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Zhang, S.

Publications and source records attributed to Zhang, S..

At least 685 records · Page 38Linked to original sources

AnnoPRO: an innovative strategy for protein function annotation based on image-like protein representation and multimodal deep learning

Protein function annotation has been one of the longstanding issues, which is key for discovering drug targets and understanding physiological or pathological process. A variety of computational methods have therefore been constructed to facilitate the research developments in this particular direction. However, the annotation of protein function based on computational methods has been suffering from the serious "long-tail problem", and it remains extremely challenging for existing methods to improve the prediction accuracies for protein families in tail label levels. In this study, an innovative strategy, entitled AnnoPRO, for protein function annotation was thus constructed. First, a novel method enabling image-like protein representations was proposed. This method is unique in capturing the intrinsic correlations among protein features, which can greatly favor the application of the state-of-the-art deep learning methods popular in image classification. Second, a multimodal framework integrating multichannel convolutional neural network and long short-term memory neural network was constructed to realize a deep learning-based protein functional annotation. Since this framework was inspired by a reputable method used in image classification for dealing with its long-tail problem, our AnnoPRO was expected to significantly improve the annotation performance of the protein families in tail label level. Multiple case studies based on benchmark were also conducted, which confirmed the superior performance of AnnoPRO among the existing methods. All source codes and models of AnnoPRO were freely available to all users at https://github.com/idrblab/AnnoPRO, and would be essential complement to existing methods.

bioinformatics↗

Population genomics reveals extensive inbreeding and purging of mutational load in wild Amur tigers

The inbreeding is a big threat for the persistence of genetic diversity in small and isolated populations of endangered species. The homozygous genome could exacerbate inbreeding depression by introducing homozygous deleterious alleles in the population. However, purging of inbreeding loads as they become homozygotes in small populations could alleviate the depression. The Amur tiger (Panthera tigris altaica) is typically exists in small population living in forests in Northeast Asia and is among the most endangered animals on the planet with great symbolic significance of conservation. By comparing with captive individuals, we revealed substantially higher and more extensive inbreeding in the wild Amur tiger population (FROH=0.51) than in captive Amur tigers (FROH=0.26). We further found much less mutational loads in wild populations when compared with captive Amur tigers. However, the frequency of loss of function and deleterious nonsynonymous mutations inside ROH regions are much lower than that in non-ROH regions in both wild and captive Amur tigers, indicating the purging may had occurred in both populations but much effective in the wild population. In addition, we found the average frequency of deleterious alleles was much lower than that of neutral alleles in the wild population, indicating that the purifying selection contributed to the purging of mutational loads in the wild Amur tigers. These findings provide valuable genome-wide evidence to support the making of future conservation plans of wild Amur tigers.

genomics↗

Modelling complex growth profiles of Bacteroides fragilis and Escherichia coli on various carbohydrates in an anaerobic environment

Previously published models for microbial growth focus only on either death or growth and are unable to account for differently shaped growth curves. Currently, there is no model capable of incorporating combinations of microbial growth trends. This study creates a bacterial growth model that incorporates growth, death, lag, and tail phases as well as applies this model to the growth trends of Bacteroides fragilis and Escherichia coli on 13 different carbohydrate substances. Growth trends were collected by measuring the optical densities over 72 hours for either B. fragilis or E. coli in a chemically defined media supplemented by a mono- or disaccharide. The Digital Environment to Enable Data-driven Science (DEEDS) platform was utilized to parse data and apply the developed model to obtain parameter values. E. coli was found to grow on the chemically defined media alone while B. fragilis was unable to grow on it alone. E. coli growth was led by 10 mM concentration of substrates while B. fragilis growth was substrate dependent. Bacterial death only occurred for B. fragilis but was found to be dependent on concentration for the two most significant substrates. A singular model was developed that does not require prior knowledge of metabolomics and is capable of incorporating a combination of growth and death trends.

