Biology subjects

Zhao, Z.

Publications and source records attributed to Zhao, Z..

At least 199 records · Page 11Linked to original sources

bioRxiv2024

A Method for the Combined Functional Assessment of Photoreceptors and Ganglion Cells in Acute Retinal Explants

Significant progress has been made in studying the individual steps of retinal signaling, yet a comprehensive understanding of the functional interplay between photoreceptors, as input cells, and retinal ganglion cells (RGCs), as output cells, remains elusive. This connection is crucial to fully unravel the retinas computational capabilities and its role in visual processing. To address this gap, this study introduces a novel technique that combines two-photon (2P) autofluorescence microscopy with multi-electrode array (MEA) recordings, enabling simultaneous testing of photoreceptor and RGC function. Unlike traditional methods that target isolated cell classes or structural analysis, this integrated technique provides the basis to investigate input-output relationships within the retinal neural network, offering a deeper understanding of its dynamic activity and adaptability to cellular dropout.

neuroscience↗

bioRxiv2024

Two distinct durable human class-switched memory B cell populations are induced by vaccination and infection

Memory lymphocytes are durable cells that persist in the absence of antigen, but few human B cell subsets have been characterized in terms of durability. The relative durability of eight non-overlapping human B cell sub-populations covering 100% of all human class-switched B cells was interrogated. Only two long-lived B cell populations persisted in the relative absence of antigen. In addition to canonical germinal center-derived switched-memory B cells with an IgD-CD27+ CXCR5+ phenotype, a second, non-canonical, but distinct memory population of IgD-CD27- CXCR5+ DN1 B cells was also durable, exhibited a unique TP63-linked transcriptional and anti-apoptotic signature, had low levels of somatic hypermutation, but was more clonally expanded than canonical switched-memory B cells. DN1 B cells likely evolved to preserve immunological breadth and may represent the human counterparts of rodent extrafollicular memory B cells that, unlike canonical memory B cells, can enter germinal centers and facilitate B cell and antibody evolution. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/624972v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@169c77forg.highwire.dtl.DTLVardef@1a872f5org.highwire.dtl.DTLVardef@1360cforg.highwire.dtl.DTLVardef@38d7ed_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

One score to rule them all: regularized ensemble polygenic risk prediction with GWAS summary statistics

Ensemble learning has become a cornerstone for improving the predictive accuracy of polygenic risk scores (PRS), and nearly all recent multi-ancestry PRS methods incorporate ensemble learning as a final step. However, existing ensemble approaches require individual-level genotype data for model training, which limits their real-world applications, especially in non-European populations without sufficient genomic samples. Here, we introduce a statistical framework for constructing regularized ensemble PRS that integrates a large number of candidate PRS models using only genome-wide association study summary statistics. Through extensive analyses across multiple traits and populations, we demonstrate that our method consistently outperforms state-of-the-art PRS approaches within and across ancestries. This framework presents "one score to rule them all" for its capability to enable seamless integration of newly developed PRS models with existing ones, providing a scalable and general solution for future PRS development and application.

genetics↗

bioRxiv2024

Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma

Glioblastoma (GBM) is uniformly lethal due to profound treatment resistance. Altered cellular metabolism is a key mediator of GBM treatment resistance. Uptake of the essential sulfur-containing amino acid methionine is drastically elevated in GBMs compared to normal cells, however, it is not known how this methionine is utilized or whether it relates to GBM treatment resistance. Here, we find that radiation acutely increases the levels of methionine-related metabolites in a variety of treatment-resistant GBM models. Stable isotope tracing studies further revealed that radiation acutely activates methionine to S-adenosyl methionine (SAM) conversion through an active signaling event mediated by the kinases of the DNA damage response. In vivo tumor SAM synthesis increases after radiation, while normal brain SAM production remains unchanged, indicating a tumor- specific metabolic alteration to radiation. Pharmacological and dietary strategies to block methionine to SAM conversion slowed DNA damage response and increased cell death following radiation in vitro. Mechanistically, these effects are due to depletion of DNA repair proteins and are reversed by SAM supplementation. These effects are selective to GBMs lacking the methionine salvage enzyme methylthioadenosine phosphorylase. Pharmacological inhibition of SAM synthesis hindered tumor growth in flank and orthotopic in vivo GBM models when combined with radiation. By contrast, methionine depletion does not reduce tumor SAM levels and fails to radiosensitize intracranial models, indicating depleting SAM, as opposed to simply lowering methionine, is critical for hindering tumor growth in intracranial models of GBM. These results highlight a new signaling link between DNA damage and SAM synthesis and define the metabolic fates of methionine in GBM in vivo. Inhibiting radiation-induced SAM synthesis slows DNA repair and augments radiation efficacy in GBM. Using MAT2A inhibitors to deplete SAM may selectively overcome treatment resistance in GBMs with defective methionine salvage while sparing normal brain.

