Biology subjects

Zhao, Z.

Publications and source records attributed to Zhao, Z..

At least 307 records · Page 17Linked to original sources

bioRxiv2023

Spatial redundancy transformer for self-supervised fluorescence image denoising

Fluorescence imaging with high signal-to-noise ratios has become the foundation of accurate visualization and analysis of biological phenomena. However, the inevitable photon shot noise poses a formidable challenge on imaging sensitivity. In this paper, we provide a spatial redundancy denoising transformer (SRDTrans) to remove noise from fluorescence images in a self-supervised manner. First, a sampling strategy based on spatial redundancy is proposed to extract adjacent orthogonal training pairs, which eliminates the dependence on high imaging speed. Secondly, to break the performance bottleneck of convolutional neural networks (CNNs), we designed a lightweight spatiotemporal transformer architecture to capture long-range dependencies and high-resolution features at a low computational cost. SRDTrans can overcome the inherent spectral bias of CNNs and restore high-frequency information without producing over-smoothed structures and distorted fluorescence traces. Finally, we demonstrate the state-of-the-art denoising performance of SRDTrans on single-molecule localization microscopy and two-photon volumetric calcium imaging. SRDTrans does not contain any assumptions about the imaging process and the sample, thus can be easily extended to a wide range of imaging modalities and biological applications.

biophysics↗

bioRxiv2023

PENet: A phenotype encoding network for automatic extraction and representation of morphological discriminative features

Discriminative traits are important in biodiversity and macroevolution, but extracting and representing these features from huge natural history collections using traditional methods can be challenging and time-consuming. To fully utilize the collections and their associated metadata, it is urgent now to increase the efficiency of automatic feature extraction and sample retrieval. We developed a Phenotype Encoding Network (PENet), a deep learning-based model that combines hashing methods to automatically extract and encode discriminative features into hash codes. We tested the performance of PENet on six datasets, including a newly constructed beetle dataset with six subfamilies and 6566 images, which covers more than 60% of the genera in the family Scarabaeidae. PENet showed excellent performance in feature extraction and image retrieval. Two visualization methods, t-SNE, and Grad-CAM, were used to evaluate the representation ability of the hash codes. Further, by using the hash codes generated from PENet, a phenetic distance tree was constructed based on the beetle dataset. The result indicated the hash codes could reveal the phenetic distances and relationships among categories to a certain extent. PENet provides an automatic way to extract and represent morphological discriminative features with higher efficiency, and the generated hash codes serve as a low-dimensional carrier of discriminative features and phenotypic distance information, allowing for broader applications in systematics and ecology.

evolutionary biology↗

bioRxiv2023

Ferroptosis induced by phenolic compound-iron complex

Phenolic compounds are the most ubiquitously distributed pollutants, and are highly toxic to living organisms, however the detailed mechanism how phenols exert toxic effects remains elusive. Here,Escherichia coli and phloroglucinol are adapted as proxy to elucidate the molecular mechanism of phenols toxicity. We demonstrated that phloroglucinol complexed with iron and promoted the generation of hydroxyl radicals in Fenton reaction, leading to reducing power depletion and lipid peroxidation, and further leading to ferroptosis-like cell death ofE. coli. This ferroptotic death can be triggered by various phenols in diverse organisms, from bacteria to mammalian cells. Furthermore, we demonstrated that phloroglucinol-induced ferroptosis suppressed tumor growth in mice effectively, indicating phloroglucinol as promising drug for therapy-resistant cancers. Its also discovered that repression of this ferroptosis-like cell death benefited microbial degradation or production of desired phenolic compounds, showing great application potential in biotechnology field.

microbiology↗

bioRxiv2023

Intensity- and frequency-specific effects of transcranial alternating current stimulation are explained by network dynamics

