Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping.

The ability to spatially map multiple layers of the omics information over different time points allows for exploring the mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed and applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) and DBiT CTRP-seq (spatial CUT&Tag- RNA-Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) to map spatial dynamic remodeling in brain development and neuroinflammation. A spatiotemporal tri-omic atlas of the mouse brain was obtained at different stages from postnatal day P0 to P21, and compared to the regions of interest in the human developing brains. Specifically, in the cortical area, we discovered temporal persistence and spatial spreading of chromatin accessibility for the layer-defining transcription factors. In corpus callosum, we observed dynamic chromatin priming of myelin genes across the subregions. Together, it suggests a role for layer specific projection neurons to coordinate axonogenesis and myelination. We further mapped the brain of a lysolecithin (LPC) neuroinflammation mouse model and observed common molecular programs in development and neuroinflammation. Microglia, exhibiting both conserved and distinct programs for inflammation and resolution, are transiently activated not only at the core of the LPC lesion, but also at distal locations presumably through neuronal circuitry. Thus, this work unveiled common and differential mechanisms in brain development and neuroinflammation, resulting in a valuable data resource to investigate brain development, function and disease.

Investigating the anti-lung cancer properties of Zhuang medicine Cycas revoluta Thunb. leaves targeting ion channels and transporters through a comprehensive strategy.

BACKGROUND: Cycas revoluta Thunb., known for its ornamental, economic, and medicinal value, has leaves often discarded as waste. However, in ethnic regions of China, the leaves (CRL) are used in folk medicine for anti-tumor properties, particularly for regulating pathways related to cancer. Recent studies on ion channels and transporters (ICTs) highlight their therapeutic potential against cancer, making it vital to identify CRL's active constituents targeting ICTs in lung cancer. PURPOSE: This study aims to uncover bioactive substances in CRL and their mechanisms in regulating ICTs for lung cancer treatment using network pharmacology, bioinformatics, molecular docking, molecular dynamics (MD) simulations, in vitro cell assays and HPLC. METHODS: We analyzed 62 CRL compounds, predicted targets using PubChem and SwissTargetPrediction, identified lung cancer and ICT targets via GeneCards, and visualized overlaps with R software. Interaction networks were constructed using Cytoscape and STRING. Gene expression, GO, and KEGG analyses were performed using R software. TCGA data provided insights into differential, correlation, survival, and immune analyses. Key interactions were validated through molecular docking and MD simulations. Main biflavonoids were quantified using HPLC, and in vitro cell viability assays were conducted for key biflavonoids. RESULTS: Venn diagram analysis identified 52 intersecting targets and ten active CRL compounds. The PPI network highlighted seven key targets. GO and KEGG analysis showed CRL-targeted ICTs involved in synaptic transmission, GABAergic synapse, and proteoglycans in cancer. Differential expression and correlation analysis revealed significant differences in five core targets in lung cancer tissues. Survival analysis linked EGFR and GABRG2 with overall survival, and immune infiltration analysis associated the core targets with most immune cell types. Molecular docking indicated strong binding of CRL ingredients to core targets. HPLC revealed amentoflavone as the most abundant biflavonoid, followed by hinokiflavone, sciadopitysin, and podocarpusflavone A. MD simulations showed that podocarpusflavone A and amentoflavone had better binding stability with GABRG2, and the cell viability assay also proved that they had better anti-lung cancer potential. CONCLUSIONS: This study identified potential active components, targets, and pathways of CRL-targeted ICTs for lung cancer treatment, suggesting CRL's utility in drug development and its potential beyond industrial waste.

The anti-apoptotic function of HSV-1 LAT in neuronal cell cultures but not its function during reactivation correlates with expression of two small non-coding RNAs, sncRNA1&2.

