Biology subjects

Qiu, S.

Publications and source records attributed to Qiu, S..

At least 73 records · Page 4Linked to original sources

bioRxiv2023

Mitochondrial DNA released by senescent cells triggers immunosuppression in cancer

DNA is a potent damage-associated molecular pattern signaling that, once in the extracellular space, triggers the activation of the innate immune system. Here we find that senescent cells release mtDNA to both the cytosol and the extracellular space. In cells undergoing cellular senescence, the release of mtDNA precedes that of nuclear DNA resulting in the activation of the cGAS/STING pathway and establishment of cellular senescence. Intriguingly, by exploiting co-culture and in vivo cross-species experiments, we show that extracellular mtDNA released by senescent tumors cells is specifically captured by polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the tumor microenvironment (TME). Mechanistically we find that PMN-MDSCs uptake mtDNA to enhance their immunosuppressive ability. Pharmacological inhibition of mtDNA released from senescent tumor cells blocks the PMN-MDSCs immunosuppressive activity, improving the efficacy of therapy-induced senescence (TIS) in cancer. These results reveal the crucial role of mtDNA in initiating cellular senescence and immunosuppression independently of the SASP. Thus, targeting mtDNA release-mediated pathway may hold promise to reprogram the immune suppressive microenvironment in patients treated with chemotherapy.

cell biology↗

bioRxiv2023

ASD mutation of Katnal2 impairs ependymal ciliary motion and causes hydrocephalus

Katanin catalytic subunit A1 like 2 (KATNAL2) is a high-risk gene associated with autism spectrum disorders (ASD), however its impact on brain development and disease remains unclear. The present study revealed an unexpected role of KATNAL2 in regulating ependymal ciliary motion and cerebrospinal fluid flow during brain development, an important contributing factor for ASD. We discovered a distinct expression pattern of KATNAL2 in multiciliated ependymal cells of both human and mouse brains. Notably, an ASD-associated mutation of Katnal2 disrupted its molecular function and resulted in ASD-related behavioral deficits in mice. Additionally, this mutation affected the polarized organization and beating of ependymal cilia, leading to delayed cerebrospinal fluid flow and sustained ventricular enlargement from the early postnatal stage. Conditional ablation of Katnal2 specifically in the ependymal cells of neonatal mice is sufficient to cause ventricular dilation, whereas no such effect was observed in adult mice. Our findings highlight the importance of ependymal motile cilia and hydrocephalus in ASD, offering insights into its pathogenesis and potential intervention.

neuroscience↗

bioRxiv2023

Multistability in neural systems with random cross-connections

Neural circuits with multiple discrete attractor states could support a variety of cognitive tasks according to both empirical data and model simulations. We assess the conditions for such multistability in neural systems, using a firing-rate model framework, in which clusters of neurons with net self-excitation are represented as units, which interact with each other through random connections. We focus on conditions in which individual units lack sufficient self-excitation to become bistable on their own. Rather, multistability can arise via recurrent input from other units as a network effect for subsets of units, whose net input to each other when active is sufficiently positive to maintain such activity. In terms of the strength of within-unit self-excitation and standard-deviation of random cross-connections, the region of multistability depends on the firing-rate curve of units. Indeed, bistability can arise with zero self-excitation, purely through zero-mean random cross-connections, if the firing-rate curve rises supralinearly at low inputs from a value near zero at zero input. We simulate and analyze finite systems, showing that the probability of multistability can peak at intermediate system size, and connect with other literature analyzing similar systems in the infinite-size limit. We find regions of multistability with a bimodal distribution for the number of active units in a stable state. Finally, we find evidence for a log-normal distribution of sizes of attractor basins, which can appear as Zipfs Law when sampled as the proportion of trials within which random initial conditions lead to a particular stable state of the system.

neuroscience↗

bioRxiv2023

Adult-onset CNS sulfatide deficiency causes sex-dependent metabolic disruption in aging