cancer biology↗

bioRxiv2024

A Mouse-adapted SARS-CoV-2 Model for Investigating Post-acute Sequelae of COVID infection

The coronavirus disease of 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), remains a major health issue after nearly 7 millions of death toll in the last four years. As the world is recovering with improving vaccines and antiviral treatments, the alarming rate of long-COVID, or Post-acute Sequelae of COVID-19 (PASC), calls for further investigations. Among a list of symptoms associated with multi-organ dysfunctions, the neurological complications are particularly intriguing, yet the underlying mechanisms remain elusive. With the recently developed mouse adapted SARS-CoV-2 stain, we are now able to model the mild COVID infection in C57BL/6 mice and study the chronic immune responses and subsequent damages in different organs long after the viruses are clearly naturally in the body. More specifically, we found adult C57BL/6J mice developed neurological impairments, including behavior changes related to sensorimotor coordination, depression- and anxiety-like behaviors, and inflammation in multiple organs including lung, liver and brain, which persisted over at least 4 weeks in mice even with mild infection. Therefore, this model can be used to further explopred the mechanisms of PASC, as well as potential intervention or therapeutic approaches.

neuroscience↗

bioRxiv2024

Elovl1 inhibition reduced very long chain fatty acids in a mouse model of adrenoleukodystrophy

Adrenoleukodystrophy (ALD) is a rare neurometabolic disease caused by mutations in the ABCD1 gene, which encodes for the peroxisomal very long chain fatty acid (VLCFAs) transporter. It is a debilitating disorder, which has a spectrum of clinical presentations. The most severe form is a rapidly progressing demyelinating disease called cerebral ALD or CALD. Patients with cALD have a life expectancy of 2-4 years after onset and symptoms often manifest in childhood. The other forms are adrenomyeloneuropathy or AMN, which is a slower progressing degeneration of the spinal cord, and adrenal insufficiency (Addison disease). Since the accumulation of VLCFAs are a common factor in all ALD pathologies, we identified therapeutic approach that could correct this metabolic defect. We developed a substrate reduction therapy (SRT) for ALD in the form of an inhibitor of the lipid elongase principally responsible for the generation of VLCFAs, Elovl1. This small molecule was able to successfully reduce the accumulation of VLCFA in the brain and spinal cord of ABCD1-/y mice. We used single nuclei RNA seq to identify the pathways altered in the ABCD1-/y mouse and corrected with Elovl1 inhibition. Though many lipid metabolism genes and pathways were indeed corrected, treatment with the Elovl1 inhibitor unexpectedly led to profound transcriptional changes beyond correction of pathways altered by loss of ABCD1. These data suggest that Elovl1 inhibition may have broader consequences in ABCD1-/y mice than correction of lipid homeostasis.

pharmacology and toxicology↗

bioRxiv2024

Phosphorylation of MdWRKY70L by MdMPK6/02G mediates reactive oxygen synthesis to regulate apple fruit senescence

Apple (Malus domestica) is a globally significant crop and a vital dietary component worldwide. During ripening, apples exhibit a longitudinal gradient, ripening first at the stalk cavity and extending toward the calyx pit. Over-ripening in the stalk cavity leads to early senescence, characterized by peel browning, which diminishes fruit quality. This study examines the natural senescence process in 6-year-old Ruixue apples by screening transcriptome data to uncover senescence-related genes and validate their molecular functions. Our analysis of antioxidant capacity and reactive oxygen species in different peel regions revealed that malondialdehyde, hydrogen peroxide, and superoxide anion levels increased with senescence, especially in the stalk cavity. Transcriptome clustering and enrichment analyses across developmental stages revealed MdWRKY70L, MdSAG101, and MdZAT12 as key regulators of peel senescence. Further in vitro and in vivo studies demonstrated that MdWRKY70L is phosphorylated at Ser199 by MdMPK6/02G, enhancing its stability and promoting peel senescence. These findings offer insights for developing strategies to delay fruit senescence and improve postharvest quality control.

