Biology subjects

Zhou, Z.

Publications and source records attributed to Zhou, Z..

At least 343 records · Page 19Linked to original sources

bioRxiv2022

Genetic variation of human myokine signaling is dominated by biologic sex and sex hormones

Abstract/IntroductionProteins secreted from skeletal muscle, termed myokines, allow muscle to impact systemic physiology and disease. Myokines play critical roles in a variety of processes, including metabolic homeostasis, exercise improvements, inflammation, cancer and cognitive functions1-6. Despite the clear relevance of these factors in mediating a multitude of physiological outcomes, the genetic architecture, regulation and functions of myokines, as well as degree of conservation of these communication circuits remains inadequately understood. Given that biologic sex controls critical aspects of nearly every physiologic outcome, it is essential to consider when relating specific mechanisms to complex genetic and metabolic interactions. Specifically, many metabolic traits impacted by myokines show striking sex differences arising from hormonal7-10, genetic7,11 or gene-by-sex interactions12,13. In this study, we performed a genetic survey of myokine gene regulation and cross-tissue signaling in humans where sex as a biological variable was emphasized. While expression levels of a majority of myokines and cell proportions within skeletal muscle showed little differences between males and females, nearly all significant cross-tissue enrichments operated in a sex-specific or hormone-dependent fashion; in particular, with estrogens. These sex- and hormone-specific effects were consistent across key metabolic tissues: liver, pancreas, hypothalamus, intestine, heart, visceral and subcutaneous adipose tissue. Skeletal muscle estrogen receptor enrichments across metabolic tissues appeared stronger than androgen receptor and, surprisingly, ~3-fold higher in males compared to females. To define the causal roles of estrogen signaling on myokine gene expression and functions, we generated male and female mice which lack estrogen receptor (Esr1) specifically in skeletal muscle and integrated global RNA-Sequencing with human data. These analyses highlighted mechanisms of sex-dependent myokine signaling conserved between species, such as myostatin enriched for divergent substrate utilization pathways between sexes. Several other sex-dependent mechanisms of myokine signaling were uncovered, such as muscle-derived TNF exerting stronger inflammatory signaling in females compared to males and GPX3 as a male-specific link between glycolytic fiber abundance and hepatic inflammation. Collectively, we provide the first genetic survey of human myokines and highlight sex and estrogen receptor signaling as critical variables when assaying myokine functions and how changes in cell composition impact other metabolic organs.

physiology↗

bioRxiv2022

GR13-type plasmids in Acinetobacter potentiate the accumulation and horizontal transfer of diverse accessory genes

Carbapenem resistance and other antibiotic resistance genes (ARGs) can be found in plasmids in Acinetobacter, but many plasmid types in this genus have not been well-characterised. Here we describe the distribution, diversity and evolutionary capacity of rep group 13 (GR13) plasmids that are found in Acinetobacter species from diverse environments. Our investigation was prompted by the discovery of two GR13 plasmids in A. baumannii isolated in an intensive care unit (ICU). The plasmids harbour distinct accessory genes: pDETAB5 contains blaNDM-1 and genes that confer resistance to four further antibiotic classes, while pDETAB13 carries putative alcohol tolerance determinants. Both plasmids contain multiple dif modules, which are flanked by pdif sites recognised by XerC/XerD tyrosine recombinases. The ARG-containing dif modules in pDETAB5 are almost identical to those found in pDETAB2, a GR34 plasmid from an unrelated A. baumannii isolated in the same ICU a month prior. Examination of a further 41 complete, publicly available plasmid sequences revealed that the GR13 pangenome consists of just four core but 1086 accessory genes, 123 in the shell and 1063 in the cloud, reflecting substantial capacity for diversification. The GR13 core genome includes genes for replication and partitioning, and for a putative tyrosine recombinase. Accessory segments encode proteins with diverse putative functions, including for metabolism, antibiotic/heavy metal/alcohol tolerance, restriction-modification, an anti-phage system and multiple toxin-antitoxin systems. The movement of dif modules and actions of insertion sequences play an important role in generating diversity in GR13 plasmids. Discrete GR13 plasmid lineages are internationally disseminated and found in multiple Acinetobacter species, which suggests they are important platforms for the accumulation, horizontal transmission and persistence of accessory genes in this genus. Impact statementAcinetobacter species are particularly well-adapted for persistence in hospital environments where they pose a life-threatening infection risk to the most clinically-vulnerable patients. Plasmids with the potential to transfer multiple antibiotic resistance determinants between Acinetobacter species are therefore concerning, but most are not well-characterised. This work sheds further light on the poorly-understood mobile gene pool associated with Acinetobacter. We show here that GR13 plasmids carry a small set of core genes but have access to a highly diverse set of accessory segments that might provide fitness advantages under certain conditions. The complex evolutionary dynamics of GR13 plasmids appear to be driven by the exchange of dif modules and by the actions of a diverse population of insertion sequences. The novel dif modules characterised here emphasise the broader importance of these elements to the dissemination of accessory genes in Acinetobacter. This study has improved our understanding of the diversity and distribution of dif modules, plasmids that carry them, and how both disseminate in the continuum of Acinetobacter populations that link hospitals and the wider environment.