microbiology↗

Photosynthetic living fibers fabrication from algal-bacterial consortia with controlled spatial distribution

Living materials that combine active cells and synthetic matrix materials have become a promising research field in recent years. While multicellular systems present exclusive benefits in developing living materials over single-cell systems, creating artificial multicellular systems can be challenging due to the difficulty in controlling the multicellular assemblies and the complexity of cell-to-cell interactions. Here, we propose a co-culture platform capable of isolating and controlling the spatial distribution of algal-bacterial consortia, which can be used to construct photosynthetic living fibers. Through coaxial extrusion-based 3D printing, hydrogel fibers containing bacteria or algae can be deposited into designated structures and further processed into materials with precise geometries. In addition, the photosynthetic living fibers demonstrate a significant synergistic catalytic effect resulting from the immobilization of both bacteria and algae, which effectively optimize sewage treatment for bioremediation purposes. The integration of microbial consortia and 3D printing gives functional living materials that have promising applications in biocatalysis, biosensing, and biomedicine. Our approach provides an optimized solution for constructing efficient multicellular systems and opens a new avenue for the development of advanced materials.

bioengineering↗

CRACD suppresses neuroendocrinal plasticity of lung adenocarcinoma

Tumor cell plasticity contributes to intratumoral heterogeneity and therapy resistance. Through cell plasticity, lung adenocarcinoma (LUAD) cells transform into neuroendocrinal (NE) tumor cells. However, the mechanisms of NE cell plasticity remain unclear. CRACD, a capping protein inhibitor, is frequently inactivated in cancers. CRACD knock-out (KO) de-represses NE-related gene expression in the pulmonary epithelium and LUAD cells. In LUAD mouse models, Cracd KO increases intratumoral heterogeneity with NE gene expression. Single-cell transcriptomic analysis showed that Cracd KO-induced NE plasticity is associated with cell de-differentiation and activated stemness-related pathways. The single-cell transcriptomes of LUAD patient tumors recapitulate that the distinct LUAD NE cell cluster expressing NE genes is co-enriched with SOX2, OCT4, and NANOG pathway activation, and impaired actin remodeling. This study reveals an unexpected role of CRACD in restricting NE cell plasticity that induces cell de-differentiation, providing new insights into cell plasticity of LUAD.

cancer biology↗

Artificial intelligence redefines RNA virus discovery

Current metagenomic tools can fail to identify highly divergent RNA viruses. We developed a deep learning algorithm, termed LucaProt, to discover highly divergent RNA-dependent RNA polymerase (RdRP) sequences in 10,487 metatranscriptomes generated from diverse global ecosystems. LucaProt integrates both sequence and predicted structural information, enabling the accurate detection of RdRP sequences. Using this approach we identified 161,979 potential RNA virus species and 180 RNA virus supergroups, including many previously poorly studied groups, as well as RNA virus genomes of exceptional length (up to 47,250 nucleotides) and genomic complexity. A subset of these novel RNA viruses were confirmed by RT-PCR and RNA/DNA sequencing. Newly discovered RNA viruses were present in diverse environments, including air, hot springs and hydrothermal vents, and both virus diversity and abundance varied substantially among ecosystems. This study advances virus discovery, highlights the scale of the virosphere, and provides computational tools to better document the global RNA virome. In briefA deep learning algorithm (LucaProt) that integrates both sequence and predicted structural information was employed to identify highly divergent RNA viral "dark matter" in 10,487 metatranscriptomes from diverse global ecosystems. A total of 161,979 potential RNA virus species and 180 RNA virus supergroups was unveiled using this AI approach, including many understudied groups.

microbiology↗

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↗

Somatic Calcium Signals from Layer II/III Motor Cortex for Continuous Neural Decoding

