Biology subjects

Deng, Y.

Publications and source records attributed to Deng, Y..

At least 163 records · Page 9Linked to original sources

bioRxiv2023

Heterogeneity and Functional Analysis of Cardiac Fibroblasts in Heart Development

BackgroundAs one of the major cell types in the heart, fibroblasts play critical roles in multiple biological processes. Cardiac fibroblasts are known to develop from multiple sources, but their transcriptional profiles have not been systematically compared. Furthermore, while the function of a few genes in cardiac fibroblasts has been studied, the overall function of fibroblasts as a cell type remains uninvestigated. MethodsSingle-cell mRNA sequencing (scRNA-seq) and bioinformatics approaches were used to analyze the genome-wide genes expression and extracellular matrix genes expression in fibroblasts, as well as the ligand-receptor interactions between fibroblasts and cardiomyocytes. Single molecular in situ hybridization was employed to analyze the expression pattern of fibroblast subpopulation-specific genes. The Diphtheria toxin fragment A (DTA) system was utilized to ablate fibroblasts at each developmental phase. ResultsUsing RNA staining of Col1a1 at different stages, we grouped cardiac fibroblasts into four developmental phases. Through the analysis of scRNA-seq profiles of fibroblasts at 18 stages from two mouse strains, we identified significant heterogeneity, preserving lineage gene expression in their precursor cells. Within the main fibroblast population, we found differential expressions of Wt1, Tbx18, and Aldh1a2 genes in various cell clusters. Lineage tracing studies showed Wt1- and Tbx18-positive fibroblasts originated from respective epicardial cells. Furthermore, using a conditional DTA system-based elimination, we identified the crucial role of fibroblasts in early embryonic and heart growth, but not in neonatal heart growth. Additionally, we identified the zone- and stage-associated expression of extracellular matrix genes and fibroblast-cardiomyocyte ligand-receptor interactions. This comprehensive understanding sheds light on fibroblast function in heart development. ConclusionWe observed cardiac fibroblast heterogeneity at embryonic and neonatal stages, with preserved lineage gene expression. Ablation studies revealed their distinct roles during development, likely influenced by varying extracellular matrix genes and ligand-receptor interactions at different stages.

developmental biology↗

bioRxiv2023

Biodegradable hyperbranched poly(amine-co-ester)-based polymeric nanoparticles for mRNA delivery

Despite the availability of mRNA vaccines utilizing LNP delivery technology, there remains a pressing need for the development of non-viral mRNA delivery vectors that are both more efficient and safe. we present a novel hyperbranched poly(amine-co-ester) (HBPA) system, catalyzed by immobilized lipase, for efficient in vitro and in vivo mRNA delivery. By polymerizing four monomers, we successfully synthesized HBPA with a hyperbranched structure, and subsequent modification of the end groups resulted in HBPA-E. Comparative evaluations revealed that HBPA-E outperforms linear PACE and the commercial transfection reagent Lipofectamine MessengerMAX (LipoMM) in terms of intracellular delivery efficiency, while demonstrating lower cytotoxicity. Furthermore, the in vivo pulmonary delivery efficiency of HBPA-E was significantly superior to that of LPA-E and the commercial in vivo delivery reagent in vivo-JetRNA. Finally, the HBPA-E can be easily dissolved in ethanol, and its mRNA formulation can be employed as a freeze-drying formulation, making it a valuable candidate for future clinical applications of mRNA delivery.

bioengineering↗

bioRxiv2023

Arabidopsis Transcription Factor WRKY45 Confers Cadmium Tolerance via Activating PCS1 and PCS2 Expression