The interconnection between obesity and central nervous system (CNS) neurological dysfunction has been widely appreciated. Accumulating evidence demonstrates that obesity is a risk factor for CNS neuroinflammation and cognitive impairment. However, the extent to which CNS disruption influences peripheral metabolism remains to be elucidated. We previously reported that myelin-enriched sulfatide loss leads to CNS neuroinflammation and cognitive decline. In this study, we further investigated the impact of CNS sulfatide deficiency on peripheral metabolism while considering sex- and age-specific effects. We found that female sulfatide-deficient mice gained significantly more body weight, exhibited higher basal glucose levels, and were glucose intolerant during glucose-tolerance test (GTT) compared to age-matched controls under a normal diet, whereas male sulfatide-deficient mice only displayed glucose intolerance at a much older age compared to female sulfatide-deficient mice. Mechanistically, we found the increased body weight was associated with increased food intake and elevated neuroinflammation, especially in the hypo-thalamus, in a sex-specific manner. Our results suggest that CNS sulfatide deficiency leads to sex-specific alterations in energy homeostasis via dysregulated hypothalamic control of food-intake.

neuroscience↗

bioRxiv2023

Has recombination changed during the recent evolution of the guppy Y chromosome?

Genome sequencing and genetic mapping of molecular markers has demonstrated Y-linkage across most of the guppy (Poecilia reticulata) XY chromosome pair. However, they also revealed exchanges with the X, consistent with classical genetic observations of occasional exchanges of factors controlling visible male-specific phenotypic traits. It remains unclear whether this fish species has an extensive sex-determining region without crossing over (whose suppressed recombination could have evolved under selection created by sexually antagonistic effects of male coloration factors), or whether the fully Y-linked region is very small, perhaps within a single gene. Population genomic data support cytogenetic results indicating that it is within the terminal 5 Mb of the 26.5 Mb chromosome 12, just proximal to a highly recombining pseudo-autosomal region, PAR1. Using molecular markers, we studied recombination, focusing on this region of the XY pair. Despite assembly errors in the small terminal PAR1, our mapping identifies very similar genetic PAR boundaries in sires from four populations, suggesting that their crossover patterns have not changed. Our results also confirmed occasional crossovers proximal to the male-determining region, defining a second pseudo-autosomal region, PAR2, recombining much more rarely than PAR1. The crossover positions suggest that the male-determining factor is within a repetitive region near 21 Mb in the female assembly. A sex-reversed XX male had few crossovers in PAR2, suggesting that this regions low crossover rate depends on the phenotypic, not the genetic, sex. Thus rare sex changes, and/or occasional crossovers in males can explain the failure to detect fully Y-linked variants.

genetics↗

bioRxiv2023

Alloreactivity and autoreactivity converge to support B cell epitope targeting in transplant rejection

Donor-specific antibody (DSA) responses against human leukocyte antigen (HLA) proteins mismatched between kidney transplant donors and recipients cause allograft loss. The rules governing the immunogenicity of non-self donor HLA are poorly understood. Using single-cell, molecular, structural, and proteomic techniques, we profiled the HLA-specific B cell response in the kidney and blood of a transplant recipient with antibody-mediated rejection (AMR). We observed an immunodominant B cell antibody response focused on topographically exposed, solvent-accessible mismatched HLA residues along the peptide-binding groove - a subregion comprising only 20% of the HLA molecule. We further demonstrated that, even within a diverse cohort of transplant recipients, the B cell alloresponse consistently converges on this same immunodominant subregion on the crown of the HLA molecule. Based on these findings, we propose that B cell immunodominance in transplant rejection relies on antigenic topography, and we suggest that this link could be exploited for organ matching and therapeutics.

immunology↗

bioRxiv2023

A high-throughput multiplex array for antigen-specific serology with automated analysis.