Transcranial alternating current stimulation (tACS) can be used to non-invasively entrain neural activity, and thereby cause changes in local neural oscillatory power. Despite an increased use in cognitive and clinical neuroscience, the fundamental mechanisms of tACS are still not fully understood. Here, we develop a computational neuronal network model of two-compartment pyramidal neurons and inhibitory interneurons which mimic the local cortical circuits. We model tACS with electric field strengths that are achievable in human applications. We then simulate intrinsic network activity and measure neural entrainment to investigate how tACS modulates ongoing endogenous oscillations. First, we show that intensity-specific effects of tACS are non-linear. At low intensities (<0.3 mV/mm), tACS desynchronizes neural firing relative to the endogenous oscillations. At higher intensities (>0.3 mV/mm), neurons are entrained to the exogenous electric field. We then further explore the stimulation parameter space and find that entrainment of ongoing cortical oscillations also depends on frequency by following an Arnold tongue. Moreover, neuronal networks can amplify the tACS induced entrainment via excitation-inhibition balance. Our model shows that pyramidal neurons are directly entrained by the exogenous electric field and drive the inhibitory neurons. Our findings can thus provide a mechanistic framework for understanding the intensity- and frequency-specific effects of oscillating electric fields on neuronal networks. This is crucial for rational parameters selection for tACS in cognitive studies and clinical applications.

neuroscience↗

bioRxiv2023

Long non-coding RNA small nucleolar RNA host genes as prognostic molecular biomarkers in hepatocellular carcinoma: a meta-analysis.

ObjectiveRecently, increasing data have suggested that the lncRNA small nucleolar RNA host genes (SNHGs) were aberrantly expressed in hepatocellular carcinoma(HCC), but the association between the prognosis of HCC and their expression remained unclear. The purpose of this meta-analysis was to determine the prognostic significance of lncRNA SNHGs in HCC. MethodsWe systematically searched Embase, Web of Science, PubMed, and Cochrane Library for eligible articles published up to October 2022. The prognostic significance of SNHGs in HCC was evaluated by hazard ratios (HRs) and 95% confidence intervals (CIs). Odds ratios (ORs) were used to assess the clinicopathological features of SNHGs. ResultsThis analysis comprised a total of 25 studies covering 2314 patients with HCC. The findings demonstrated that over-expressed SNHGs were associated with larger tumor size, multiple tumor numbers, poor histologic grade, earlier lymphatic metastasis, vein invasion, advanced tumor stage, portal vein tumor thrombosis (PVTT), and higher AFP level, but not with gender, age, HBV infection, and cirrhosis. In terms of prognosis, patients with higher SNHG expression were more likely to have shorter overall survival (OS), relapse-free survival (RFS), and disease-free survival (DFS). ConclusionsIn conclusion, upregulation of SNHG expression correlated with clinicopathological parameters and could predict a poor prognosis for HCC patients.

cancer biology↗

bioRxiv2023

Remodeling the central metabolism of Escherichia coli enables a universal chassis

E. coli is the host of choice to produce a wide variety of chemicals and proteins. Overflow metabolism is considered as the widespread and major obstacle in microbial synthesis, and overcoming this common bottleneck may enable a universal chassis. Here, we constructed an E. coli universal chassis (ABKS strain) with significantly suppressed overflow metabolism, presenting similar growth rate, decreased glucose consumption, and increased production of desired chemicals and proteins when compared with wild-type BL21(DE3) strain. Furthermore, we demonstrated that metabolic flux of ABKS strain was reprogrammed from TCA cycle to glyoxylate bypass at isocitrate node via the synergistic effect of multi-layer regulation in gene transcription and protein modification. This metabolic reconfiguration alleviates overflow metabolism, avoids CO2 release in TCA cycle, finally improving the carbon atom economy in bioprocess. Our chassis has widespread and practical use for elevating the production and yield of multiple desired chemicals and proteins from different carbon source. The metabolic reconfiguration also provides theoretical basis for rational design of efficient bioproduction strains.