Cadmium (Cd) has long been recognized as toxic pollutant to crops worldwide. The biosynthesis of glutathione-dependent phytochelatin plays crucial roles in the detoxification of Cd in plants. However, its regulatory mechanism remains elusive. Here, we revealed that Arabidopsis transcription factor WRKY45 confers Cd tolerance via promoting the expression of PC synthesis-related genes PCS1 and PCS2, respectively. Firstly, we found that Cd stress induces the transcript levels of WRKY45 and its protein abundance. Accordingly, in contrast to wild type Col-0, the increased sensitivity to Cd is observed in wrky45 mutant, while overexpressing WRKY45 plants are more tolerant to Cd. Secondly, quantitative real-time PCR revealed that the expression of AtPCS1 and AtPCS2 is stimulated in overexpressing WRKY45 plants, but decreased in wrky45 mutant. Thirdly, WRKY45 promotes the expression of PCS1 and PCS2, electrophoresis mobility shift assay analysis uncovered that WRKY45 directly bind to the W-box cis-element of PCS2 promoter. Lastly, the overexpression of WRKY45 in Col-0 leads to more accumulation of PCs in Arabidopsis, and the overexpression of PCS1 or PCS2 in wrky45 mutant plants rescues the phenotypes induced by Cd stress. In conclusion, our results show that AtWRKY45 positively regulate Cd tolerance in Arabidopsis via activating PCS1 and PCS2 expression. Environmental implicationAccumulation of cadmium (Cd) in soils poses a threat to crop productivity and food safety. It has been revealed that phytochelatin (PC) plays an essential role in plants to alleviate Cd toxicity, yet the regulatory mechanisms governing its expression remain unclear. We have demonstrated that the Arabidopsis transcription factor WRKY45 directly activates the expression of PCS1 and PCS2, which encode PC synthase, thereby increasing the content of PC and enhancing Arabidopsis tolerance to Cd stress. These findings offer insights into precise regulation strategies for crop Cd tolerance via modulation of WRKY45 homologue in crops.

molecular biology↗

bioRxiv2023

Stanniocalcin 2 (STC2) is a potent biomarker of hepatocellular carcinoma with its expression being augmented in Nrf1α-deficient cells, but diminished in Nrf2-deficient cells

For insights into the fact that liver-specific knockout of Nrf1 leads to development of non-alcoholic steatohepatitis and spontaneous hepatoma, we previously found that loss of Nrf1 (i.e., a full-length isoform encoded by Nfe2l1) promotes HepG2-derived tumor growth in xenograft mice, but malgrowth of the xenograft tumor is significantly suppressed by knockout of Nrf2 (encoded by Nfe2l2). The mechanism underlying such marked distinctions in their pathologic phenotypes remains elusive, however, to date. Herein, we mined the transcriptome data of liver cancer from the TCGA database to establish a prognostic model of liver cancer and then calculated the predicted risk score of each cell line. The results indicated that knockout of Nrf1 significantly increased the risk score in HepG2 cells, whereas the risk score was reduced by knockout of Nrf2. Of note, stanniocalcin 2 (STC2, a biomarker of liver cancer, that is up-expressed in hepatocellular carcinoma (HCC) tissues with a reduction in the overall survival ratio of those patients) was augmented in Nrf1Nrf2-/- cells, but diminished in Nrf2-/- cells. Thereby, it is inferable that STC2 is likely involved in mediating the distinction between Nrf1Nrf2-/- and Nrf2-/-. Further investigation revealed that HIF1A is an upstream regulator of STC2 in caNrf2{Delta}N, rather than Nrf1Nrf2-/-, cells, and regulation of STC2 and HIF1A in Nrf1Nrf2-/- is determined by Nrf2, but the regulation of STC2 by Nrf2 may be independent on HIF1A. In turn, STC2 can regulate Nrf2 via the putative calcium-mediated Keap1-p62 signaling so to form a feedback regulatory loop. Such potential function of STC2 was further corroborated by a series of experiments combined with transcriptomic sequencing. The results unraveled that STC2 manifests as a dominant tumor-promoter, because the STC2-leading increases in clonogenicity of hepatoma cells and malgrowth of relevant xenograft tumor were almost completely abolished in STC2-/-cells. Together, these demonstrate that STC2 could be paved as a novel potent therapeutic target, albeit as a diagnostic marker, for hepatocellular carcinoma.