microbiology↗

bioRxiv2022

EnteroBase: Hierarchical clustering of 100,000s of bacterial genomes into species/sub-species and populations

The definition of bacterial species is traditionally a taxonomic issue while bacterial populations are identified by population genetics. These assignments are species specific, and depend on the practitioner. Legacy multilocus sequence typing is commonly used to identify sequence types (STs) and clusters (ST Complexes). However, these approaches are not adequate for the millions of genomic sequences from bacterial pathogens that have been generated since 2012. EnteroBase (http://enterobase.warwick.ac.uk) automatically clusters core genome MLST allelic profiles into hierarchical clusters (HierCC) after assembling annotated draft genomes from short read sequences. HierCC clusters span core sequence diversity from the species level down to individual transmission chains. Here we evaluate HierCCs ability to correctly assign 100,000s of genomes to the species/subspecies and population levels for Salmonella, Escherichia, Clostridoides, Yersinia, Vibrio and Streptococcus. HierCC assignments were more consistent with maximum-likelihood super-trees of core SNPs or presence/absence of accessory genes than classical taxonomic assignments or 95% ANI. However, neither HierCC nor ANI were uniformly consistent with classical taxonomy of Streptococcus. HierCC was also consistent with legacy eBGs/ST Complexes in Salmonella or Escherichia and with O serogroups in Salmonella. Thus, EnteroBase HierCC supports the automated identification of and assignment to species/subspecies and populations for multiple genera.

microbiology↗

bioRxiv2022

CHDbase: A Comprehensive Knowledgebase for Congenital Heart Disease-related Genes and Clinical Manifestations

Congenital heart disease (CHD) is the most common cause of major birth defects, with a prevalence of 1%. Although an increasing number of studies reporting the etiology of CHD, the findings scattered throughout the literature are difficult to retrieve and utilize in research and clinical practice. We therefore developed CHDbase, an evidence-based knowledgebase with CHD-related genes and clinical manifestations manually curated from 1114 publications, linking 1124 susceptibility genes and 3591 variations to more than 300 CHD types and related syndromes. Metadata such as the information of each publication and the selected population and samples, the strategy of studies, and the major findings of study were integrated with each item of research record. We also integrated functional annotations through parsing ~50 databases/tools to facilitate the interpretation of these genes and variations in disease pathogenicity. We further prioritized the significance of these CHD-related genes with a gene interaction network approach, and extracted a core CHD sub-network with 163 genes. The clear genetic landscape of CHD enables the phenotype classification based on the shared genetic origin. Overall, CHDbase provides a comprehensive and freely available resource to study CHD susceptibility, supporting a wide range of users in the scientific and medical communities. CHDbase is accessible at http://chddb.fwgenetics.org/.