The latest research shows that calcium signals can provide a new signal source for brain-machine interfaces (BMI). However, it remains a question whether the calcium signals from layer 2/3 motor cortex can be used for continuous neural decoding. And how they are involved in movement coding is also worth investigating. Here we collect the somatic signals in M1 layer 2/3 while mice performed a lever-press task under the one-photon imaging. We first present the potential of somatic calcium signals from layer 2/3 in continuous neural decoding through an improved recurrent neural network. Layer 2/3 neurons exhibit three types of calcium dynamics with distinct spatiotemporal coding patterns involved in the movement. Pre-pressing and pressing neurons enable sparse coding of movement through complementary spatiotemporal information. While post-pressing neurons predict the lever movement most accurately through the calcium dynamics with higher fidelity. These results demonstrate the capability of calcium signals from layer 2/3 neurons as a motor BMI driver and underscore their diversity in motor coding, opening a new avenue for studying the motor cortex and designing optical BMIs.

neuroscience↗

Mitigating a TDP-43 proteinopathy using RNA-targeting CRISPR effector proteins

The TDP-43 proteinopathies, which include amyotrophic lateral sclerosis and frontotemporal dementia, are a devastating group of neurodegenerative disorders that are characterized by the mislocalization and aggregation of TDP-43. Here we demonstrate that RNA-targeting CRISPR effector proteins, a programmable class of gene silencing agents that includes the Cas13 family of enzymes and Cas7-11, can be used to mitigate TDP-43 pathology when programmed to target ataxin-2, a modifier of TDP-43-associated toxicity. In addition to inhibiting the aggregation and transit of TDP-43 to stress granules, we find that the in vivo delivery of an ataxin-2-targeting Cas13 system to a mouse model of TDP-43 proteinopathy improved functional deficits, extended survival, and reduced the severity of neuropathological hallmarks. Further, we benchmark RNA-targeting CRISPR platforms against ataxin-2 and find that high-fidelity forms of Cas13 possess improved transcriptome-wide specificity compared to Cas7-11 and a first-generation effector. Our results demonstrate the potential of CRISPR technology for TDP-43 proteinopathies.

bioengineering↗

Characterization of mitotic phenotypes associated with a MYC synthetic lethal compound

Therapeutic targeting of MYC directly has proven difficult, but several means to target MYC indirectly using a synthetic lethal drug approach have been proposed. Synthetic lethal approaches for MYC have sought to take advantage of vulnerabilities MYC imposes related to either metabolic reprogramming, apoptotic signaling or the cycling of cancer cells. Here, we describe in detail the cell division phenotypes induced by a MYC synthetic lethal compound, dimethylfasudil (diMF). DiMF is a known ROCK inhibitor, but structurally related ROCK inhibitors are not synthetic lethal with MYC, so the activity of diMF is not related to blockade of this family of kinases. Instead, this compound induced multiple cell cycle-related liabilities. These included the early mitotic arrest of cycling cells followed by mitotic catastrophe-induced death and the induction of polyploidy in cells that do manage to pass through mitosis. As early as prometaphase, we noted diminished staining for BUB1 kinase, which binds to kinetochores and regulates the mitotic spindle checkpoint and chromosome congression. Kinetochore proteins, such as CENP-F, failed to localize at the metaphase plate, confirming a deficit in centromere assembly. This, presumably, contributed to the development of segregation anomalies in diMF-treated cells. In anaphase cells, the protein regulator of cytokinesis 1 (PRC1), failed to be recruited to the midzone, leading to a cascade of defects that included failed recruitment of the chromosomal passenger protein complex, the centralspindlin complex and polo-like-kinase 1 (PLK1). These observations correlate well with the cell death phenotypes induced by diMF, which may serve as a prototype MYC synthetic lethal compound to explore synthetic lethal therapy or as a scaffold upon which to build superior compounds. The phenotypes described here serve as examples of MYC synthetic lethal drug effects that can be used to explore and maximize drug discovery programs.

cancer biology↗

The autophagy protein Atg9 functions in glia and contributes to parkinsonian symptoms in a Drosophila model of Parkinson's disease