Multiple functions are associated with HSV-1 latency associated transcript (LAT), including establishment of latency, virus reactivation, and antiapoptotic activity. LAT encodes two sncRNAs that are not miRNAs and previously it was shown that they have antiapoptotic activity in vitro. To determine if we can separate the antiapoptotic function of LAT from its latency-reactivation function, we deleted sncRNA1 and sncRNA2 sequences in HSV-1 strain McKrae, creating ΔsncRNA1&2 recombinant virus. Deletion of the sncRNA1&2 in ΔsncRNA1&2 virus was confirmed by complete sequencing of ΔsncRNA1&2 virus and its parental virus. Replication of ΔsncRNA1&2 virus in tissue culture or in the eyes of WT infected mice was similar to that of HSV-1 strain McKrae (LAT-plus) and dLAT2903 (LAT-minus) viruses. The levels of gB DNA in trigeminal ganglia (TG) of mice latently infected with ΔsncRNA1&2 virus was intermediate to that of dLAT2903 and McKrae infected mice, while levels of LAT in TG of latently infected ΔsncRNA1&2 mice was significantly higher than in McKrae infected mice. Similarly, the levels of LAT expression in Neuro-2A cells infected with ΔsncRNA1&2 virus was significantly higher than in McKrae infected cells. Reactivation in TG of ΔsncRNA1&2 infected mice was similar to that of McKrae and time of reactivation in both groups were significantly faster than dLAT2903 infected mice. However, levels of apoptosis in Neuro-2A cells infected with ΔsncRNA1&2 virus was similar to that of dLAT2903 and significantly higher than that of McKrae infected cells. Our results suggest that the antiapoptotic function of LAT resides within the two sncRNAs, which works independently of its latency-reactivation function and it has suppressive effect on LAT expression in vivo and in vitro.

Sugar delivery at the tomato root and root galls after Meloidogyne incognita infestation.

Root-knot nematodes (RKNs) infect host plants and obtain nutrients such as sugars for their own development. Therefore, inhibiting the nutrient supply to RKNs may be an effective method for alleviating root-knot nematode disease. At present, the pathway by which sucrose is unloaded from the phloem cells to giant cells (GCs) in root galls and which genes related to sugar metabolism and transport play key roles in this process are unclear. In this study, we found that sugars could be unloaded into GCs only from neighboring phloem cells through the apoplastic pathway. With the development of galls, the contents of sucrose, fructose and glucose in the galls and adjacent tissue increased gradually. SUT1, SUT2, SWEET7a, STP10, SUS3 and SPS1 may provide sugar sources for GCs, while STP1, STP2 and STP12 may transport more sugar to phloem parenchyma cells. At the early stage of Meloidogyne incognita infestation, the sucrose content in tomato roots and leaves increased, while the glucose and fructose contents decreased. SWEET7a, SPS1, INV-INH1, INV-INH2, SUS1 and SUS3 likely play key roles in root sugar delivery. These results elucidated the pathway of sugar unloading in tomato galls and provided an important theoretical reference for eliminating the sugar source of RKNs and preventing root-knot nematode disease.

Revealing the potential bioactive components and mechanism of Qianhua Gout Capsules in the treatment of gouty arthritis through network pharmacology, molecular docking and pharmacodynamic study strategies.

Recent clinical studies have confirmed the effectiveness of Qianhua Gout Capsules (QGC) in the treatment of gouty arthritis (GA). However, the specific regulatory targets and mechanisms of action of QGC are still unclear. To address this gap, we utilized network pharmacology, molecular docking, and pharmacodynamic approaches to investigate the bioactive components and associated mechanisms of QGC in the treatment of GA. By employing UPLC-Q Exactive-MS, we identified the compounds present in QGC, with active ingredients defined as those with oral bioavailability ≥30 % and drug similarity ≥0.18. Subsequently, the targets of these active compounds were determined using the TCMSP database, while GA-related targets were identified from DisGeNET, GeneCards, TTD, OMIM, and DrugBank databases. Further analysis including PPI analysis, GO analysis, and KEGG pathway enrichment was conducted on the targets. Validation of the predicted results was performed using a GA rat model, evaluating pathological changes, inflammatory markers, and pathway protein expression. Our results revealed a total of 130 components, 44 active components, 16 potential shared targets, GO-enriched terms, and 47 signaling pathways related to disease targets. Key active ingredients included quercetin, kaempferol, ß-sitosterol, luteolin, and wogonin. The PPI analysis highlighted five targets (PPARG, IL-6, MMP-9, IL-1ß, CXCL-8) with the highest connectivity, predominantly enriched in the IL-17 signaling pathway. Molecular docking experiments demonstrated strong binding of CXCL8, IL-1ß, IL-6, MMP9, and PPARG targets with the top five active compounds. Furthermore, animal experiments confirmed the efficacy of QGC in treating GA in rats, showing reductions in TNF-α, IL-6, and MDA levels, and increases in SOD levels in serum. In synovial tissues, QGC treatment upregulated CXCL8 and PPARG expression, while downregulating IL-1ß, MMP9, and IL-6 expression. In conclusion, this study applied a network pharmacology approach to uncover the composition of QGC, predict its pharmacological interactions, and demonstrate its in vivo efficacy, providing insights into the anti-GA mechanisms of QGC. These findings pave the way for future investigations into the therapeutic mechanisms underlying QGC's effectiveness in the treatment of GA.