genetics↗

bioRxiv2021

Non-rapid eye movement sleep and wake neurophysiology in schizophrenia

Motivated by the potential of objective neurophysiological markers to index thalamocortical function in patients with severe psychiatric illnesses, we comprehensively characterized key NREM sleep parameters across multiple domains, their interdependencies, and their relationship to waking event-related potentials and symptom severity. In 130 schizophrenia (SCZ) patients and controls, we confirmed a marked reduction in sleep spindle density in SCZ and extended these findings to show that only slow spindles predicted symptom severity, and that fast and slow spindle properties were largely uncorrelated. We also describe a novel measure of slow oscillation and spindle interaction that was attenuated in SCZ. The main sleep findings were replicated in a demographically distinct sample, and a joint model, based on multiple NREM components, predicted disease status in the replication cohort. Although also altered in patients, auditory event-related potentials elicited during wake were unrelated to NREM metrics. Consistent with a growing literature implicating thalamocortical dysfunction in SCZ, our characterization identifies independent NREM and wake EEG biomarkers that may index distinct aspects of SCZ pathophysiology and point to multiple neural mechanisms underlying disease heterogeneity. This study lays the groundwork for evaluating these neurophysiological markers, individually or in combination, to guide efforts at treatment and prevention as well as identifying individuals most likely to benefit from specific interventions.

neuroscience↗

bioRxiv2021

The consequence of fiber orientation downsampling on the computation of white matter tract-related deformation

Incorporating neuroimaging-revealed structural details into finite element (FE) head models opens vast new opportunities to better understand brain injury mechanisms. Recently, growing efforts have been made to integrate fiber orientation from diffusion tensor imaging (DTI) into FE models to predict white matter (WM) tract-related deformation that is biomechanically characterized by tract-related strains. Commonly used approaches often downsample the spatially enriched fiber orientation to match the FE resolution with one orientation per element (i.e., element-wise orientation implementation). However, the validity of such downsampling operation and corresponding influences on the computed tract-related strains remain elusive. To address this, the current study proposed a new approach to integrate voxel-wise fiber orientation from one DTI atlas (isotropic resolution of 1 mm3) into FE models by embedding orientations from multiple voxels within one element (i.e., voxel-wise orientation implementation). By setting the responses revealed by the newly proposed voxel-wise orientation implementation as the reference, we evaluated the reliability of two previous downsampling approaches by examining the downsampled fiber orientation and the computationally predicted tract-related strains secondary to one concussive impact. Two FE models with varying element sizes (i.e., 6.37 {+/-} 1.60 mm and 1.28 {+/-} 0.55 mm, respectively) were incorporated. The results showed that, for the model with a large voxel-mesh resolution mismatch, the downsampled element-wise fiber orientation, with respect to its voxel-wise counterpart, exhibited an absolute deviation over 30{degrees} across the WM/gray matter interface and the pons regions. Accordingly, this orientation deviation compromised the computation of tract-related strains with normalized root-mean-square errors up to 30% and underestimated the peak tract-related strains up to 10%. For the other FE model with finer meshes, the downsampling-induced effects were lower, both on the fiber orientation and tract-related strains. Taken together, the voxel-wise orientation implementation is recommended in future studies as it leverages the DTI-delineated fiber orientation to a larger extent than the element-wise orientation implementation. Thus, this study yields novel insights on integrating neuroimaging-revealed fiber orientation into FE models and may better inform the computation of WM tract-related deformation, which are crucial for advancing the etiological understanding and computational predictability of brain injury. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/471622v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@12ebda9org.highwire.dtl.DTLVardef@1a5d624org.highwire.dtl.DTLVardef@8e068borg.highwire.dtl.DTLVardef@4f8ff5_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2021

The Presence of the Temporal Horn Exacerbates the Vulnerability of Hippocampus during Head Impacts

Hippocampal injury is common in traumatic brain injury (TBI) patients, but the underlying pathogenesis remains elusive. In this study, we hypothesize that the presence of the adjacent fluid-containing temporal horn exacerbates the biomechanical vulnerability of the hippocampus. Two finite element models of the human head were used to investigate this hypothesis, one with and one without the temporal horn, and both including a detailed hippocampal subfield delineation. A fluid-structure interaction coupling approach was used to simulate the brain-ventricle interface, in which the intraventricular cerebrospinal fluid was represented by an arbitrary Lagrangian-Eulerian multi-material formation to account for its fluid behavior. By comparing the response of these two models under identical loadings, the model that included the temporal horn predicted increased magnitudes of strain and strain rate in the hippocampus with respect to its counterpart without the temporal horn. This specifically affected cornu ammonis (CA) 1 (CA1), CA2/3, hippocampal tail, subiculum, and the adjacent amygdala and ventral diencephalon. These computational results suggest that the presence of the temporal horn exacerbate the vulnerability of the hippocampus, highlighting the mechanobiological dependency of the hippocampus on the temporal horn.