Parkinsons disease (PD) is a progressive neurodegenerative disorder characterized by the motor deficits, selective loss of dopaminergic (DA) neurons, and the brain accumulation of -synuclein (-syn)-composed protein aggregates called Lewy bodies (LBs). Whereas dysfunction in the protein degradation pathway, like autophagy in neurons, has been demonstrated as a critical mechanism for eliminating protein aggregates in PD, how protein aggregates are eliminated in the other brain cell type, glia, is less well characterized. In the present study, we show that Atg9, the only transmembrane protein in the core autophagy pathway, is highly expressed in Drosophila adult brain glia. Results from immunostaining and live-cell imaging analysis reveal that a significant portion of Atg9 localizes to the trans-Golgi network (TGN), autophagosomes, and lysosomes in glia; Atg9 is persistently in contact with these organelles. Lacking glial atg9 reduces the number of omegasome and autophagosome and impairs autophagic substrate degradation, suggesting that glial Atg9 participates in the early steps of autophagy, hence the control of autophagic degradation. Importantly, loss of glial atg9 induces parkinsonian symptoms in Drosophila including progressive DA neuron loss and locomotion deficits. Our findings identify a functional role of Atg9 in glial autophagy and establish a potential link between glial autophagy and PD. These results provide new insights on the underlying mechanism of PD.

neuroscience↗

Modeling, dissecting, and subtyping of E-Cadherin inactivation-associated diffuse-type gastric adenocarcinoma

This study investigates diffuse-type gastric adenocarcinoma (DGAC), a deadly and treatment-resistant cancer. It reveals that CDH1 inactivation occurs in a subset of DGAC patient tumors, leading to the identification of two distinct DGAC subtypes. The findings emphasize the importance of understanding DGACs molecular diversity for personalized medicine in patients with CDH1 inactivation.

cancer biology↗

The Potential of Low Press and Hypoxia Environment in Assisting Pan-cancer Treatment

ObjectiveA low incidence and mortality rate of cancer has been observed in high-altitude regions, suggesting a potential positive effect of low press and hypoxia (LPH) environment on cancer. Based on this finding, our study aimed to construct a pan-cancer prognosis risk model using a series of ADME genes intervened by low oxygen, to explore the impact of LPH environment on the overall survival (OS) of various kinds of cancers, and to provide new ideas and approaches for cancer prevention and treatment. Datasets and MeasuresThe study used multiple sources of data to construct the pan-cancer prognosis risk model, including gene expression and survival data of 8,628 samples from the cancer genome atlas, and three gene expression omnibus databases were employed to validate the prediction efficiency of the prognostic model. The AltitudeOmics dataset was specifically used to validate the significant changes in model gene expression in LPH. To further identify the biomarkers and refine the model, various analytical approaches were employed such as single-gene prognostic analysis, weighted gene co-expression network analysis, and stepwise cox regression. And LINCS L1000, AutoDockTools, and STITCH were utilized to explore effective interacting drugs for model genes. Main Outcomes and ConclusionsThe study identified eight ADME genes with significant changes in the LPH environment to describe the prognostic features of pan-cancer. Lower risk scores calculated by the model were associated with better prognosis in 25 types of tumors, with a p-value of less than 0.05. The LPH environment was found to reduce the overall expression value of model genes, which could decrease the death risk of tumor prognosis. Additionally, it is found that the low-risk group had a higher degree of T cell infiltration based on immune infiltration analysis. Finally, drug exploration led to the identification of three potential model-regulating drugs. Overall, the study provided a new approach to construct a pan-cancer survival prognosis model based on ADME genes from the perspective of LPH and offered new ideas for future tumor prognosis research.

cancer biology↗

ANXA11 biomolecular condensates facilitate protein-lipid phase coupling on lysosomal membranes