Genetic distribution, characterization, and function of Escherichia coli type III secretion system 2 (ETT2).

Many Gram-negative bacteria use type Ⅲ secretion system (T3SS) to inject effector proteins and subvert host signaling pathways, facilitating the growth, survival, and virulence. Notably, some bacteria harbor multiple distinct T3SSs with different functions. An extraordinary T3SS, the Escherichia coli Type III Secretion System 2 (ETT2), is widespread among Escherichia coli (E. coli) strains. Since many ETT2 carry genetic mutations or deletions, it is thought to be nonfunctional. However, increasing studies highlight ETT2 contributes to E. coli pathogenesis. Here, we present a comprehensive overview of genetic distribution and characterization of ETT2. Subsequently, we outline its functional potential, contending that an intact ETT2 may retain the capacity to translocate effector proteins and manipulate the host's innate immune response. Given the potential zoonotic implications associated with ETT2-carrying bacteria, further investigations into the structure, function and regulation of ETT2 are imperative for comprehensive understanding of E. coli pathogenicity and the development of effective control strategies.

Mangiferin, a Potential Supplement to Improve Metabolic Syndrome: Current Status and Future Opportunities.

Metabolic syndrome (MetS) represents a considerable clinical and public health burden worldwide. Mangiferin (MF), a flavonoid compound present in diverse species such as mango (Mangifera indica L.), papaya (Pseudocydonia sinensis (Thouin) C. K. Schneid.), zhimu (Anemarrhena asphodeloides Bunge), and honeybush tea (Cyclopia genistoides), boasts a broad array of pharmacological effects. It holds promising uses in nutritionally and functionally targeted foods, particularly concerning MetS treatment. It is therefore pivotal to systematically investigate MF's therapeutic mechanism for MetS and its applications in food and pharmaceutical sectors. This review, with the aid of a network pharmacology approach complemented by this experimental studies, unravels possible mechanisms underlying MF's MetS treatment. Network pharmacology results suggest that MF treats MetS effectively through promoting insulin secretion, targeting obesity and inflammation, alleviating insulin resistance (IR), and mainly operating via the phosphatidylinositol 3 kinase (PI3K)/Akt, nuclear factor kappa-B (NF-[Formula: see text]B), microtubule-associated protein kinase (MAPK), and oxidative stress signaling pathways while repairing damaged insulin signaling. These insights provide a comprehensive framework to understand MF's potential mechanisms in treating MetS. These, however, warrant further experimental validation. Moreover, molecular docking techniques confirmed the plausibility of the predicted outcomes. Hereafter, these findings might form the theoretical bedrock for prospective research into MF's therapeutic potential in MetS therapy.

Baicalein induces apoptosis by inhibiting the glutamine-mTOR metabolic pathway in lung cancer.