bioengineering↗

bioRxiv2021

Age-dependent aggregation of ribosomal RNA-binding proteins links deterioration in chromatin stability with loss of proteostasis

Chromatin instability and loss of protein homeostasis (proteostasis) are two well-established hallmarks of aging, which have been considered largely independent of each other. Using microfluidics and single-cell imaging approaches, we observed that, during the replicative aging of S.cerevisiae, proteostasis decline occurred specifically in the fraction of cells with decreased stability at the ribosomal DNA (rDNA) region. A screen of 170 yeast RNA-binding proteins identified ribosomal RNA (rRNA)- binding proteins as the most enriched group that aggregate upon a decrease in rDNA stability. We further found that loss of rDNA stability contributes to age-dependent aggregation of rRNA-binding proteins through aberrant overproduction of rRNAs. These aggregates negatively impact nucleolar integrity and global proteostasis and hence limit cellular lifespan. Our findings reveal a mechanism underlying the interconnection between chromatin instability and proteostasis decline and highlight the importance of cell-to-cell variability in aging processes.

cell biology↗

bioRxiv2021

Functional classification and validation of yeast prenylation motifs using machine learning and genetic reporters

Protein prenylation by farnesyltransferase (FTase) is often described as the targeting of a cysteine-containing motif (CaaX) that is enriched for aliphatic amino acids at the a1 and a2 positions, while quite flexible at the X position. Prenylation prediction methods often rely on these features despite emerging evidence that FTase has broader target specificity than previously considered. Using a machine learning approach and training sets based on canonical (prenylated, proteolyzed, and carboxymethylated) and recently identified shunted motifs (prenylation only), this study aims to improve prenylation predictions with the goal of determining the full scope of prenylation potential among the 8000 possible Cxxx sequence combinations. Further, this study aims to subdivide the prenylated sequences as either shunted (i.e., uncleaved) or cleaved (i.e., canonical). Predictions were determined for Saccharomyces cerevisiae FTase and compared to results derived using currently available prenylation prediction methods. In silico predictions were further evaluated using in vivo methods coupled to two yeast reporters, the yeast mating pheromone a-factor and Hsp40 Ydj1p, that represent proteins with canonical and shunted CaaX motifs, respectively. Our machine learning based approach expands the repertoire of predicted FTase targets and provides a framework for functional classification.

biochemistry↗

bioRxiv2021

Generation of Infant-dedicated Fine-grained Functional Parcellation Maps of Cerebral Cortex

Infancy is a dynamic and immensely important period in human brain development. Studies of infant functional development using resting-state fMRI rely on precisely defined cortical parcellation maps. However, available adult-based functional parcellation maps are not applicable for infants due to their substantial differences in functional organizations. Fine-grained infant-dedicated cortical parcellation maps are highly desired but remain scarce, due to difficulties ranging from acquiring to processing of infant brain MRIs. In this study, leveraging 1,064 high-resolution longitudinal rs-fMRIs from 197 infants from birth to 24 months and advanced infant-dedicated processing tools, we create the first set of infant-specific, fine-grained cortical functional parcellation maps. Besides the conventional folding-based cortical registration, we specifically establish the functional correspondences across individuals using functional gradient densities and generate both age-specific and age-common fine-grained parcellation maps. The first set of comprehensive brain functional developmental maps are accordingly derived, and reveals a complex, hitherto unseen multi-peak fluctuation development pattern in temporal variations of gradient density, network sizes, and local efficiency, with more dynamic changes during the first 9 months than other ages. Our proposed method is applicable in generating fine-grained parcellations for the whole lifespan, and our parcellation maps will be available online to advance the neuroimaging field.

neuroscience↗

bioRxiv2021

RPRM negatively regulates ATM levels involving its phosphorylation mediated by CDK4/CDK6