bioengineering↗

bioRxiv2023

Integrative mapping of spatial transcriptomic and amyloid pathology in Alzheimer's disease at single-cell resolution

Alzheimers disease (AD) is a complex neurodegenerative disorder that affects millions of people worldwide. Despite decades of research, the underlying molecular and cellular changes of AD remain unresolved, especially in terms of the spatial structure of gene expression changes that correlates with pathology, e.g. amyloid beta (A-beta) plaques. Recent advances in imaging-or sequencing-based single-cell spatial transcriptomics have allowed a systematic dissection of molecular and cell architectures in the brain and other tissues. In this study, we employed the recently developed Stereo-seq technology to spatially profile the whole-genome transcriptomics in the 5xFAD mouse model and established the methodology to analyze the specific neuronal transcriptomic changes spatially correlated with amyloid pathology at single cell resolution. More specifically, we developed a pipeline for integrative image- and non-image-based cell segmentation, VoxelMorph-based non-linear alignment, and Unet-based object detection to achieve reliable transcriptomics analysis at the single-cell resolution, and investigated the spatial relationship between diverse neuronal clusters and A-beta depositions. This work has demonstrated the potential of using the Stereo-seq technology as a powerful tool to investigate AD and other complex neurological disorders.

neuroscience↗

bioRxiv2023

An anterior forebrain pathway in parrots is necessary for individual signatures of learned vocalizations

Parrots have enormous vocal imitation capacities and produce individually unique vocal signatures. Like songbirds, parrots have a nucleated neural song system with distinct anterior (AFP) and posterior forebrain pathways (PFP). To test if song systems of parrots and songbirds, which diverged over 50 million years ago, have a similar functional organization, we first established a neuroscience-compatible call-and-response behavioral paradigm to elicit learned contact calls in budgerigars (Melopsittacus undulatus). Using variational autoencoder-based machine learning methods, we show that contact calls within affiliated groups converge but that individuals maintain unique acoustic features, or vocal signatures, even after call convergence. Next, we transiently inactivated the outputs of AFP to test if learned vocalizations can be produced by the PFP alone. As in songbirds, AFP inactivation had an immediate effect on vocalizations, consistent with a premotor role. But in contrast to songbirds, where the isolated PFP is sufficient to produce stereotyped and acoustically normal vocalizations, isolation of the budgerigar PFP caused a degradation of call acoustic structure, stereotypy, and individual uniqueness. Thus the contribution of AFP and the capacity of isolated PFP to produce learned vocalizations have diverged substantially between songbirds and parrots, likely driven by their distinct behavioral ecology and neural connectivity.

neuroscience↗

bioRxiv2023

A parabrachial-hypothalamic parallel circuit governs cold defense in mice

Thermal homeostasis is vital for mammals and is controlled by brain neurocircuits. Remarkable advances have been made in understanding how neurocircuits centered in the hypothalamic preoptic area (POA), the brains thermoregulation center, control warm defense, whereas mechanisms by which the POA regulates cold defense remain unclear. Here, we confirmed that the pathway from the lateral parabrachial nucleus (LPB) to the POA, is critical for cold defense. Parallel to this pathway, we uncovered that a pathway from the LPB to the dorsomedial hypothalamus (DMH), namely the LPB[->]DMH pathway, is also essential for cold defense. Projection-specific blockings revealed that both pathways provide an equivalent and cumulative contribution to cold defense, forming a parallel circuit. Specifically, activation of the LPB[->]DMH pathway induced strong cold-defense responses, including increases in thermogenesis of brown adipose tissue (BAT), muscle shivering, heart rate, and physical activity. Further, we identified a subpopulation of somatostatin+ neurons in the LPB that target the DMH to promote BAT thermogenesis. Therefore, we reveal a parabrachial-hypothalamic parallel circuit in governing cold defense in mice. This not only enables resilience to hypothermia but also provides a scalable and robust network in heat production, reshaping our understanding of how neural circuits regulate essential homeostatic behaviors.