High-throughput customizable CBA automated script-based analysisThe utility of high-throughput systems to evaluate antigen-specific antibody (Ab) has been highlighted by the SARS-CoV-2 pandemic. Pathogen-specific Ab levels are often used to assess protection following vaccination and, in the case of novel pathogens, an indication of prior exposure. Several platforms exist to visualize antigen-specific Ab, however most are not quantitative and are difficult to scale for population level studies. Additionally, the sensitivity across platforms differs making direct comparisons between studies difficult. Cytometric bead arrays (CBA) are an attractive platform for antigen-specific Ab measurements as they can be used to assess Ab reactivity against several antigens and of several isotypes to be performed simultaneously. Additionally, CBAs exhibit high sensitivity and can be designed to provide quantitative measurements. Using commercially available particles, a biotin-Streptavidin bead loading strategy, and the inclusion of indirect standards, we describe a flexible system that can be modified to include a variety of antigens. Here we describe two arrays, focused on antigens derived from either {beta}-coronaviruses or influenza virus. To support the high-throughput capacity of this system, we developed a suit of automated software tools, the CBA Toolbox, to process raw data into antigen-reactive IgM, IgA, and IgG concentrations. We describe quality control requirements, assay performance, and normalizations to accurately quantitate antigen-specific Ig.

immunology↗

bioRxiv2023

Mapping Neurophysiological Subtypes of Major Depressive Disorder Using Normative Models of the Functional Connectome

Major depressive disorder (MDD) is the most burdensome psychiatric disorder characterized by remarkably heterogeneous clinical phenotypes. It remains challenging to delineate the heterogeneity of neurobiological abnormalities underlying the clinical variance and, on this basis, to identify neurophysiological subtypes of MDD patients. Here, using a large multisite resting-state functional MRI data from 1,148 MDD patients and 1,079 healthy controls, we generated lifespan normative models of functional connectivity strengths, mapped the heterogeneity of patients individual deviations, and identified neurobiological MDD subtypes. MDD patients showed positive deviations mainly in the default mode and subcortical areas, and negative deviations widely distributed over the cortex. However, there was a great inter-subject heterogeneity as indicated by that no more than 3.14% of patients deviated from the normative range for any brain region. Two neurophysiological MDD subtypes were identified. Subtype 1 showed severe deviations with positive deviations in the default mode, limbic, and subcortical areas, and negative deviations in the sensorimotor, dorsal and ventral attention areas, while subtype 2 showed a moderate but conversed deviation pattern. The severe-deviation subtype had older age, higher medicated proportion, and higher Suicide item score, while the moderate-deviation subtype showed higher Work and Activities and Depressed Mood item scores. Moreover, the baseline deviations in the severe-deviation subtype were predictive of 6-month antidepressant treatment effects in a subsample. To our knowledge, the current study is the largest multisite analysis of neurophysiological MDD subtyping to date and the findings shed light on our understanding of the biological mechanisms underlying the intersubject heterogeneity of clinical phenotypes, which are informative for the development of personalized treatments for this disorder.

neuroscience↗

bioRxiv2022

Mechanical vibration modulates regional cerebral blood flow and biomechanical co-variance network in a frequency-dependent manner

Human brain experiences vibration of certain frequency during various physical activities such as vehicle transportation and machine operation or accidents, which may cause traumatic brain injury or other brain diseases. However, little is known about what happened to brain after vibration stimuli. Here, with a custom-built electromagnetic actuator, vibration was induced in the brain while cerebral blood flow (CBF) and brain stiffness were measured at 20, 30, 40 Hz for 52 healthy volunteers. With increasing frequency, multiple regions of the brain showed increasingly reduced CBF, while the size of such regions also expanded. The vibration-induced CBF reduction regions largely fell inside the brains default mode network (DMN), with about 58 or 46 % overlap at 30 or 40 Hz, respectively. By establishing a biomechanical co-variance network based on tissue stiffness, analysis of small-world properties and modularity showed an increased disruption of the network with increased frequency. These findings demonstrate frequency-dependent features of vibration modulation to brain. Furthermore, the overlap between CBF reduction regions and DMN, and the vibration-induced decrease of biomechanical network connections suggest a interweaved relationship between blood flow, tissue stiffness, and cognitive functions. These may provide critical insights into the mechanical stimulus to brain and vibration-induced brain pathologies.