Sensitizing cancer cells to radio- and chemotherapy remains a hot topic in cancer treatment. Here it is identified that Protein Reprimo (RPRM) negatively regulates the levels of ataxia-telangiectasia mutated (ATM) protein kinase, a master regulator of DNA damage response (DDR) in the presence of DNA double-strand breaks (DSBs), resulting in impaired DNA repair efficiency and enhanced cellular sensitivity to genotoxic agents. Mechanistically, although RPRM is primarily located in cytoplasm, it rapidly translocates to nucleus shortly after induced by X-irradiation, interacts with ATM and promotes the nuclear export and proteasomal degradation of ATM. The nuclear translocation of RPRM is associated with its phosphorylation at serine 98, which is mediated by cyclin-dependent kinases 4/6 (CDK4/6). Inhibition of CDK4/6 stabilizes RPRM and promotes its nuclear import, in turn enhances the nuclear export of ATM and the reduction of ATM levels. As a result, RPRM overexpression and its phosphorylation inhibition sensitize cells to genotoxic agents. Moreover, RPRM deficiency significantly increases resistance to radiation-induced damage both in vitro and in vivo. These findings establish a crucial regulatory mechanism in which ATM is negatively modulated by RPRM, suggesting that RPRM may serve as a novel target for both cancer therapy and radiation protection.

cancer biology↗

bioRxiv2021

Characterization of pyridomycin B reveals the formation of functional groups in antimycobacterial pyridomycin

Pyridomycin, a cyclodepsipeptide with potent antimycobacterial activity, specifically inhibits the InhA enoyl reductase of Mycobacteria tuberculosis. Structure-activity relationship studies indicated that the enolic acid moiety in pyridomycin core system is an important pharmacophoric group and the natural configuration of the C-10 hydroxyl contributes to the bioactivity of pyridomycin. The ring structure of pyridomycin was generated by the nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) hybrid system (PyrE-F-G). Bioinformatics analysis reveals that SDR family protein Pyr2 functions as a 3-oxoacyl ACP reductase in the pyridomycin pathway. Inactivation of pyr2 resulted in accumulation of pyridomycin B, a new pyridomycin analogue featured with enol moiety in pyridyl alanine moiety and a saturated 3-methylvaleric acid group. The elucidated structure of pyridomycin B suggests that rather than functioning as a post-tailoring enzyme, Pyr2 catalyzes ketoreduction to form the C-10 hydroxyl group in pyridyl alanine moiety and the double bond formation of the enolic acid moiety derived from isoleucine when the intermediate assembled by PKS-NRPS machinery is still tethered to the last NRPS module, in a special energy-saving manner. Ser-His-Lys residues constitute the active site of Pyr2, which is different from the typically conserved Tyr based catalytic triad in the majority of SDRs. Site-directed mutation identified that His154 in the active site is a critical residue for pyridomycin B production. These findings will improve our understanding of the pyridomycin biosynthetic logic, identify the missing link for the double bound formation of enol ester in pyridomycin and enable creating chemical diversity of pyridomycin derivatives. ImportanceTuberculosis (TB) is one of the worlds leading causes of death by infection. Recently, pyridomycin, the antituberculous natural product from Streptomyces has garnered considerable attention for being determined as a target inhibitor of InhA enoyl reductase of Mycobacteria tuberculosis. In this study, we report a new pyridomycin analogue from mutant HTT12, demonstrate the essential role of a previously ignored gene pyr2 in pyridomycin biosynthetic pathway, and imply that Pyr2 functions as a trans ketoreductase (KR) contributing to the formation of functional groups of pyridomycin utilize a distinct catalytic mechanism. As enol moiety are important for pharmaceutical activities of pyridomycin, our work would expand the understanding the mechanism of SDR family proteins and set the stage for future bioengineering of new pyridomycin derivatives.

microbiology↗

bioRxiv2021

Calcium-independent but voltage-dependent secretion (CiVDS) mediates synaptic transmission in a mammalian central synapse