neuroscience↗

bioRxiv2023

SEL1L-HRD1 ER-associated degradation is a new ataxia gene

The SEL1L-HRD1 protein complex represents the most conserved branch of endoplasmic reticulum (ER)-associated degradation (ERAD); however, definitive evidence for the importance of SEL1L in HRD1 ERAD is lacking. Here we report that attenuation of the interaction between SEL1L and HRD1 impairs HRD1 ERAD function and has pathological consequences in mice. Our data show that SEL1L variant p.Ser658Pro (SEL1LS658P) previously identified in Finnish Hound suffering cerebellar ataxia is a recessive hypomorphic mutation, causing partial embryonic lethality, developmental delay, and early-onset cerebellar ataxia in homozygous mice carrying the bi-allelic variant. Mechanistically, SEL1LS658P variant attenuates the SEL1L-HRD1 interaction and causes HRD1 dysfunction by generating electrostatic repulsion between SEL1L F668 and HRD1 Y30 residues. Proteomic screens of SEL1L and HRD1 interactomes revealed that the SEL1L-HRD1 interaction is prerequisite for the formation of a functional HRD1 ERAD complex, as SEL1L recruits not only the lectins OS9 and ERLEC1, but the E2 UBE2J1 and retrotranslocon DERLIN, to HRD1. These data underscore the pathophysiological importance and disease relevance of the SEL1L-HRD1 complex, and identify a key step in organizing the HRD1 ERAD complex.

cell biology↗

bioRxiv2023

GTP signaling links metabolism, DNA repair, and responses to genotoxic stress

How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a G protein, that promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes non-homologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard of care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in non-malignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment.

cancer biology↗

bioRxiv2023

A comprehensive catalog with 100 million genes and 3,000 metagenome-assembled genomes from global cold seep sediments

Cold seeps harbor abundant and diverse microbes that represent a tremendous potential for biological applications and also have a significant influence on biogeochemical cycles. Though recent metagenomic studies have expanded our understanding of the microbial community and function of seep microorganisms, the knowledge of diversity and genetic repertoire of global seep microbes is lacking. Here, we collected a compilation of 165 metagenomic data from 16 cold seep sites across the globe to construct comprehensive gene and genome catalogs. The non-redundant gene catalog was comprised of 147 million genes (clustered at 95% amino acid identity), and 35.72% of them could not be assigned to a function with the currently available databases. A total of 3,164 species-level representative metagenome-assembled genomes (MAGs) are obtained, most of which (94.31%) belong to novel species. Of them, 81 ANME species are identified covering all subclades except ANME-2d, and 23 syntrophic SRB species spanning Seep-SRB1a Seep-SRB1g, and Seep-SRB2 clades. The non-redundant gene and MAGs catalogs are a valuable resource that enables expanded knowledge of the structure and functions of cold seep microbiomes.

microbiology↗

bioRxiv2023

Toleration of Frameshift Mutations in mRNA Sequences Encoding the N-terminal Peptides of Bacterial Type III Effectors