neuroscience↗

bioRxiv2022

Quantitative sequence basis for the E. coli transcriptional regulatory network

The transcriptional regulatory network (TRN) of E. coli consists of thousands of interactions between regulators and DNA sequences. Inherently the DNA sequence is the primary determinant of the TRN; however, it is well established that the presence of a DNA binding motif does not guarantee a functional regulatory protein binding site. Thus, the extent to which the TRN architecture can be predicted by the genome DNA sequence alone remains unclear. Here, we developed machine learning models that predict the TRN structure of E. coli based on genome sequence. Models were constructed successfully (cross-validation AUROC >= 0.8) for 84% (57/68) of valid E. coli regulons identified from top-down analysis of RNA-seq data. We found that: 1) While regulatory motif strength is the most important sequence feature for determining regulon membership, additional features such as DNA shape substantially influence membership; 2) complex regulons involving multiple interacting regulators could be unraveled by machine learning; 3) investigating regulons where initial ML models failed revealed new regulator-specific sequence features that improved model accuracy. Finally, while regulon structure can appear to be variable across estimation methods and strains, we found that strong regulatory sequence features underlie both the genes that appear most consistently in regulons across estimation methods as well as the core regulon genes in the Fur pan-regulon. This work develops a quantitative understanding of the sequence basis of the TRN and suggests a path towards computationally-guided control of transcriptional regulation for synthetic biology applications.

bioinformatics↗

bioRxiv2022

A longitudinal CA2/3 to CA1 circuit for initiating context-dependent associative learning

Associating environmental context with emotional experience is a vital brain function that requires the activity in both dorsal and ventral hippocampus. While only ventral hippocampus connects with the amygdala, a hub for fear learning, it remains unclear how the two hippocampal areas interact during contextual fear conditioning (CFC). We found that projections from dorsal CA2/CA3 (dCA2/3) to the dorsal part of ventral CA1 (vCA1d) contributed significantly to CFC. Deep-brain Ca2+ imaging revealed a CFC-enhanced difference in neuronal activities evoked by conditioned vs. neutral environmental context in both dCA2/3 and vCA1d areas. Notably, contextual fear retrieval correlated with changes in conditioned context-evoked activity in vCA1d, but not in dCA2/3. Furthermore, slice recordings showed that CFC potentiated dCA2/3-to-vCA1d projection strength, in line with coordinated elevation of monosynaptic excitation and reduction of disynaptic inhibition mediated by somatostatin-expressing interneurons. Thus, vCA1d represents a critical site for initiating emotional association with contextual information from dCA2/3.

neuroscience↗

bioRxiv2022

Partial sex linkage and linkage disequilibrium on the guppy sex chromosome

The guppy Y chromosome has been considered a model system for the evolution of suppressed recombination between sex chromosomes, and it has been proposed that complete sex-linkage has evolved across about 3 Mb surrounding this fishs sex-determining locus, followed by recombination suppression across a further 7 Mb of the 23 Mb XY pair, forming younger "evolutionary strata". Sequences of the guppy genome show that Y is very similar to the X chromosome, making it important to understand which parts of the Y are completely non-recombining, and whether there is indeed a large completely non-recombining region. Here, we describe new evidence that supports a different interpretation of the data that suggested the presence of such a region. We analysed PoolSeq data in samples from multiple natural populations from Trinidad. This yields evidence for linkage disequilibrium (LD) between sequence variants and the sex-determining locus. Downstream populations have higher diversity than upstream ones (which display the expected signs of bottlenecks). The associations we observe conform to predictions for a genome region with infrequent recombination that carries one or more sexually antagonistic polymorphisms. They also suggest the region in which the sex-determining locus must be located. However, no consistently male-specific variants were found, supporting the suggestion that any completely sex-linked region may be very small.