A central principle of synaptic transmission is that action potential-induced presynaptic neurotransmitter release occurs exclusively via Ca2+-dependent secretion (CDS). The discovery and mechanistic investigations of Ca2+-independent but voltage-dependent secretion (CiVDS) have demonstrated that the action potential per se is sufficient to trigger neurotransmission in the somata of primary sensory and sympathetic neurons in mammals. One key question remains, however, whether CiVDS contributes to central synaptic transmission. Here we report, in the central transmission from presynaptic (dorsal root ganglion) to postsynaptic (spinal dorsal horn) neurons, (1) excitatory postsynaptic currents (EPSCs) are mediated by glutamate transmission through both CiVDS (up to 87%) and CDS; (2) CiVDS-EPSCs are independent of extracellular and intracellular Ca2+; (3) CiVDS is >100 times faster than CDS in vesicle recycling with much less short-term depression; (4) the fusion machinery of CiVDS includes Cav2.2 (voltage sensor) and SNARE (fusion pore). Together, an essential component of activity-induced EPSCs is mediated by CiVDS in a central synapse.

neuroscience↗

bioRxiv2021

E3 ligase TRIM47 positively regulates endothelial activation and pulmonary inflammation through potentiating the K63-linked ubiquitination

Endothelial activation plays an essential role in the pathology of sepsis-induced acute lung injury, but the detailed regulatory mechanisms remain largely unknown. Here, we demonstrated that TRIM47, an ubiquitin E3 ligase of tripartite protein family, is highly expressed in vascular endothelial cells and is up-regulated during TNF-induced endothelial activation. Knockdown of TRIM47 in endothelial cells prevents the transcription of multiple pro-inflammatory cytokines, reduces monocyte adhesion and the expression of adhesion molecules, and inhibits the secretion of IL-1{beta} and IL-6 into the supernatant. By contrast, overexpression of TRIM47 promotes inflammatory response and monocyte adhesion upon TNF stimulation. TRIM47 modulates the activation of NF-{kappa}B and MAPK signaling pathways during endothelial activation. Further experiment confirmed that TRIM47 interacts with TRAF2 and mediates K63-linked ubiquitination. In addition, TRIM47-deficient mice are more resistant to lipopolysaccharide-induced acute lung injury and death, due to attenuated pulmonary inflammation. Taken together, our studies suggest that TRIM47 promotes pulmonary inflammation and injury at least partly through potentiating the K63-linked ubiquitination of TRAF2, which in turn activates NF-{kappa}B and MAPK signaling pathways to trigger inflammatory response in endothelial cells.

cell biology↗

bioRxiv2021

Drought restricted sucrose transport from outer cottonseed coat to fiber and further inhibited cellulose synthesis during cotton fiber thickening

The formation of cotton fiber strength largely relies on continuous and steady sucrose supply to cellulose synthesis and is greatly impaired by drought. However, the effects of drought on sucrose import into fiber and its involvement in cellulose biosynthesis within fiber remain unclear. To end this, moisture deficiency experiments were conducted using two Gossypium hirsutum cultivars of Dexiamian 1 (drought-tolerant) and Yuzaomian 9110 (drought-sensitive). Fiber strength was significantly decreased under drought. The results of 13C isotope labeling indicated that drought notably reduced sucrose efflux from cottonseed coat to fiber, and this was caused by down-regulation of sucrose transporter genes (GhSWEET10 and GhSWEET15) in the outer cottonseed coat, finally leading to decreased sucrose accumulation in fiber. Further, under drought, the balance of sucrose allocation within fiber was disrupted by increasing the flow of sucrose into {beta}-1,3-glucan synthesis and lignin synthesis but hindering that into cellulose synthesis in both cultivars. Additionally, glycolysis and starch synthesis were specifically enhanced by drought in Yuzaomian 9110, which further reduced the flow of sucrose into cellulose synthesis. Under drought, the cellulose deposition was decreased due to promoted cellulose degrading process in Dexiamian 1 and stunted cellulose synthesis in Yuzaomian 9110. Consequently, reduced cellulose content was measured in drought-stressed fibers for both cultivars. In summary, the inhibited cellulose accumulation caused by drought was mainly due to reduced sucrose translocation from the outer cottonseed coat to fiber, and less sucrose partitioned to cellulose synthesis pathway under the condition of intensified competition for sucrose by different metabolic pathways within fiber, finally degrading the fiber strength. HighlightThis article revealed the path of sucrose flow from cottonseed coat to cotton fiber and sucrose competition patterns within cotton fiber under drought and their relationships with fiber strength loss.