cell biology↗

bioRxiv2023

SETDB1 Triple Tudor Domain Ligand, (R,R)-59, Promotes Methylation of Akt1 in Cells

Increased expression and hyperactivation of the methyltransferase SETDB1 are commonly observed in cancer and central nervous system disorders. However, there are currently no reported SETDB1-specific methyltransferase inhibitors in the literature, suggesting this is a challenging target. Here, we disclose that the previously reported small-molecule ligand for SETDB1s Triple Tudor Domain, (R,R)-59, is unexpectedly able to increase SETDB1 methyltransferase activity both in vitro and in cells. Specifically, (R,R)-59 promotes in vitro SETDB1-mediated methylation of lysine 64 of the protein kinase Akt1. Treatment with (R,R)-59 also increased Akt1 threonine 308 phosphorylation and activation, a known consequence of Akt1 methylation, resulting in stimulated cell proliferation in a dose-dependent manner. (R,R)-59 is the first SETDB1 small-molecule positive activator for the methyltransferase activity of this protein. Mechanism of action studies show that full-length SETDB1 is required for significant in vitro methylation of an Akt1-K64 peptide, and that this activity is stimulated by (R,R)-59 primarily through an increase in catalytic activity rather than a change in SAM binding. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=63 SRC="FIGDIR/small/539986v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@5f4022org.highwire.dtl.DTLVardef@16ba47borg.highwire.dtl.DTLVardef@1fb8b0borg.highwire.dtl.DTLVardef@16595bc_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

Virus-induced overexpression of heterologous FT for efficient speed breeding in tomato.

Potato Virus X (PVX) vectors expressing the Arabidopsis thaliana FT or tomato FT ortholog SINGLE-FLOWER TRUSS (SFT) accelerated tomato flowering time by 14-21d and increased by 2-3 fold the number of flowers and ripe fruit compared with non-infected or empty vector-infected plants. The Arabidopsis FT was more effective than the tomato orthologue and there was no alteration of the plant architecture, leaf, flower, or fruit morphology. The virus is not transmitted to the next generation and viral vectors with expression of a heterologous FT will be a useful approach to speed breeding in tomato and other species.

genetics↗

bioRxiv2023

Modeling the role of immune cell conversion in the tumor-immune microenviroment

Tumors develop in a complex physical, biochemical, and cellular milieu, referred to as the tumor microenvironment. Of special interest is the set of immune cells that reciprocally interact with the tumor, the tumor-immune microenvironment (TIME). The diversity of cell types and cell-cell interactions in the TIME has led researchers to apply concepts from ecology to describe the dynamics. However, while tumor cells are known to induce immune cells to switch from anti-tumor to pro-tumor phenotypes, this type of ecological interaction has been largely overlooked. To address this gap in cancer modeling, we develop a minimal, ecological model of the TIME with immune cell conversion, to highlight this important interaction and explore its consequences. A key finding is that immune conversion increases the range of parameters supporting a co-existence phase in which the immune system and the tumor reach a stalemate. Our results suggest that further investigation of the consequences of immune cell conversion, using detailed, data-driven models, will be critical for greater understanding of TIME dynamics.

cancer biology↗

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

Infinite Physical Monkey: Do Deep Learning Methods Really Perform Better in Conformation Generation?