evolutionary biology↗

bioRxiv2022

Identification of candidate virulence loci in Striga hermonthica, a devastating parasite of African cereal crops

O_LIParasites have evolved proteins, Virulence Factors (VFs), that facilitate plant colonization, yet VFs mediating parasitic plant-host interactions are poorly understood. Striga hermonthica is an obligate, root-parasitic plant of cereal hosts in sub-Saharan Africa, causing devastating yield losses. Understanding the molecular nature and allelic variation of VFs in S. hermonthica is essential for breeding resistance and delaying the evolution of parasite virulence. C_LIO_LIWe assembled the S. hermonthica genome and identified secreted proteins by in silico prediction. Pooled sequencing of parasites growing on a susceptible and a strongly resistant rice host allowed us to scan for loci where selection imposed by the resistant host had elevated the frequency of alleles contributing to successful colonisation. C_LIO_LIThirty-eight putatively secreted VFs had extremely different allele frequencies with functions including host cell wall modification, protease inhibitors, oxidoreductase and kinase activities. These candidate loci had significantly higher Tajimas D than the genomic background, consistent with balancing selection. C_LIO_LIOur results reveal diverse strategies used by S. hermonthica to overcome different layers of host resistance. Understanding the maintenance of variation at virulence loci by balancing selection will be critical to managing the evolution of virulence as a part of a sustainable control strategy. C_LI

plant biology↗

bioRxiv2021

Population model of Temnothorax albipennis as a distributed dynamical system II: secret of "chemical reaction" in collective house-hunting in ant colonies is unveiled by operator methods

The collective intelligence of animal groups is a complex algorithm for computer scientist and a many-body problem for physics of living system. We show how the time evolution of features in such a system, like number of ants in particular state for colonies, can be mapped to many-body problems in non-equilibrium statistical mechanics. There exist role transitions of active and passive ant between distributed functions, including exploration, assessing, recruiting and transportation in the house-hunting process. Theoretically, such a process can be approximately described as birth-death process where large number of particles living in the Fock space and particles of one sub-type transfer to a different sub-type with some probability. Started from the master equation with constrain of the quorum criterion, we express the evolution operator as a functional integral mapping from operators acting on Fock space in number representation to functional space in coherent state representation. We then read out the action from the evolution operator, and we use least action principal equations of motion, which are the number field equations. The equations we get are couple ordinary differential equations, which can faithfully describe the original master equation, and hence fully describe the system. This method provides us differential equation-based algorithm, which allow us explore parameter space with respect to more complicated agent-based algorithm. The algorithm also allows exploring stochastic process with memory in a Markovian way, which provide testable prediction on collective decision making.

biophysics↗

bioRxiv2021

Population model of Temnothorax albipennis as a distributed dynamical system: I. self-consistent threshold is an emergent property in combination of quorum sensing and chemical perception of limited resource

House hunting of ant, such as Temnothorax albipennis, has been shown to be a distributed dynamical system. Such a system includes agent-based algorithm [1], with agents in different roles including nest exploration, nest assessment, quorum sensing, and brood item transportation. Such an algorithm, if used properly, can be applied on artificial intelligent system, like robotic swarms. Despite of its complexity, we are focusing on the quorum sensing mechanism, which is also observed in bacteria model. In bacterial model, multiple biochemical networks co-exist within each cell, including binding of autoinducer and cognate receptors, and phosphorylation-dephosphorylation cycle. In ant hunting, we also have ant commitment to the nest, mimicking binding between autoinducer and cognate receptors. We also have assessment ant specific to one nest and information exchange between two assessment ants corresponding to different nests, which is similar process to the phosphorylation-dephosphorylation cycle in bacteria quorum sensing network. Due to the similarity between the two models, we borrow the idea from bacteria quorum sensing to clarify the definition of quorum threshold through biological plausible mechanism related to limited resource model. We further made use of the contraction analysis to explore the trade-off between decision split and decision consensus within ant population. Our work provides new generation model for understanding how ant adapt to the changing environment during quorum sensing.