plant biology↗

bioRxiv2021

Effective and Efficient Neural Networks for Spike Inference from In Vivo Calcium Imaging

Calcium imaging technique provides the advantages in monitoring large population of neuronal activities simultaneously. However, it lacks the signal quality provided by neural spike recording in traditional electrophysiology. To address this issue, we developed a supervised data-driven approach to extract spike information from calcium signals. We propose the ENS2 (effective and efficient neural networks for spike inference from calcium signals) system for spike-rate and spike-event predictions using raw calcium inputs based on U-Net deep neural network. When testing on a large, ground truth public database, it consistently outperformed state-of-the-arts algorithms in both spike-rate and spike-event predictions with reduced computational load. We further demonstrated that ENS2 can be applied to analyses of orientation selectivity in primary visual cortex neurons. We concluded that it would be a versatile inference system that benefits diverse neuroscience studies.

neuroscience↗

bioRxiv2021

A missense KCNQ1 Mutation Impairs Insulin Secretion in Neonatal Diabetes

KCNQ1/Kv7 is a voltage-gated K+ channel that regulates heart rhythm, glucose and salt homeostasis. Mutations of KCNQ1 are primarily associated with long-QT syndrome and type 2 diabetes; however, thus far KCNQ1 mutations have not been associated with monogenetic diabetes. Here, we identified a homozygous KCNQ1 missense mutation (R397W) in an individual with permanent neonatal diabetes (PND). To identify the mechanisms that link the mutation to the disease, we introduced the mutation into human embryonic stem cells (hESCs), and used them to derived pancreatic {beta}-like cells (hESC-{beta} cell). In early {beta}-like cells, we observed atypical membrane electrical activity, increased levels of cytoplasmic Ca2+, and a hypersecretion of insulin. Upon extended culture, their insulin secretion decreased and the number of apoptotic cells increased, resulting in a reduction in the numbers of {beta}-like cells. Late-stage {beta}-like cells exhibited a decrease in the expression of metabolic genes, e.g. HNF4, PDX1 and GLUT1, providing a possible mechanism for {beta}-cell dysfunction. Our study identifies KCNQ1 as a novel candidate gene of monogenetic diabetes and shows that KCNQ1 regulates {beta}-cell function and survival.

cell biology↗

bioRxiv2021

Structural (dys)connectivity associates with cholinergic cell density of the nucleus basalis of Meynert in Alzheimer's disease

Cognitive deficits in Alzheimers disease, specifically amnestic (memory dominant) deficits, are associated with cholinergic degeneration in the basal forebrain. The cholinergic nucleus within the basal forebrain, the nucleus basalis of Meynert, exhibits local atrophy and reduced cortical tract integrity on MRI, and reveals amyloid-{beta} and phosphorylated-tau pathology at autopsy. To better understand the pathophysiology of nucleus basalis of Meynert atrophy and its neocortical projections in Alzheimers disease, we utilized a combined post-mortem in-situ MRI and histopathology approach. A total of 19 Alzheimers disease (10 amnestic and 9 non-amnestic) and 9 non-neurological control donors underwent 3T T1-weighted MRI for anatomical delineation and volume assessment of the nucleus basalis of Meynert, and diffusion-weighted imaging for microstructural assessment of the nucleus and its projections. At subsequent brain autopsy, tissue dissection and immunohistochemistry were performed for amyloid-{beta}, phosphorylated-tau and choline acetyltransferase. Compared to controls, we observed an MRI-derived volume reduction and altered microstructural integrity of the nucleus basalis of Meynert in Alzheimers disease donors. Furthermore, decreased cholinergic cell density was associated with reduced integrity of the nucleus and its tracts to the temporal lobe, specifically to the temporal pole of the superior temporal gyrus, and the parahippocampal gyrus. The association between cholinergic cell density and alteration to cortical tracts was specific for amnestic, compared to non-amnestic Alzheimers disease donors. Our study illustrates that the nucleus basalis of Meynert is severely affected in amnestic Alzheimers disease, both in terms of pathology within the nucleus, but also in terms of damage to its cortical projections, specifically to the temporal lobe, which may contribute to the observed cognitive deterioration.

neuroscience↗