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Visual behavior and visual cortex function in adulthood are affected by early visual experience. In humans, the developmental origins of these differences amongst adults are not known. It is often assumed that differences reflect reorganizing effects of blindness on cortical function. Whether vision also plays an instructive role is not known. Here we compare newly available resting state (functional connectivity) data from two large cohorts of sighted infants (Developing Human Connectome Project (dHCP), second release: n=327, third release: n=475) to data from sighted adults (blindfolded, n=50) and blind adults (n=30). By comparing the “starting state” of infants to that of blind and sighted adults, we dissociate the instructive contributions of visual experience from the reorganizing effects of blindness on functional connectivity of visual cortices. As previously reported, we find that in sighted adults, visual networks show stronger functional connectivity with other sensory-motor networks (i.e., auditory, somatosensory) than with higher-cognitive prefrontal networks. Adults born blind show the opposite pattern: stronger functional connectivity between visual and prefrontal than visual and other non-visual sensory-motor networks. The resting state patterns of infants resemble those of blind adults in secondary visual cortices, revealing an instructive role of vision in establishing the sighted adult connectivity pattern. In primary visual cortex (V1), the sighted infants show an intermediate pattern between that of sighted and blind adults, suggesting both instructive effects of vision and reorganizing effects of blindness in V1. Relative to both adult groups, when comparing connectivity across different sub-regions of visual and prefrontal cortex, infants show less specialization relative to both adult groups. Finally, lateralization of connectivity in infants resembles that of sighted adults, consistent with reorganizing effects of blindness. These results dissociate instructive and reorganizing effect of experience on visual cortex functional connectivity, providing insight into developmental mechanisms.

Functional interplay between CIF4 and CIF1 and between CIF4 and FPRC in T. brucei.

In vivo phosphosites on CIF2 identified by phosphoproteome assays in previous studies.

In vivo phosphosites on CIF1 identified by phosphoproteome assays in previous studies.

TbAUK1 phosphosites on CIF1 identified by in vitro kinase assays and mass spectrometry.

TbPLK phosphosites on CIF2 identified by in vitro kinase assays and mass spectrometry.

TbPLK phosphosites on CIF1 identified by in vitro kinase assays and mass spectrometry.

Determination of the subcellular localization of CIF2 and co-localization with CIF1 using the anti-CIF2 antibody.

TbAUK1 phosphosites on CIF2 identified by in vitro kinase assays and mass spectrometry.

Stress abounds in daily life and is closely related to psychiatric disease. Less is known about the neural basis for the gender differences in stress, and the common and specific neural mechanism for physiological and psychosocial stress. The current study obtained 141 stress-oriented neuroimaging experiments from 126 eligible articles and sorted them into nine types of neuroimaging datasets based on the combination of stress (general, physiological or psychosocial) and gender (overall, male or female). An activation likelihood estimation (ALE) meta-analysis was conducted on each dataset to detect the spatial convergence of activations. A hierarchical clustering analysis was also conducted to uncover the relationship between the stress-induced paradigms and spatial distribution of brain activations. We found that the physiological stress and psychosocial stress showed common activation in the bilateral anterior insula and brainstem, but different activation likelihood in the bilateral insula, thalami, middle cingulate cortex, left fusiform gyri, and left amygdala. Men were more likely to activate the bilateral thalami during physiological stress, whereas women were more likely to activate the left amygdala during psychosocial stress. The activation patterns are more consistent among different physiological stress paradigms than psychosocial stress paradigms. Our results suggest that physiological stress and psychosocial stress activate common brain regions for movement and attentional regulation but different brain regions for sensory and affective processing.

Background Mesenchymal stem cells (MSCs) show promising therapeutic potential in treating type 2 diabetes mellitus (T2DM) in clinical studies. Accumulating evidence has suggested that the therapeutic effects of MSCs are not due to their direct differentiation into functional β-cells but are instead mediated by their paracrine functions. Among them, exosomes, nano-sized extracellular vesicles, are important substances that exert paracrine functions. However, the underlying mechanisms of exosomes in ameliorating T2DM remain largely unknown. Methods Bone marrow mesenchymal stem cell (bmMSC)-derived exosomes (bmMDEs) were administrated to T2DM rats and high-glucose-treated primary islets in order to detect their effects on β-cell dedifferentiation. Differential miRNAs were then screened via miRNA sequencing, and miR-146a was isolated after functional verification. TargetScan, reporter gene detection, insulin secretion assays, and qPCR validation were used to predict downstream target genes and involved signaling pathways of miR-146a. Results Our results showed that bmMDEs reversed diabetic β-cell dedifferentiation and improved β-cell insulin secretion both in vitro and in vivo. Results of miRNA sequencing in bmMDEs and subsequent functional screening demonstrated that miR-146a, a highly conserved miRNA, improved β-cell function. We further found that miR-146a directly targeted Numb, a membrane-bound protein involved in cell fate determination, leading to activation of β-catenin signaling in β-cells. Exosomes derived from miR-146a-knockdown bmMSCs lost the ability to improve β-cell function. Conclusions These findings demonstrate that bmMSC-derived exosomal miR-146a protects against diabetic β-cell dysfunction by acting on the NUMB/β-catenin signaling pathway, which may represent a novel therapeutic strategy for T2DM. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02371-0.