Gram-negative bacteria deliver effector proteins into eukaryotic host cells through type III and type IV secretion systems, causing infections and diseases. It remains unclear about the signals guiding the specific secretion of the effectors. Here, we adopted an in silico approach to analyze the mRNA sequences encoding the putative peptides essential for effective secretion and translocation of type III and IV effectors. A surprisingly high proportion of type III effectors showed tolerance on frameshift mutations in signal-encoding mRNA sequences, and in contrast, very low percentage of type IV effectors showed the similar frameshift tolerance. The type III effectors with frameshift tolerance of secretion signals were widely distributed in effector or signal families and bacterial species. Natural frameshifts could be identified in type III effector genes, which were often remedied in time by nearby paired insertions or deletions. Frameshift-derived peptide sequences also retained the common properties present in the signal peptides of raw type III effectors. Natural language processing models were adopted to represent the common features in the mRNA sequences encoding N-terminal peptides of type III effectors or C-terminal peptides of type IV effectors, with which transfer learning models could well predict the effectors, especially type IV effectors. The observations in the study would facilitate us understand the nature and evolution of secretion signals of type III and IV effectors. SignificanceIt has been a debate on the nature of signals for translocation of type III secreted effectors for a long time. Meanwhile, there has been no examination on the possibility of mRNA being as translocation signals for type IV or other types of secreted effectors. By computational simulation, the study demonstrated the protein nature of translocation signals for both type IV effectors and most type III effectors. Despite wide frameshift tolerance and atypical common features in mRNA sequences encoding the putative N-terminal signal sequences of type III effectors, more typical common physicochemical and amino acid composition properties between the mutation-derived and raw peptides, and the frequent self-correction phenomenon for naturally happening frameshifts supported the translocation signals at protein level of type III effectors. The common features in mRNA sequences encoding the translocation signal peptides of type III and IV effectors could also be combined in models for better prediction of the effectors respectively.

microbiology↗

bioRxiv2023

Induced neural phase precession through exogeneous electric fields

The gradual shifting of preferred neural spiking relative to local field potentials (LFPs), known as phase precession, plays a prominent role in neural coding. Correlations between the phase precession and behavior have been observed throughout various brain regions. As such, phase precession is suggested to be a global neural mechanism that promotes local neuroplasticity. However, causal evidence and neuroplastic mechanisms of phase precession are lacking so far. Here we show a causal link between LFP dynamics and phase precession. In three experiments, we modulated LFPs in humans, a non-human primate, and computational models using alternating current stimulation. We show that continuous stimulation of motor cortex oscillations in humans lead to a gradual phase shift of maximal corticospinal excitability by [~]90{degrees}. Further, exogenous alternating current stimulation induced phase precession in a subset of entrained neurons ([~]30%) in the non-human primate. Multiscale modeling of realistic neural circuits suggests that alternating current stimulation-induced phase precession is driven by NMDA-mediated synaptic plasticity. Altogether, the three experiments provide mechanistic and causal evidence for phase precession as a global neocortical process. Alternating current-induced phase precession and consequently synaptic plasticity is crucial for the development of novel therapeutic neuromodulation methods.

neuroscience↗

bioRxiv2023

LIFR recruits HGF-producing neutrophils to promote liver injury repair and regeneration

The molecular links between tissue repair and tumorigenesis remain elusive. Here, we report that loss of the liver tumor suppressor Lifr in mouse hepatocytes impairs the recruitment and activity of reparative neutrophils, resulting in the inhibition of liver regeneration after partial hepatectomy or toxic injuries. On the other hand, overexpression of LIFR promotes liver repair and regeneration after injury. Interestingly, LIFR deficiency or overexpression does not affect hepatocyte proliferation ex vivo or in vitro. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of the neutrophil chemoattractant CXCL1 (which binds CXCR2 to recruit neutrophils) and cholesterol in a STAT3-dependent manner. Cholesterol, in turn, acts on the recruited neutrophils to secrete hepatocyte growth factor (HGF) to accelerate hepatocyte proliferation and regeneration. Altogether, our findings reveal a LIFR-STAT3- CXCL1-CXCR2 axis and a LIFR-STAT3-cholesterol-HGF axis that mediate hepatic damage- induced crosstalk between hepatocytes and neutrophils to repair and regenerate the liver.