plant biology↗

bioRxiv2024

Annotating CryoET Volumes: A Machine Learning Challenge

Cryo-electron tomography (cryoET) has emerged as a powerful structural biology tool for understanding protein complexes in their native cellular environments. Presently, 3D volumes of cellular environments can be acquired in the thousands in a few days where each volume provides a rich and complex cellular landscape. Despite numerous innovations, localizing and identifying the vast majority of protein species in these volumes remains prohibitively difficult. Machine learning based methods provide an opportunity to automate the process of labeling and annotating cryoET volumes. Due to current bottlenecks in the annotation process, and a lack of large standardized datasets, training datasets for machine learning algorithms have been scarce. Here, we present a defined "phantom" sample, along with "ground truth" annotations, that will be the basis of a machine learning challenge to bring cryoET and ML experts together and spur creativity to address this annotation problem. We have also set up a cryoET data portal that provides additional diverse sets of annotated 3D volumes from cryoET experts across the world for the machine learning challenge.

cell biology↗

bioRxiv2024

Open-source Tools for CryoET Particle Picking Machine Learning Competitions

We are launching a machine learning (ML) competition focused on particle picking in cryo-electron tomography (cryoET) data, a crucial task in structural biology. To support this, we have created a comprehensive suite of open-source tools to develop resources for our competition, including copick for dataset management, napari plugins for interactive visualization, utilities for converting particle picks to segmentation masks, and PyTorch tools for custom dataset sampling. These resources streamline the processes of data handling, labeling, and visualization, allowing participants to focus on model development. By leveraging these tools, competitors will be better equipped to tackle the unique challenges of cryoET data and push forward advancements in particle picking techniques.

bioinformatics↗

bioRxiv2024

Domain-specific Schema Reuse Supports Flexible Learning to Learn in Primate Brain

Prior knowledge accelerates subsequent learning of similarly structured problems - a phenomenon termed "learning to learn" - by forming and reusing generalizable neural representations, i.e., the schemas. However, the stability-plasticity dilemma, i.e., how to exploit stable schemas to facilitate learning while remaining flexible towards possible changes, is not well understood. We hypothesize that restricting schemas to specific functional, e.g., decision-making, subspace and making it orthogonal to other subspaces allows the brain to balance stability and plasticity. To test it, we trained three macaques on visuomotor mapping tasks and recorded neural activity in the dorsolateral premotor cortex. By delineating decision and stimulus subspaces, we identified a schema-like manifold within only the decision subspace. The reuse of decision schemas significantly facilitated subsequent learning. In addition, the decision subspace exhibited a trend to be orthogonal to the stimulus subspace, minimizing interference between these two domains. Our results revealed that restricting schemas to specific functional domains can preserve useful knowledge while maintaining orthogonality with other subspaces, allowing for flexible adaptation to new environments, thereby resolving the stability-plasticity dilemma. This finding provides new insights into the mechanisms underlying brains capability to learn both fast and flexibly, which can also inspire more efficient learning algorithms for artificial intelligence systems towards working in open, dynamic environments.

neuroscience↗

bioRxiv2024

Differential Sensitivity of Midline Patterning to Mitosis during and after Primitive Streak Extension

BackgroundMidline establishment is a fundamental process during early embryogenesis for Bilaterians. Midline patterning in nonamniotes can occur without mitosis, through Planar Cell Polarity (PCP) signaling. By contrast, amniotes utilize both cell proliferation and PCP signaling for patterning early midline landmark, the primitive streak (PS). This study examined their roles for midline patterning at post PS-extension. ResultsIn contrast to PS extension stages, embryos under mitotic arrest during the post PS-extension preserved notochord (NC) extension and Hensens node (HN)/PS regression judged by both morphology and marker genes, although they became shorter, and laterality was lost. Remarkably, no or background level of expression was detected for the majority of PCP core components in the NC-HN-PS area at post PS-extension stages, except for robustly detected prickle-1. Morpholino knockdown of Prickle-1 showed little influence on midline patterning, except for suppressed embryonic growth. Lastly, associated with mitotic arrest-induced size reduction, midline tissue cells displayed hypertrophy. ConclusionThus, the study has identified at least two distinct mitosis sensitivity phases during early midline pattering: One is PS extension that requires both mitosis and PCP, and the other is mitotic arrest-resistant midline patterning with little influence by PCP at post PS-extension stages.

developmental biology↗

bioRxiv2024

Layer-specific dynamics of local field potentials in monkey V1 during electrical stimulation