animal behavior and cognition↗

bioRxiv2021

An intein-split transactivator for intersectional neural imaging and optogenetic manipulation

The complexity of brain circuitry is manifested by numerous cell types based on genetic marker, location and neural connectivity. Cell-type specific recording and manipulation is essential to disentangle causal neural mechanisms in physiology and behavior; however, many current approaches are largely limited by number of intersectional features, incompatibility of common effectors and insufficient gene expression. To tackle these limitations, we devise an intein-based intersectional synthesis of transactivator (IBIST) to selectively control gene expression of common effectors in specific cell types defined by a combination of multiple features. We validate the specificity and sufficiency of IBIST to control common effectors including fluorophores, optogenetic opsins and Ca2+ indicators in various intersectional conditions in vivo. Using IBIST-based Ca2+ imaging, we show that the IBIST can intersect up to five features, and that hippocampal cells tune differently to distinct emotional valences depending on the pattern of projection targets. Collectively, the IBIST multiplexes the capability to intersect cell-type features and is compatible with common effectors to effectively control gene expression, monitor and manipulate neural activities.

neuroscience↗

bioRxiv2021

Metabolic characteristics of taste differences under the soil and hydroponic cultures of sweet potato leaves by using non-targeted metabolomics

Sweet potato leaves are consumed as green leafy vegetables in most of the world due to their nutritional and functional values, and the taste characteristics determine their commodity value and consumer acceptance. However, the metabolic composition and formation mechanism of taste quality in its leaves are not clear. In this study, we found that sweet potato leaves under different growing patterns, soil culture and hydroponic culture, which result in different taste quality. In particular, the taste quality in leafy sweet potato was effectively improved under hydroponic culture. Meanwhile, we further profiled metabolites in leaves of sweet potatoes under different growing patterns by using GC-QToF-MS. A total of 200 metabolites were identified, covering most of the metabolic pathways in plants. A comparison of the good taste and poor taste of sweet potato leaves resulted in 71 metabolites related to taste quality formation. In addition, the leaves with poor taste had lower levels of metabolites regarding amino acids metabolism, whereas was accompanied by high levels of metabolites in carbohydrates and secondary metabolism. This study provides new insights into the improvement of taste quality in leafy sweet potato.

plant biology↗

bioRxiv2021

Locomotor performance and CNS responses to hypoxia in a cyclic nucleotide-gated channel mutant of adult Drosophila

Drosophila provides an excellent opportunity to explore the genetic basis for behavioral and CNS responses to hypoxia. Cyclic guanosine monophosphate (cGMP) modulates the speed of recovery from anoxia in adults and mediates hypoxia-related behaviors in larvae. Cyclic nucleotide-gated channels (CNG) and cGMP-activated protein kinase (PKG) are two cGMP downstream targets. PKG is involved in behavioral tolerance to hypoxia and anoxia in adults, however little is known about CNG channels. We used a CNGL mutant with reduced CNGL transcripts to investigate the contribution of CNGL to the hypoxia response. In control flies (w1118), hypoxia immediately reduced path length per minute in a locomotor assay. Flies took 30-40 mins in air to recover from 15 mins hypoxia. CNGL mutants had reduced locomotion under normoxia and impaired recovery from hypoxia, similar to the effects of pan-neural CNGL knockdown. In the CNGL mutants hypoxia caused an acute increase in path length per minute followed by a gradual increase during hypoxia. Basal levels of CNS extracellular K+ concentrations were reduced in the mutants. In response to hypoxia, the mutants had an increased extracellular K+ concentration change, reduced time to reach the K+ concentration peak, and delayed recovery time. Genetic manipulation to increase cGMP in the CNGL mutants eliminated the impairment of recovery from hypoxia and partially compensated for the effects of hypoxia on CNS K+. Although the neural mechanisms have yet to be determined, CNGL channels and cGMP signaling are involved in the hypoxia response of adult Drosophila.

physiology↗