INTRODUCTION: Baicalein, a bioactive component of Scutellaria baicalensis Georgi, has been shown to promote apoptosis in non-small cell lung cancer cells. However, previous studies have not determined if baicalein exerts proapoptotic effects by modulating the metabolic pathways. OBJECTIVE: To investigate if baicalein induces apoptosis in lung cancer cells by modulating the glutamine-mTOR metabolic pathway. METHODS: The in vivo anti-lung cancer activity of baicalein (50, 100, and 200 mg/kg) was evaluated using a xenograft model. In vitro experiments were used to assess the efficacy of baicalein (for H1299: 12.5, 25, and 50 µM; for A549: 10, 20, and 40 µM) on lung cancer cell proliferation, colony formation, and apoptosis. Metabolomics analysis was performed using liquid chromatography-mass spectrometry. The binding of baicalein to glutamine transporters and glutaminase was examined using molecular docking. The overexpression of glutamine transporters was validated using qRT-PCR and western blot analyses. The levels of ASCT2, LAT1, GLS1, p-mTOR, mTOR, and apoptosis-related proteins were evaluated using western blot analysis. RESULTS: Baicalein inhibited lung cancer xenograft tumor growth in vivo and suppressed proliferation and promoted apoptosis in lung cancer cells in vitro. Additionally, baicalein altered amino acid metabolites, especially glutamine metabolites, in H1299 and A549 cells. Mechanistically, baicalein interacted with glutamine transporters as well as glutaminase and inhibited their activation. The expression of mTOR, an apoptosis-related protein and downstream target of glutamine metabolism, was also inhibited by baicalein treatment. Importantly, we next demonstrated the suppression of mTOR signaling and the induction of apoptosis by baicalein were achieved by regulating glutamine metabolism. CONCLUSION: Baicalein inhibited the mTOR signaling pathway and induced apoptosis by downregulating glutamine metabolism. The potential of baicalein to induce apoptosis in lung cancer cells by selectively targeting the glutamine-mTOR pathway suggests an encouraging approach for treating lung cancer.

Antimicrobial Guanidinylate Polycarbonates Show Oral In Vivo Efficacy Against Clostridioides Difficile.

The emerging antibiotic resistance has been named by the World Health Organization (WHO) as one of the top 10 threats to public health. Notably, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VREF) are designated as serious threats, whereas Clostridioides difficile (C. difficile) is recognized as one of the most urgent threats to human health and unmet medical need. Herein, they report the design and application of novel biodegradable polymers - the lipidated antimicrobial guanidinylate polycarbonates. These polymers showed potent antimicrobial activity against a panel of bacteria with fast-killing kinetics and low resistance development tendency, mainly due to their bacterial membrane disruption mechanism. More importantly, the optimal polymer showed excellent antibacterial activity against C. difficile infection (CDI) in vivo via oral administration. In addition, compared with vancomycin, the polymer demonstrated a much-prolonged therapeutic effect and virtually diminished recurrence rate of CDI. The convenient synthesis, easy scale-up, low cost, as well as biodegradability of this class of polycarbonates, together with their in vitro broad-spectrum antimicrobial activity and orally in vivo efficacy against CDI, suggest the great potential of lipidated guandinylate polycarbonates as a new class of antibacterial biomaterials to treat CDI and combat emerging antibiotic resistance.

The aroA and luxS Double-Gene Mutant Strain Has Potential to Be a Live Attenuated Vaccine against Salmonella Typhimurium.

Salmonella Typhimurium (S. Typhimurium) is a zoonotic pathogen posing a threat to animal husbandry and public health. Due to the emergence of antibiotic-resistant strains, alternative prevention and control strategies are needed. Live attenuated vaccines are an ideal option that provide protection against an S. Typhimurium pandemic. To develop a safe and effective vaccine, double-gene mutations are recommended to attenuate virulence. In this study, we chose aroA and luxS genes, whose deletion significantly attenuates S. Typhimurium's virulence and enhances immunogenicity, to construct the double-gene mutant vaccine strain SAT52ΔaroAΔluxS. The results show that the mutant strain's growth rate, adherence and invasion of susceptible cells are comparable to a wild-type strain, but the intracellular survival, virulence and host persistence are significantly attenuated. Immunization assay showed that 106 colony-forming units (CFUs) of SAT52ΔaroAΔluxS conferred 100% protection against wild-type challenges; the bacteria persistence in liver and spleen were significantly reduced, and no obvious pathological lesions were observed. Therefore, the double-gene mutant strain SAT52ΔaroAΔluxS exhibits potential as a live attenuated vaccine candidate against S. Typhimurium infection.

Moving beyond traditional therapies: the role of nanomedicines in lung cancer.