The mammalian neocortex, organized into six cellular layers or laminae, forms a cortical network within layers. Layer specific computations are crucial for sensory processing of visual stimuli within primary visual cortex. Laminar recordings of local field potentials (LFPs) are a powerful tool to study neural activity within cortical layers. Electric brain stimulation is widely used in basic neuroscience and in a large range of clinical applications. However, the layer-specific effects of electric stimulation on LFPs remain unclear. To address this gap, we conducted laminar LFP recordings of the primary visual cortex in monkeys while presenting a flash visual stimulus. Simultaneously, we applied a low frequency sinusoidal current to the occipital lobe with offset frequency to the flash stimulus repetition rate. We analyzed the modulation of visual-evoked potentials with respect to the applied phase of the electric stimulation. Our results reveal that only the deeper layers, but not the superficial layers, show phase-dependent changes in LFP components with respect to the applied current. Employing a cortical column model, we demonstrate that these in vivo observations can be explained by phase-dependent changes in the driving force within neurons of deeper layers. Our findings offer crucial insight into the selective modulation of cortical layers through electric stimulation, thus advancing approaches for more targeted neuromodulation.

biophysics↗

bioRxiv2024

Nitrogen ionome dynamics on leafy vegetables in tropical climate

Nitrogen is known to be a critical macro-nutrient influencing plant physiology, growth, and mineral composition. In tropical conditions, which are challenging for leafy vegetable farming, the nitrogen delivery effect is unclear. In this study, we aimed to investigate the effect of nitrogen application on key physiological traits and the mineral composition of the plants, the plant ionome. Experiments were conducted under tropical conditions greenhouse with varying levels of nitrogen supply to examine the effect on plant transpiration, yield, use efficiency of water and nitrogen, and nutrient uptake dynamics followed by cross-correlation analysis, trying to understand the physiological behavior-uptake dynamics relationships. The results demonstrated that transpiration, yield and WUE theoretic optimum curve, which peaking in nitrogen concentration of 120 mg/L for Chinese spinach and 200 mg/L for Chinese broccoli. Conversely, NUE reduce significantly with increasing nitrogen delivery which reflected on antagonistic increase of excess nitrogen. In terms of mineral composition, nitrogen application resulted in an increase I nitrogen content in the plant leaf tissue, while concentration of certain macronutrients and micronutrients were affected, including potassium, phosphorus, calcium, magnesium, iron, zinc, and molybdenum. Part of the minerals exhibited decreasing pattern due to potential competitive uptake mechanism, iron revealed increasing pattern that correlated with nitrogen delivery, and some minerals correlated with the measured physiological parameters. These results underscore the importance of optimizing nitrogen fertilization to balance plant growth, physiological processes, and plant nutrient homeostasis. The study offers valuable insights for sustainable nitrogen management in agricultural systems aimed at maximizing crop yield while maintaining nutritional quality.

plant biology↗

bioRxiv2024

Ductal pancreatic cancer interception by FGFR2 abrogation

Activating KRAS mutations are a key feature of pancreatic ductal adenocarcinoma (PDA) and drive tumor initiation and progression. However, mutant KRAS by itself is weakly oncogenic. The pathways that cooperate with mutant KRAS to induce tumorigenesis are less-defined. Analyzing organoids and murine and human pancreatic specimens, we found that the receptor tyrosine kinase FGFR2 was progressively up-regulated in mutant KRAS-driven metaplasia, pre-neoplasia and Classical PDA. Using genetic mouse models, we showed that FGFR2 supported mutant KRAS-driven transformation of acinar cells by promoting proliferation and MAPK pathway activation. FGFR2 abrogation significantly delayed tumor formation and extended the survival of these mice. Furthermore, we discovered that FGFR2 collaborated with EGFR and dual blockade of these receptor signaling pathways significantly reduced mutant KRAS-induced pre-neoplastic lesion formation. Together, our data have uncovered a pivotal role for FGFR2 in the early phases of pancreatic tumorigenesis, paving the way for future therapeutic applications of FGFR2 inhibitors for pancreatic cancer interception. STATEMENT OF SIGNIFICANCEMutant KRAS-expressing pancreatic intraepithelial neoplasias (PanINs), the precursor lesions of PDA, are prevalent in the average healthy adult but rarely advance to invasive carcinoma. Here, we discovered that FGFR2 promoted PDA progression by amplifying mutant KRAS signaling and that inactivation of FGFR2 intercepted disease progression.

cancer biology↗

bioRxiv2024

Hand Position Fields of Neurons in the Premotor Cortex of Macaques during Natural Reaching