Phase transitions of cellular proteins and lipids play a key role in governing the organisation and coordination of intracellular biology. The frequent juxtaposition of proteinaceous biomolecular condensates to cellular membranes raises the intriguing prospect that phase transitions in proteins and lipids could be co-regulated. Here we investigate this possibility in the ribonucleoprotein (RNP) granule-ANXA11-lysosome ensemble, where ANXA11 tethers RNP granule condensates to lysosomal membranes to enable their co-trafficking. We show that changes to the protein phase state within this system, driven by the low complexity ANXA11 N-terminus, induce a coupled phase state change in the lipids of the underlying membrane. We identify the ANXA11 interacting proteins ALG2 and CALC as potent regulators of ANXA11-based phase coupling and demonstrate their influence on the nanomechanical properties of the ANXA11-lysosome ensemble and its capacity to engage RNP granules. The phenomenon of protein-lipid phase coupling we observe within this system offers an important template to understand the numerous other examples across the cell whereby biomolecular condensates closely juxtapose cell membranes. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/533832v1_ufig1.gif" ALT="Figure 1"> View larger version (76K): org.highwire.dtl.DTLVardef@16f3e10org.highwire.dtl.DTLVardef@538f39org.highwire.dtl.DTLVardef@1e00d4eorg.highwire.dtl.DTLVardef@89967d_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

Long-term reliable neural decoding based on flexible implantable microelectronics and machine learning for seizure prediction application

Neural decoding is useful for understanding brain functions and developing neural interface applications. However, neural interfaces based on rigid electronics often suffer from recording instability due to the foreign body responses caused by their mechanical mismatch with soft tissues, limiting the longitudinal accuracy of neural decoding methods. Herein, it is reported that flexible electronics can be integrated with machine learning algorithms to achieve long-term reliable neural decoding. Wet-spun conductive polymer microfibers showed mechanical robustness and flexibility, low impedance, and chronic biocompatibility, enabling intracerebral neural recordings in epileptic mice at a high signal-to-noise ratio eight weeks after implantation. When the signals recorded by the flexible electrodes were used in machine learning analyses with diverse complex algorithms, they consistently showed higher prediction accuracy for epileptic seizures than stiff metal electrode signals, particularly in the case of using long-term recordings for testing or small-sample datasets for training. A real-time warning system based on the flexible neural electrodes was built that predicted seizures eight minutes in advance with a low false alarm rate. Our work bridges flexible electronics and artificial intelligence for neural decoding applications such as long-term treatment of chronic neurological disorders.

bioengineering↗

Structurally divergent and recurrently mutated regions of primate genomes

To better understand the pattern of primate genome structural variation, we sequenced and assembled using multiple long-read sequencing technologies the genomes of eight nonhuman primate species, including New World monkeys (owl monkey and marmoset), Old World monkey (macaque), Asian apes (orangutan and gibbon), and African ape lineages (gorilla, bonobo, and chimpanzee). Compared to the human genome, we identified 1,338,997 lineage-specific fixed structural variants (SVs) disrupting 1,561 protein-coding genes and 136,932 regulatory elements, including the most complete set of human-specific fixed differences. Across 50 million years of primate evolution, we estimate that 819.47 Mbp or ~27% of the genome has been affected by SVs based on analysis of these primate lineages. We identify 1,607 structurally divergent regions (SDRs) wherein recurrent structural variation contributes to creating SV hotspots where genes are recurrently lost (CARDs, ABCD7, OLAH) and new lineage-specific genes are generated (e.g., CKAP2, NEK5) and have become targets of rapid chromosomal diversification and positive selection (e.g., RGPDs). High-fidelity long-read sequencing has made these dynamic regions of the genome accessible for sequence-level analyses within and between primate species for the first time.