cell biology↗

bioRxiv2023

Rigid Scaffolds are Promising for Designing Macrocyclic Kinase Inhibitors

Macrocyclic kinase inhibitors (MKIs) are gaining attention due to their favorable selectivity and potential to overcome drug resistance, yet they remain challenging to design because of their novel structures. To facilitate the design and discovery of MKIs, we investigate MKI rational design starting from initial acyclic compounds by performing microsecond-scale atomistic simulations for multiple MKIs, constructing an MKI database, and analyzing MKIs using hierarchical cluster analysis. Our studies demonstrate that the binding modes of MKIs are like that of their corresponding acyclic counterparts against the same kinase targets. Importantly, within the respective binding sites, the MKI scaffolds retain the same conformations as their corresponding acyclic counterparts, demonstrating the rigidity of scaffolds before and after molecular cyclization. The MKI database includes 641 nanomole-level MKIs from 56 human kinases elucidating the features of rigid scaffolds, and the tendency of core structures among MKIs. Collectively these results and resources can facilitate MKI development.

bioinformatics↗

bioRxiv2023

Viruses in deep-sea cold seep sediments harbor diverse survival mechanisms and remain genetically conserved within species

Deep sea cold seep sediments have been discovered to harbor novel, abundant, and diverse bacterial and archaeal viruses. However, little is known about viral genetic features and evolutionary patterns in these environments. Here, we examined the evolutionary ecology of viruses across active and extinct seep stages in the area of Haima cold seeps in the South China Sea. Diverse antiviral defense systems in 487 microbial genomes spanning 43 families inform the dynamics of host-virus interactions. Accordingly, a total of 338 viral operational taxonomic units are identified and linked to 36 bacterial and archaeal phyla. Cold seep viruses are predicted to harbor diverse adaptive strategies to persist in this environment, including counter-defense systems, reverse transcriptases, auxiliary metabolic genes, and alternative genetic code assignments. Extremely low nucleotide diversity is observed in cold seep viral populations, being influenced by factors including microbial host, sediment depth and cold seep stage. Most cold seep viral genes are under strong purifying selection with trajectories that differ depending on whether cold seeps are active or extinct. This work sheds light on the understanding of environmental adaptation mechanisms and evolutionary patterns of viruses in the sub-seafloor biosphere.

microbiology↗

bioRxiv2023

FAM122A ensures cell cycle interphase progression and checkpoint control as a SLiM-dependent substrate-competitive inhibitor to the B55/PP2A phosphatase

The Ser/Thr protein phosphatase 2A (PP2A) is a highly conserved collection of heterotrimeric holoenzymes responsible for the dephosphorylation of many regulated phosphoproteins. Substrate recognition and the integration of regulatory cues are mediated by B regulatory subunits that are complexed to the catalytic subunit (C) by a scaffold protein (A). PP2A/B55 substrate recruitment was thought to be mediated by charge-charge interactions between the surface of B55 and its substrates. Challenging this view, we recently discovered a conserved SLiM [RK]-V-x-x-[VI]-R in a range of proteins, including substrates such as the retinoblastoma-related protein p107 and TAU (Fowle et al. eLife 2021;10:e63181). Here we report the identification of this SLiM in FAM122A, an inhibitor of B55/PP2A. This conserved SLiM is necessary for FAM122A binding to B55 in vitro and in cells. Computational structure prediction with AlphaFold2 predicts an interaction consistent with the mutational and biochemical data and supports a mechanism whereby FAM122A uses the SLiM in the form of a short -helix to dock to the B55 top groove. In this model, FAM122A spatially constrains substrate access by occluding the catalytic subunit with a second -helix immediately adjacent to helix 1. Consistently, FAM122A functions as a competitive inhibitor as it prevents binding of substrates in in vitro competition assays and the dephosphorylation of CDK substrates by B55/PP2A in cell lysates. Ablation of FAM122A in human cell lines reduces the rate of proliferation, progression through cell cycle transitions and abrogates G1/S and intra-S phase cell cycle checkpoints. FAM122A-KO in HEK293 cells results in attenuation of CHK1 and CHK2 activation in response to replication stress. Overall, these data strongly suggest that FAM122A is a SLiM-dependent, substrate-competitive inhibitor of B55/PP2A that suppresses multiple functions of B55 in the DNA damage response and in timely progression through the cell cycle interphase.

molecular biology↗