Amidst a global rise in lung cancer occurrences, conventional therapies continue to pose substantial side effects and possess notable toxicities while lacking specificity. Counteracting this, the incorporation of nanomedicines can notably enhance drug delivery at tumor sites, extend a drug's half-life and mitigate inadvertent toxic and adverse impacts on healthy tissues, substantially influencing lung cancer's early detection and targeted therapy. Numerous studies signal that while the nano-characteristics of lung cancer nanomedicines play a pivotal role, further interplay with immune, photothermal, and genetic factors exist. This review posits that the progression towards multimodal combination therapies could potentially establish an efficacious platform for multimodal targeted lung cancer treatments. Current nanomedicines split into active and passive targeting. Active therapies focus on a single target, often with unsatisfactory results. Yet, developing combination systems targeting multiple sites could chart new paths in lung cancer therapy. Conversely, low drug delivery rates limit passive therapies. Utilizing the EPR effect to bind specific ligands on nanoparticles to tumor cell receptors might create a new regime combining active-passive targeting, potentially elevating the nanomedicines' concentration at target sites. This review collates recent advancements through the lens of nanomedicine's attributes for lung cancer therapeutics, the novel carrier classifications, targeted therapeutic modalities and their mechanisms, proposing that the emergence of multi-target nanocomposite therapeutics, combined active-passive targeting therapies and multimodal combined treatments will pioneer novel approaches and tools for future lung cancer clinical therapies.

Cycads: A comprehensive review of its botany, traditional uses, phytochemistry, pharmacology and toxicology.

Cycads, which primarily consist of the families Cycadaceae and Zamiaceae, possess intrinsic therapeutic attributes that are prominently expressed across their morphological spectrum, including roots, leaves, flowers, and seeds. In Chinese traditional medicine, the leaves of cycads are particularly revered for their profound healing capabilities. This meticulous review engages with existing literature on cycads and presents insightful avenues for future research. Over 210 phytoconstituents have been isolated and identified from various cycad tissues, including flavonoids, azoxy metabolites, sterols, lignans, non-proteogenic amino acids, terpenoids, and other organic constituents. The contemporary pharmacological discourse highlights the antineoplastic, antimicrobial, and antidiabetic activities inherent in these ancient plants, which are of particular importance to the field of oncology. Despite the prevalent focus on crude extracts and total flavonoid content, our understanding of the nuanced pharmacodynamics of cycads lags considerably behind. The notoriety of cycads derived toxicity, notably within the context of Guam's neurological disease cluster, has precipitated an established emphasis on toxicological research within this field. As such, this critical review emphasizes nascent domains deserving of academic and clinical pursuit, whilst nested within the broader matrix of current scientific understanding. The systematic taxonomy, traditional applications, phytochemical composition, therapeutic potential, and safety profile of cycads are holistically interrogated, assimilating an indispensable repository for future scholarly inquiries. In conclusion, cycads stand as a veritable treasure trove of pharmacological virtue, displaying remarkable therapeutic prowess and holding vast promise for ongoing scientific discovery and clinical utilization.

Synthesis of Tubular Hydroxyapatite and Its Application in Polycaprolactone Scaffold Materials.

Nano-hydroxyapatite (HAp) is an ideal material in the field of biomedicine due to its good biocompatibility and bioactivity. However, a significant drawback of pure HAp materials is their inferior mechanical properties. Therefore, in this rigorous investigation, the optimal calcium-to-phosphorus ratio for the synthesis of HAp was meticulously delineated, followed by its nuanced modification using KH550 (γ-aminopropyltriethoxysilane). This was further amalgamated with polycaprolactone (PCL) with the aim of providing a superior material alternative within the domain of bone scaffold materials. The post-modified HAp demonstrated enhanced interfacial compatibility with PCL, bestowing the composite with superior mechanical characteristics, notably a peak bending strength of 6.38 ± 0.037 MPa and a tensile strength of 3.71 ± 0.040 MPa. Scanning electron microscope (SEM) imagery revealed an intriguing characteristic of the composite: an initial ascension in porosity upon HAp integration, subsequently followed by a decline. Beyond this, the composite not only exhibited stellar auto-degradation prowess but also realized a sustained release cycle of 24 h, markedly optimizing drug utility efficiency. A kinetic model for drug dispensation was developed, positing an adherence to a pseudo-second-order kinetic principle. In tandem, through the formulation of an intra-particle diffusion model, the diffusion mechanisms pre- and post-modification were deeply probed. Cytotoxicity assays underscored the composite's exemplary biocompatibility. Such findings accentuate the vast potential of the modified HAp-PCL composite in bone tissue engineering, heralding a novel and efficacious avenue for impending bone defect amelioration.