Conformation Generation is a fundamental problem in drug discovery and cheminformatics. Generally, it can be categorized into three different classes according to physical scales, i.e., micro molecule (organic), meso molecule (nano particle-like), and macro molecule (protein and nucleic acid). Organic molecule conformation generation, particularly in vacuum and protein pocket environments, is most relevant to drug design. Recently, with the development of geometric neural networks, the data-driven schemes have been successfully applied in this field, both for molecular conformation generation (in vacuum) and binding pose generation (in protein pocket). The former beats the traditional ETKDG method, while the latter achieves similar accuracy compared with the widely used molecular docking software. Although these methods have shown promising results for real-world drug design campaigns, some researchers have recently questioned whether deep learning (DL) methods perform better in molecular conformation generation via a "parameter-free" method. To our surprise, what they have designed is some kind analogous to the famous infinite monkey theorem, the monkeys that are even equipped with physics education. To discuss the feasibility of their proving, we constructed a real infinite stochastic monkey for molecular conformation generation, showing that even with a more stochastic sampler for geometry generation, the coverage of the benchmark QM-computed conformations are higher than those of most DL-based methods. By extending their physical monkey algorithm for binding pose prediction (with 2000 random samples), we also discover that the successful docking rate also achieves near-best performance among existing DL-based docking models. Thus, though their conclusions are right, their proof process needs more concern. In addition to evaluating the rationality of their algorithms and conclusions, we dig into the inspirations of infinite physical monkeys. We find that, for docking pose generation, DL-based models truly learn the interaction rules between residues and ligands, and discover an inductive bias hidden in the training of the pocket-given docking problem. The code of the proposed algorithm could be found at: https://github.com/HaotianZhangAI4Science/infinite-physical-monkey. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/531607v2_ufig1.gif" ALT="Figure 1"> View larger version (126K): org.highwire.dtl.DTLVardef@188ac2eorg.highwire.dtl.DTLVardef@1e006f3org.highwire.dtl.DTLVardef@e83f8forg.highwire.dtl.DTLVardef@1a4c7cd_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOTOC:C_FLOATNO Infinite Physical Monkey. This image was created with the assistance of DALL{middle dot}E 2 C_FIG

biophysics↗

bioRxiv2023

An Acoustically Controlled Microrobot Modelled on Spirochete Bacteria

As a next-generation toolkit, microrobots can transform a wide range of fields, including micromanufacturing, electronics, microfluidics, tissue engineering, and medicine. While still in their infancy, acoustically actuated wireless microrobots are becoming increasingly attractive, as acoustic control can generate large propulsive forces, requires relatively simple microrobot design, and does not entail complex manipulation systems. However, the interaction of acoustics with microstructure geometry is poorly understood to date, and its study is necessary for developing next-generation acoustically powered microrobots. We present here a mass-manufactured acoustically driven helical microrobot capable of locomotion using a fin-like double-helix microstructure. This microrobot responds to sound stimuli and mimics the spiral motion of natural microswimmers such as spirochetes. The asymmetric double helix interacts with the incident acoustic field, inducing a propulsion torque that causes the microrobot to rotate around its long axis. Moreover, our microrobot has the unique feature of its directionality being switchable by simply tuning the acoustic frequency. We demonstrate this locomotion in 2D and 3D artificial vasculatures using a single sound source. Since ultrasound is widely used as an imaging modality in clinical settings, our robotic system can integrate seamlessly into practice; thus, our findings could contribute to the development of next-generation smart microrobots. One-Sentence SummaryWe present an acoustically driven helical microrobot capable of corkscrew-like locomotion using a double-helix microstructure.

bioengineering↗

bioRxiv2023

U1 AMO (antisense morpholino oligos) disrupts U1 snRNP structure to promote intronic PCPA (premature cleavage and polyadenylation)