genomics↗

ALOX15, a new potential functional target of lung adenocarcinoma

PurposeThe purpose of this study is to explore whether the down-regulation of ALOX15 is related to the stage, differentiation and prognosis of lung adenocarcinoma, whether the overexpression of ALOX15 can inhibit tumor proliferation and metastasis, and whether it is related to the functional target of lung adenocarcinoma(LUAD). MethodsFirstly, bioinformatics of lung cancer patients was analyzed using the TCGA database to study the differential expression of ALOX15 in LUAD and its effect on the survival of LUAD. Then, 50 clinical tissue samples of LUAD were collected to detect the expression of ALOX15 and its relationship with the differentiation degree and stage of lung cancer. Finally, the relationship between the expression of ALOX15 and the proliferation and differentiation of LUAD cell lines (NCI-H1944, A549, PC9) with different degrees of differentiation and the construction of ALOX15 overexpression stable lines was detected. ResultsALOX15 bioinformatics analysis showed that ALOX15 decreased significantly in the early stage of LUAD and had no correlation with the survival of lung cancer patients. ALOX15 was downregulated in LUAD with low differentiation and metastasis in LUAD. LUAD cell lines showed that the lower the degree of differentiation, the lower the expression of ALOX15, and the overexpression of ALOX15 in LUAD cells inhibited the proliferation and migration of cancer cells. ConclusionThese results suggest that the expression of ALOX15 is closely related to the differentiation, proliferation, and metastasis of LUAD, and that upregulation of ALOX15 may inhibit the development of LUAD, suggesting that ALOX15 is a potential biological therapeutic target. Author summaryO_ST_ABSWhy was this study done?C_ST_ABSO_LILung cancer is one of the most frequently diagnosed cancers in the world and the leading cause of cancer-related deaths worldwide. C_LIO_LILung cancer is a heterogeneous disease with a wide range of clinicopathologic features. Lung cancer is roughly divided into non-small cell lung cancer (85% of all diagnoses) and small cell lung cancer (15% of all diagnoses). Adenocarcinoma is a common subtype of non-small cell lung cancer, and its recurrence rate is high, and the prognosis is poor. Therefore, the pathogenesis and characteristics of adenocarcinoma are studied and explored. C_LI What did the researchers do and find?O_LIBiological information database was used to analyze the expression level of arachidonic acid-15-lipoxygenase (ALOX15) in lung adenocarcinoma, and then the expression differences were discussed through clinical samples and cell experiments. C_LIO_LILow ALOX15 expression was detected in lung adenocarcinoma (LAUD) patients compared with normal tissues, and ALOX15 levels influenced LUAD development. C_LIO_LIBy infecting A549 with lentivirus and overexpressing ALOX15 of A549 and PC-9 with PC9, it was found that ALOX15 inhibited the proliferation of tumor cells C_LI What do these findings mean?O_LIarachidonic acid-15-lipoxygenase may be one novel potential biomarker for LUAD and a potential therapeutic target C_LI

cancer biology↗

Light-Guided Rabies Virus Tracing for Neural Circuit Analysis

Neuronal tracing methods are essential tools to understand the fundamental architecture of neural circuits and their connection to the overall functional behavior of the brain. Viral vectors used to map these transsynaptic connections are capable of cell-type-specific and directional-specific labeling of the neuronal connections. Herein, we describe a novel approach to guide the transsynaptic spreading of the Rabies Virus (RV) retrograde tracer using light. We built a Baculovirus (BV) as a helper virus to deliver all the functional components necessary and sufficient for a nontoxic RV to spread from neuron to neuron, with a light-actuated gene switch to control the RV polymerase, the L gene. This design should allow for precisely controlled polysynaptic viral tracing with minimal viral toxicity. To use this system in a highly scalable and automated manner, we built optoelectronics for controlling this system in vitro with a large field of view using an off-the-shelf CMOS sensor, OLED display panel, and microcontrollers. We describe the assembly of these genetic circuits using the uLoop DNA assembly method and a library of genetic parts designed for the uLoop system. Combining these tools provides a framework for increasing the capabilities of nontoxic tracing through multiple synapses and increasing the throughput of neural tracing using viruses.

neuroscience↗