Planning and execution for goal-directed movements requires the integration of the current position of body or body parts with various kinematic parameters of the movement itself. In the hippocampus, the field-based representation of spatial information plays an essential role in this process during navigation. However, if a similar, field-based encoding framework is also utilized by the motor areas during hand reaching remains unclear. In this study, we investigated the hand position tuning in the dorsal premotor cortex (PMd) neurons (n = 601) when four monkeys performing a naturalistic reach-and-grasp task. We show that 132/601 (22%) of PMd neurons increased their firing rates when the monkeys hand occupied specific positions in the space, forming the "position fields" in their spatial firing maps that can be well described by 2D Gaussian functions/kernels. We further analyzed how the field-tuning of hand position is co-represented with other task-related parameters including the hand moving direction, speed, and reward location in the same population of PMd neurons, revealing a mixed-selective framework also similar to that discovered in the hippocampus. These position-tuned cells demonstrated high efficiency in encoding hand position, with ~10% of overall recorded neurons contributing >80% of accuracy in decoding instantaneous hand moving trajectories. These results suggest that a field-based encoding framework of position may be a common component to representing spatial information and integrating it with kinematic parameters for guiding goal-directed movements of the body or body parts.

neuroscience↗

bioRxiv2024

Identification and catalogue of viral transcriptional regulators in human diseases

Viral genomes encode viral transcriptional regulators (vTRs) that manipulate host gene expression to facilitate replication and evade immune detection. Nevertheless, their role in non-cancerous diseases remains largely underexplored. Here, we unveiled 268 new candidate vTRs from 14 viral families. We mapped vTRs genome-wide binding profiles and identified their potential human targets, which were enriched in immune-mediated pathways, neurodegenerative disorders, and cancers. Through vTR DNA-binding preference analysis, 283 virus-specific and human-like motifs were identified. Prioritized Epstein-Barr virus (EBV) vTR target genes were associated with multiple sclerosis (MS), rheumatoid arthritis, and systemic lupus erythematosus. The partitioned heritability study among 19 diseases indicated significant enrichment of these diseases in EBV vTR-binding sites, implicating EBV vTRs roles in immune-mediated disorders. Finally, drug repurposing analysis pinpointed candidate drugs for MS, asthma, and Alzheimers disease. This study enhances our understanding of vTRs in diverse human diseases and identifies potential therapeutic targets for future investigation.

bioinformatics↗

bioRxiv2024

Proteomic analysis of papillary thyroid carcinoma in the context of Hashimoto's thyroiditis

ObjectiveTo analyze the proteomic characteristics of papillary thyroid carcinoma in the context of Hashimotos thyroiditis by mass spectrometry and screen the corresponding differential proteins. MethodsPostoperative paraffin specimens of 3 patients with Hashimotos thyroiditis combined with papillary thyroid carcinoma and 3 patients with Hashimotos thyroiditis and benign nodules were collected. The differential proteins were obtained by qualitative and quantitative analysis using Q ExactiveTM mass spectrometer. Functional enrichment cluster analysis and protein interaction analysis were then performed on these differential proteins. Finally, key proteins were screened out and immunohistochemical verification was performed. Results72 up-regulated differentially expressed proteins and 21 down-regulated differentially expressed proteins were screened out. THBS2 and COL12A1 were further identified by bioinformatics analysis. After immunohistochemical verification, it was concluded that COL12A1 can be used as a specific tumor marker. ConclusionThere are differentially expressed proteins between the Hashimotos thyroiditis combined with papillary thyroid carcinoma group and the Hashimotos thyroiditis combined with benign nodules group. The up-regulated expression of COL12A1 can become an auxiliary diagnostic marker for papillary thyroid carcinoma with Hashimotos thyroiditis.

genomics↗

bioRxiv2024

Microbial strategies of environmental adaptation revealed by trait-environmental relationships

Microbial trait variation along environment gradients is crucial to understanding their ecological adaptation mechanisms. With the increasing availability of microbial genomes, making full use of the genome-based traits to decipher their adaptation strategies becomes promising and urgent. Here, we examined microbial communities in water and sediments of 20 East African lakes with pH values ranging from 7.2 to 10.1 through taxonomic-profiling and genome-centric metagenomics. We identified functional traits important for microbial adaptation to the stresses of alkalinity and salinity based on the significant trait-environment relationships (TERs), including those involved in cytoplasmic pH homeostasis, compatible solute accumulation, cell envelope modification and energy requisition. By integrating these significant-TER traits, we further developed an environmental adaptation index to quantify the species-level adaptive capacity for environmental stresses, such as high pH environments. The adaptation index of pH showed consistently significant positive relationships with species pH optima across regional and global genomic datasets from freshwater, marine and soda lake ecosystems. The generality of the index for quantifying environmental adaptation was demonstrated by showing significant relationships with the species niche optima for the gradients of soil temperature and seawater salinity. These results highlight the importance of trait-environment relationships in facilitating the inference of microbial genomic-based adaptation mechanisms, and expand our understanding of ecological adaptative strategies along environmental gradients.

ecology↗