Functional depletion of U1 snRNP with a 25 nt U1 AMO (antisense morpholino oligonucleotides) may lead to intronic premature cleavage and polyadenylation (PCPA) of thousands of genes, a phenomenon known as U1 snRNP telescripting; however, the underlying mechanism remains elusive. In this study, we demonstrated that U1 AMO could disrupt U1 snRNP structure both in vitro and in vivo, thereby affecting U1 snRNP/RNAP polymerase II (RNAPII) interaction. We further showed that U1 AMO treatment might promote RNAPII disassociation with pre-mRNA in an RNA pull-down assay. By performing ChIP-seq for phosphorylation of Ser2 (Ser2P) and Ser5 (Ser5P) of the C-terminal domain (CTD) of RNA polymerase II (RNAPII), we showed that transcription elongation was disturbed upon U1 AMO treatment, with a particular high Ser2P signal at intronic cryptic polyadenylation sites (PASs). In addition, we showed that core 3 processing factors CPSF/CstF are involved in the processing of intronic cryptic PAS. Their recruitment accumulated toward cryptic PASs upon U1 AMO treatment, as indicated by ChIP-seq and iCLIP-seq analysis. Furthermore, we showed that most of these PCPAed transcripts could be exported to cytoplasm and have the potential to be translated. Conclusively, our data provide more insight into U1 snRNP telescripting, and suggest a common theme that modulation of transcription elongation may be an important mode for the regulation of mRNA polyadenylation.

molecular biology↗

bioRxiv2023

Network Pharmacology and Bioinformatics Methods Reveal the Mechanism of Sishenwan in the Treatment of diabetic nephropathy

Objective. In order to decipher the bioactive components and potential mechanisms of the traditional Chinese medicine (TCM) formula Sishenwan (SSW) for diabetic nephropathy (DN), we integrated network pharmacology and bioinformatics. Methods. The candidate compounds of SSW and relative targets were obtained from the TCMSP, BATMAN-TCM, SiwssTartgetPrediction, STITCH, and ChEMBL web servers. The UniProt database was used to translate the target names into gene names, and then constructed the herbal-compound-target network. DN-related targets were ascertained based on OMIM, CTD, GeneCards, DisGeNET, and GEO. Furthermore, there was a protein-protein interaction (PPI) network to explore the overlapping targets between SSW and DN, which focused on screening the pivotal targets by topology. GO and KEGG enrichment analyses were carried out to further understand the potential functions associated with the effect of SSW against DN. Eventually, molecular docking simulations were performed to validate the binding affinity between major bioactive components and hub genes. Results. A total of 120 candidate active compounds and 542 corresponding drug targets were derived, in which 195 targets intersected with DN. Then, KEGG pathway analysis showed that several signaling pathways were closely related to the process of SSW against DN, including the AGE-RAGE signaling pathway in diabetic complications, the TNF signaling pathway, and IL-17 signaling pathway, ect. The PPI network analysis identified PTGS2, CREB1, ESR1, TNF, IL1B, INS, AKT1, PPARG, and JUN were the top 9 hub targets. The molecular docking confirmed that the bioactive compounds of SSW had a firm binding affinity with hub targets. Conclusions. As a whole, the present study revealed that SSW exerted therapeutic effects on DN via modulating multi-targets with multi-compounds through multi-pathways.

bioinformatics↗

bioRxiv2023

Human FAM111A inhibits vaccinia virus replication by degrading viral uncoating factor I3 and is antagonized by poxvirus host range factor SPI-1

