment was 43.1% (27.2%). Regressions identified multiple significant associations with caregivers’ HRQoL and productivity. Caregivers’ HRQoL (EQ-5D utility and EQ VAS) was associated with care recipients’ EQ-5D utility and caregivers’ age. Outcomes relating to caregivers’ employment and productivity (hours spent caring, employment status, hours in employment, hours of employment missed, absenteeism, presenteeism, work impairment and activity impairment) were most frequently associated with care recipients’ EQ-5D utility, caregivers’ age and sex, caregiver living with the care recipient, the presence of a professional caregiver, and the care recipient having HD. Conclusions The substantial burden of providing non-professional caregiving to adults with rare diseases is associated with multiple factors. Interventions improving care recipient HRQoL could enhance caregiver HRQoL and productivity.

Hematopoietic stem cell (HSC) homeostasis in the adult bone marrow (BM) is regulated by both intrinsic gene expression products and interactions with extrinsic factors in the HSC niche. GRP94, an endoplasmic reticulum chaperone, has been reported to be essential for the expression of specific integrins and to selectively regulate early T and B lymphopoiesis. In GRP94 deficient BM chimeras, multipotent hematopoietic progenitors persisted and even increased, however, the mechanism is not well understood. Here we employed a conditional knockout (KO) strategy to acutely eliminate GRP94 in the hematopoietic system. We observed an increase in HSCs and granulocyte-monocyte progenitors in the Grp94 KO BM, correlating with an increased number of colony forming units. Cell cycle analysis revealed that a loss of quiescence and an increase in proliferation led to an increase in Grp94 KO HSCs. This expansion of the HSC pool can be attributed to the impaired interaction of HSCs with the niche, evidenced by enhanced HSC mobilization and severely compromised homing and lodging ability of primitive hematopoietic cells. Transplanting wild-type (WT) hematopoietic cells into a GRP94 null microenvironment yielded a normal hematology profile and comparable numbers of HSCs as compared to WT control, suggesting that GRP94 in HSCs, but not niche cells, is required for maintaining HSC homeostasis. Investigating this, we further determined that there was a near complete loss of integrin α4 expression on the cell surface of Grp94 KO HSCs, which showed impaired binding with fibronectin, an extracellular matrix molecule known to play a role in mediating HSC-niche interactions. Furthermore, the Grp94 KO mice displayed altered myeloid and lymphoid differentiation. Collectively, our studies establish GRP94 as a novel cell intrinsic factor required to maintain the interaction of HSCs with their niche, and thus regulate their physiology.