Additional file 1.

Fast and reliable ambiguity resolution (AR) over long baselines is one of the major challenges for large-scale GNSS network real-time kinematic (RTK) positioning. In the dual-frequency case, wide-lane (WL) ambiguities are usually fixed firstly, followed by the procedure of determination of the narrow-lane (NL) ambiguity integers based on the ionosphere-free model. For long-baseline network RTK, there are still some problems faced, for instance the WL AR still needs to take over tens of epochs due to the influence of pseudorange noises and multipath effects; the NL AR model is weak since more parameters are introduced, thus much time is needed to guarantee the precision of float ambiguity solutions. Along with the deployment of modernized GPS, BDS and other GNSS, the triple-frequency AR with real data gradually becomes feasible. Many literatures have proven the third signal will make AR faster and more reliable. In this paper based on the characteristics of network RTK, a modified ionosphere-free model was proposed to improve EWL/WL AR performance for long baselines, followed by the comparison with several commonly-used EWL/WL AR models. The NL AR performance with triple-frequency and dual-frequency observations was also tested. In NL AR, a partial AR strategy is adopted to weaken the negative influence of new-rising or low-elevation satellites. Experiments were conducted using real BDS triple-frequency data on 74 km and 241 km baselines. Results show that the modified ionosphere-free model can balance the ambiguity precision and ambiguity bias better for the EWL/WL AR. The NL AR with triple-frequency observations also performs significantly better than that in dual-frequency mode, with 29.9% and 32.9% improvement in time-to-first-fix (TTFF) for the 74 km and 241 km baselines respectively.

Morphogenesis of a vascular network requires dynamic vessel growth and regression. To investigate the cellular mechanism underlying this process, we deleted focal adhesion kinase (FAK), a key signaling mediator, in endothelial cells (ECs) using Tie2-Cre mice. Targeted FAK depletion occurred efficiently early in development, where mutants exhibited a distinctive and irregular vasculature, resulting in hemorrhage and lethality between embryonic day (e) 10.5 and 11.5. Capillaries and intercapillary spaces in yolk sacs were dilated before any other detectable abnormalities at e9.5, and explants demonstrate that the defects resulted from the loss of FAK and not from organ failure. Time-lapse microscopy monitoring EC behavior during vascular formation in explants revealed no apparent decrease in proliferation or migration but revealed increases in cell retraction and death leading to reduced vessel growth and increased vessel regression. Consistent with this phenotype, ECs derived from mutant embryos exhibited aberrant lamellipodial extensions, altered actin cytoskeleton, and nonpolarized cell movement. This study reveals that FAK is crucial for vascular morphogenesis and the regulation of EC survival and morphology.

The c-myc proto-oncogene, which is crucial for the progression of many human cancers, has been implicated in key cellular processes in diverse cell types, including endothelial cells that line the blood vessels and are critical for angiogenesis. The de novo differentiation of endothelial cells is known as vasculogenesis, whereas the growth of new blood vessels from pre-existing vessels is known as angiogenesis. To ascertain the function of c-myc in vascular development, we deleted c-myc in selected cell lineages. Embryos lacking c-myc in endothelial and hematopoietic lineages phenocopied those lacking c-myc in the entire embryo proper. At embryonic day (E) 10.5, both mutant embryos were grossly normal, had initiated primitive hematopoiesis, and both survived until E11.5-12.5, longer than the complete null. However, they progressively developed defective hematopoiesis and angiogenesis. The majority of embryos lacking c-myc specifically in hematopoietic cells phenocopied those lacking c-myc in endothelial and hematopoietic lineages, with impaired definitive hematopoiesis as well as angiogenic remodeling. c-myc is required for embryonic hematopoietic stem cell differentiation, through a cell-autonomous mechanism. Surprisingly, c-myc is not required for vasculogenesis in the embryo. c-myc deletion in endothelial cells does not abrogate endothelial proliferation, survival, migration or capillary formation. Embryos lacking c-myc in a majority of endothelial cells can survive beyond E12.5. Our findings reveal that hematopoiesis is a major function of c-myc in embryos and support the notion that c-myc functions in selected cell lineages rather than in a ubiquitous manner in mammalian development.