Poxviruses are large double-stranded DNA viruses that infect a wide range of animals including humans. Since the eradication of smallpox, other members of the poxvirus family, such as monkeypox virus (MPXV) are still posing a great threat to public health. Vaccinia virus (VACV) is a prototypic poxvirus used as the vaccine strain for smallpox eradication. VACV encodes a serine protease inhibitor 1 (SPI-1) conserved in all orthopoxviruses, which has been recognized as a host range factor for modified vaccinia virus Ankara (MVA), an approved smallpox vaccine and a promising vaccine vector. FAM111A, a nuclear protein that regulates host DNA replication, was shown to restrict the replication of VACV-{Delta}SPI-1 in human cells. Nevertheless, the detailed antiviral mechanisms of FAM111A were unresolved. Here, we show that FAM111A is a potent restriction factor for VACV-{Delta}SPI-1 and MVA. Deletion of FAM111A rescued the replication of MVA and VACV-{Delta}SPI-1 and overexpression of FAM111A significantly reduced viral DNA replication and virus titers but did not affect viral early gene expression. The antiviral effect of FAM111A necessitated its trypsin-like protease domain and DNA binding domain but not the PCNA-interacting motif. We further discovered that FAM111A translocated into the cytoplasm upon VACV infection and this process was mediated by the cGAS-STING signaling pathway. Infection-triggered FAM111A degraded the nuclear pore complex via its protease activity, translocated to the cytoplasm, and interacted with and promoted the degradation of virus DNA binding protein I3 in a DNA-dependent manner. Interestingly, the protease activity of FAM111A was only needed for nuclear export but not I3 degradation as further analysis showed I3 was degraded through autophagy. Moreover, VACV SPI-1 was found primarily in the nucleus of infected cells and antagonized FAM111A by prohibiting its nuclear export. MPXV and lumpy skin disease virus SPI-1s also inhibited human FAM111A. Our findings reveal the detailed mechanism by which FAM111A functions to restrict a cytoplasmic DNA virus and provide explanations for the immune evasive function of VACV SPI-1.

microbiology↗

bioRxiv2023

Structure-informed Language Models Are Protein Designers

This paper demonstrates that language models are strong structure-based protein designers. We present LM-DO_SCPLOWESIGNC_SCPLOW, a generic approach to reprogramming sequence-based protein language models (pLMs), that have learned massive sequential evolutionary knowledge from the universe of natural protein sequences, to acquire an immediate capability to design preferable protein sequences for given folds. We conduct a structural surgery on pLMs, where a lightweight structural adapter is implanted into pLMs and endows it with structural awareness. During inference, iterative refinement is performed to effectively optimize the generated protein sequences. Experiments show that LM-DO_SCPLOWESIGNC_SCPLOW improves the state-of-the-art results by a large margin, leading to 4% to 12% accuracy gains in sequence recovery (e.g., 55.65%/56.63% on CATH 4.2/4.3 single-chain benchmarks, and >60% when designing protein complexes). We provide extensive and in-depth analyses, which verify that LM-DO_SCPLOWESIGNC_SCPLOW can (1) indeed leverage both structural and sequential knowledge to accurately handle structurally non-deterministic regions, (2) benefit from scaling data and model size, and (3) generalize to other proteins (e.g., antibodies and de novo proteins).

bioinformatics↗

bioRxiv2023

Myricetin protected against Aβ oligomer-induced synaptic impairment, mitochondrial function and oxidative stress in SH-SY5Y cells via ERK1/2/GSK-3β pathways

Alzheimers disease is characterized by abnormal {beta}-amyloid (A{beta}) plaque accumulation, tau hyperphosphorylation, reactive oxidative stress, mitochondrial dysfunction and synaptic loss. Myricetin, a dietary flavonoid, has been shown to have neuroprotective effects in vitro and in vivo. Here, we aimed to elucidate the mechanism and pathways involved in myricetins protective effect on the toxicity induced by the A{beta}42 oligomer. Neuronal SH-SY5Y cells were pretreated with myricetin before incubation with A{beta}42 oligomer. The levels of pre- and postsynaptic proteins, mitochondrial division and fusion proteins, glycogen synthase kinase-3 {beta} (GSK-3{beta}) and extracellular regulated kinase (ERK) 1/2 were assessed by Western blotting. Flow cytometry assays for mitochondrial membrane potential (JC1) and reactive oxidative stress, as well immunofluorescence staining for lipid peroxidation (4-HNE) and DNA oxidation (8-OHdG), were performed. We found that myricetin prevented A{beta}42 oligomer-induced tau phosphorylation and the reduction in pre/postsynaptic proteins. In addition, myricetin reduced reactive oxygen species generation, lipid peroxidation, and DNA oxidation induced by the A{beta}42 oligomer. Moreover, myricetin prevented the A{beta}42 oligomer-induced reduction in mitochondrial fusion proteins (mitofusin-1, mitofusin-2), fission protein (dynamin-related protein 1) phosphorylation, and mitochondrial membrane potential via the associated GSK-3{beta} and ERK 1/2 signaling pathways. In conclusion, this study provides new insight into the neuroprotective mechanism of myricetin against A{beta}42 oligomer-induced toxicity.