Comprehensive mining of information in Weakly Supervised Semantic Segmentation: Saliency semantics and edge semantics.

In the studies of Weakly Supervised Semantic Segmentation (WSSS) with image-level labels, there is an issue of incomplete semantic information, which we summarize as insufficient saliency semantic mining and neglected edge semantics. We proposes a two-stage framework, Saliency Semantic Full Mining-Edge Semantic Mining (SSFM-ESM), which views WSSS from the perspective of comprehensive information mining. In the first stage, we rely on SSFM to address the insufficient saliency semantic mining. The network learns feature representations consistent with salient regions via the proposed pixel-level class-agnostic distance loss. Then, the full saliency semantic information is mined by explicitly receiving pixel-level feedback. The initial pseudo-label with complete saliency semantic information can be obtained after the first stage. In the second stage, we focus on the mining of edge semantic information through the proposed edge semantic mining module. Specifically, we guide the initial pseudo-label avoid learning about false semantic information and obtain high-confidence edge semantics. The self-correction ability of the segmentation network is also fully utilized to obtain more edge semantic information. Extensive experiments are conducted on the PASCAL VOC 2012 and MS COCO 2014 datasets to verify the feasibility and superiority of this approach.

Comprehensive insight into the pharmacology, pharmacokinetics, toxicity, detoxification and extraction of hypaconitine from Aconitum plants.

ETHNOPHARMACOLOGICAL RELEVANCE: Hypaconitine (HA), a diterpenoid alkaloid, mainly derived from Aconitum plants such as Acoitum carmichaeli Debx. And Aconitum nagarum Stapf., has recently piqued significant interest among the scientific community given its multifaceted attributes including anti-inflammatory, anticancer, analgesic, and cardio-protective properties. AIM OF THE STUDY: This review presents a comprehensive exploration of the research advancements regarding the traditional uses, pharmacology, pharmacokinetics, toxicity, and toxicity reduction of HA. It aims to provide a thorough understanding of HA's multifaceted properties and its potential applications in various fields. MATERIALS AND METHODS: A systematic literature search was conducted using several prominent databases including PubMed, Web of Science, NCBI, and CNKI. The search was performed using specific keywords such as "hypaconitine," "heart failure," "anti-inflammatory," "aconite decoction," "pharmacological," "pharmacokinetics," "toxicity," "detoxification or toxicity reduction," and "extraction and isolation." The inclusion of these keywords ensured a comprehensive exploration of relevant studies and enabled the retrieval of valuable information pertaining to the various aspects of HA. RESULTS: Existing research has firmly established that HA possesses a range of pharmacological effects, encompassing anti-cardiac failure, anti-inflammatory, analgesic, and anti-tumor properties. The therapeutic potential of HA is promising, with potential applications in heart failure, ulcerative colitis, cancer, and other diseases. Pharmacokinetic studies suggest that HA exhibits high absorption rates, broad distribution, and rapid metabolism. However, toxic effects of HA on the nerves, heart, and embryos have also been observed. To mitigate these risks, HA needs attenuation before use, with the most common detoxification methods being processing and combined use with other drugs. Extraction methods for HA most commonly include cold maceration, soxhlet reflux extraction, and ultrasonic-assisted extraction. Despite the potential therapeutic benefits of HA, further research is warranted to elucidate its anti-heart failure effects, particularly in vivo, exploring aspects such as in vivo metabolism, distribution, and metabolites. Additionally, the therapeutic effects of HA monomers on inflammation-induced diseases and tumors should be validated in a more diverse range of experimental models, while the mechanisms underlying the therapeutic effects of HA should be investigated in greater detail. CONCLUSION: This review serves to emphasize the therapeutic potential of HA and highlights the crucial need to address its toxicity concerns before considering clinical application. Further research is required to comprehensively investigate the pharmacological properties of HA, with particular emphasis on its anti-cardiac failure and anti-inflammatory activities. Such research endeavors have the potential to unveil novel treatment avenues for a broad spectrum of diseases.

The functions of EF-hand proteins from host and zoonotic pathogens.

EF-hand proteins not only regulate biological processes, but also influence immunity and infection. In this review, we summarize EF-hand proteins' functions in host and zoonotic pathogens, with details in structures, Ca2+ affinity, downstream targets and functional mechanisms. Studies entitled as EF-hand-related but with less solid features were also discussed. We believe it could raise cautions and facilitate proper research strategy for researchers.

Genome degradation promotes Salmonella pathoadaptation by remodeling fimbriae-mediated proinflammatory response.

Understanding changes in pathogen behavior (e.g. increased virulence, a shift in transmission channel) is critical for the public health management of emerging infectious diseases. Genome degradation via gene depletion or inactivation is recognized as a pathoadaptive feature of the pathogen evolving with the host. However, little is known about the exact role of genome degradation in affecting pathogenic behavior, and the underlying molecular detail has yet to be examined. Using large-scale global avian-restricted Salmonella genomes spanning more than a century, we projected the genetic diversity of Salmonella Pullorum (bvSP) by showing increasingly antimicrobial-resistant ST92 prevalent in Chinese flocks. The phylogenomic analysis identified three lineages in bvSP, with an enhancement of virulence in the two recently emerged lineages (L2/L3), as evidenced in chicken and embryo infection assays. Notably, the ancestor L1 lineage resembles the Salmonella serovars with higher metabolic flexibilities and more robust environmental tolerance, indicating stepwise evolutionary trajectories towards avian-restricted lineages. Pan-genome analysis pinpointed fimbrial degradation from a virulent lineage. The later engineered fim-deletion mutant, and all other five fimbrial systems, revealed behavior switching that restricted horizontal fecal-oral transmission but boosted virulence in chicks. By depleting fimbrial appendages, bvSP established persistent replication with less proinflammation in chick macrophages and adopted vertical transovarial transmission, accompanied by ever-increasing intensification in the poultry industry. Together, we uncovered a previously unseen paradigm for remodeling bacterial surface appendages that supplements virulence-enhanced evolution with increased vertical transmission.

Single cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism.

Duplication 15q (dup15q) syndrome is the most common genetic cause of autism spectrum disorder (ASD). Due to a higher genetic and phenotypic homogeneity compared to idiopathic autism, dup15q syndrome provides a well-defined setting to investigate ASD mechanisms. Previous bulk gene expression studies identified shared molecular changes in ASD. However, how cell type specific changes compare across different autism subtypes and how they change during development is largely unknown. In this study, we used single cell and single nucleus mRNA sequencing of dup15q cortical organoids from patient iPSCs, as well as post-mortem patient brain samples. We find cell-type specific dysregulated programs that underlie dup15q pathogenesis, which we validate by spatial resolved transcriptomics using brain tissue samples. We find degraded identity and vulnerability of deep-layer neurons in fetal stage organoids and highlight increased molecular burden of postmortem upper-layer neurons implicated in synaptic signaling, a finding shared between idiopathic ASD and dup15q syndrome. Gene co-expression network analysis of organoid and postmortem excitatory neurons uncovers modules enriched with autism risk genes. Organoid developmental modules were involved in transcription regulation via chromatin remodeling, while postmortem modules were associated with synaptic transmission and plasticity. The findings reveal a shifting landscape of ASD cellular vulnerability during brain development.

Single-cell analysis of prenatal and postnatal human cortical development.

We analyzed >700,000 single-nucleus RNA sequencing profiles from 106 donors during prenatal and postnatal developmental stages and identified lineage-specific programs that underlie the development of specific subtypes of excitatory cortical neurons, interneurons, glial cell types, and brain vasculature. By leveraging single-nucleus chromatin accessibility data, we delineated enhancer gene regulatory networks and transcription factors that control commitment of specific cortical lineages. By intersecting our results with genetic risk factors for human brain diseases, we identified the cortical cell types and lineages most vulnerable to genetic insults of different brain disorders, especially autism. We find that lineage-specific gene expression programs up-regulated in female cells are especially enriched for the genetic risk factors of autism. Our study captures the molecular progression of cortical lineages across human development.