neuroscience↗

bioRxiv2022

CherryML: Scalable Maximum Likelihood Estimation of Phylogenetic Models

Phylogenetic models of molecular evolution are central to diverse problems in biology, but maximum likelihood estimation of model parameters is a computationally expensive task, in some cases prohibitively so. To address this challenge, we here introduce CherryML, a broadly applicable method that achieves several orders of magnitude speedup. We demonstrate its utility by applying it to estimate a general 400 x 400 rate matrix for amino acid co-evolution at protein contact sites.

evolutionary biology↗

bioRxiv2022

Prenatal maternal stress promotes neural stem cell proliferation in the ependymal-subventricular zone of adult male offspring

Perturbations during critical time windows during embryonic development can lead to adverse functional consequences that manifest later in life. Here, we report that prenatal maternal stress (PNS) during the peak of embryonic neurogenesis (E14-delivery) dramatically increased numbers of proliferating neural stem/progenitor cells (NSC/NPCs) in the ependymal-subventricular zone (E-SVZ) and neuroblasts (NBs) in the rostral migratory stream and newborn neurons in the olfactory bulb (OB) of male mouse offspring without causing significant cell death or a deficit in cell migration to the OB. Mechanistically, bulk and single-nucleus transcriptomic analyses showed that PNS affected gene regulatory networks controlling cell cycle progression and stem cell maintenance, maturation of neural circuits, and gliogenesis in prenatally stressed (STR) offspring. More specifically, we found that prenatal exposure to mild maternal restraint-stress sustained MAPK (ERK) activity in the E-SVZ and thus prolonged NSC/NPC/NB proliferation in stressed brains. Moreover, we found PNS disorganized the cytoarchitecture of the glomerular layer of the OB, which may directly relate to the deficit in discriminating different social orders in stressed offspring. Compared to STR males, their female littermates showed less change in the number of proliferating cells in the E-SVZ.

neuroscience↗

bioRxiv2022

Sex-dependent interactions between prodromal intestinal inflammation and LRRK2 G2019S in mice promote symptoms of Parkinson's disease

Gastrointestinal (GI) disruptions, such as inflammatory bowel disease (IBD), are common prodromal symptoms of Parkinsons disease (PD), but how they may impact risk for PD remains poorly understood. Herein, we provide evidence that prodromal intestinal inflammation expedites and exacerbates PD symptoms in rodent carriers of the human PD risk allele LRRK2 G2019S in a sex-dependent manner. Chronic intestinal damage in genetically predisposed male, but not female, mice promotes -synuclein aggregation in the substantia nigra, elevated -synuclein loads in microglia, loss of dopaminergic neurons, and motor impairment. This male bias in gene-environment interaction is preserved in gonadectomized males, and similarly conferred by sex chromosomal complement in gonadal females expressing human LRRK2 G2019S, revealing that XY chromosomes, not testicular hormones, mediate the male bias in the gut-brain-driven risk for endophenotypes of PD. The early onset and heightened severity of neuropathological and behavioral outcomes in male LRRK2 G2019S mice is preceded by the accumulation of -synuclein in the colon, increases in -synuclein-positive macrophages in the colonic lamina propria, and elevations in -synuclein loads within microglia in the substantia nigra. Taken together, these data reveal that prodromal intestinal inflammation promotes the pathogenesis of PD symptoms in male carriers of LRRK2 G2019S, through mechanisms that depend on genotypic sex and involve early accumulation of -synuclein in myeloid cells within the gut and brain.

physiology↗