Tracking diarrhea viruses and mpox virus using the wastewater surveillance network in Hong Kong.

The wastewater surveillance network successfully established for COVID-19 showed great potential to monitor other infectious viruses, such as norovirus, rotavirus and mpox virus. In this study, we established and validated detection methods for these viruses in wastewater. We developed a supernatant-based method to detect RNA viruses from wastewater samples and applied it to the monthly diarrhea viruses (norovirus genogroup I & II, and rotavirus) surveillance in wastewater treatment plants (WWTPs) at a city-wide level for 16 months. Significant correlations were observed between the diarrhea viruses concentrations in wastewater and detection rates in faecal specimens by clinical surveillance. The highest norovirus concentration in wastewater was obtained in winter, consistent with the seasonal pattern of norovirus outbreak in Hong Kong. Additionally, we established a pellet-based method to monitor DNA viruses in wastewater and detected weak signals for mpox virus in wastewater from a WWTP serving approximately 16,700 people, when the first mpox patient in Hong Kong was admitted to the hospital within the catchment area. Genomic sequencing provided confirmatory evidence for the validity of the results. Our findings emphasized the efficacy of the wastewater surveillance network in WWTPs as a cost-effective tool to track the transmission trend of diarrhea viruses and to provide sensitive detection of novel emerging viruses such as mpox virus in low-prevalence areas. The developed methods and surveillance results provide confidence for establishing robust wastewater surveillance programs to control infectious diseases in the post-pandemic era.

Post-infarction ventricular septal rupture complicated with cardiogenic shock and multiple organ hemorrhage: An autopsy case report.

Ventricular septal rupture (VSR) is a catastrophic mechanical complication of acute myocardial infarction (AMI) that can result in acute heart failure. Delaying operative intervention frequently leads to cardiogenic shock and multi-organ failure. Here we report a case of massive anterior MI complicated with VSR that was discovered through cardiac Doppler ultrasound and suspected multiple organ hemorrhage. The patient showed signs of rapid cardiogenic shock and eventually died. The morphological changes of VSR and MI were identified during necropsy, and microscopic examinations of the heart, brain, and kidney revealed multiple organ hemorrhage. This autopsy case suggested that the complication of VSR caused by AMI results in a reduction of oxygen and nutrient content of the circulating blood throughout the body and, eventually, functional failure of multiple organs. We provide clinical and pathological evidence elucidating changes in multiple organs under the severe condition of post-infarction VSR and demonstrate the consequences of a lack of immediate surgery and sufficient medical intervention for a patient suffering from AMI with VSR.

Enhanced nitrate reduction in hypotrophic waters with integrated photocatalysis and biodegradation.

Addressing nitrate contamination in water bodies is a critical environmental challenge, and Intimately Coupling Photocatalysis and Biodegradation (ICPB) presents a promising solution. However, there is still debate about the effectiveness of ICPB in reducing nitrate under hypotrophic conditions. Further research is needed to understand its microbial metabolic mechanism and the functional changes in bacterial structure. Here we explored microbial metabolic mechanisms and changes in bacterial structure in ICPB reactors integrating a meticulously screened TiO2/g-C3N4 photocatalyst with biofilm. We achieved a 26.3% increase in nitrate reduction using 12.2% less organic carbon compared to traditional biodegradation methods. Metagenomic analysis of the microbial communities in ICPB reactors revealed evolving metabolic pathways conducive to nitrate reduction. This research not only elucidates the photocatalytic mechanism behind nitrate reduction in hypotrophic conditions but also provides genomic insights that pave the way for alternative approaches in water remediation technologies.

A genome-wide overexpression screen reveals Mycobacterium smegmatis growth inhibitors encoded by mycobacteriophage Hammy.

During infection, bacteriophages produce diverse gene products to overcome bacterial antiphage defenses, to outcompete other phages, and to take over cellular processes. Even in the best-studied model phages, the roles of most phage-encoded gene products are unknown, and the phage population represents a largely untapped reservoir of novel gene functions. Considering the sheer size of this population, experimental screening methods are needed to sort through the enormous collection of available sequences and identify gene products that can modulate bacterial behavior for downstream functional characterization. Here, we describe the construction of a plasmid-based overexpression library of 94 genes encoded by Hammy, a Cluster K mycobacteriophage closely related to those infecting clinically important mycobacteria. The arrayed library was systematically screened in a plate-based cytotoxicity assay, identifying a diverse set of 24 gene products (representing ∼25% of the Hammy genome) capable of inhibiting growth of the host bacterium Mycobacterium smegmatis. Half of these are related to growth inhibitors previously identified in related phage Waterfoul, supporting their functional conservation; the other genes represent novel additions to the list of known antimycobacterial growth inhibitors. This work, conducted as part of the HHMI-supported Science Education Alliance Gene-function Exploration by a Network of Emerging Scientists (SEA-GENES) project, highlights the value of parallel, comprehensive overexpression screens in exploring genome-wide patterns of phage gene function and novel interactions between phages and their hosts.

Elucidation of the mechanism of Yiqi Tongluo Granule against cerebral ischemia/reperfusion injury based on a combined strategy of network pharmacology, multi-omics and molecular biology.

BACKGROUND: Ischemic stroke is caused by local lesions of the central nervous system and is a severe cerebrovascular disease. A traditional Chinese medicine, Yiqi Tongluo Granule (YQTL), shows valuable therapeutic effects. However, the substances and mechanisms remain unclear. PURPOSE: We combined network pharmacology, multi-omics, and molecular biology to elucidate the mechanisms by which YQTL protects against CIRI. STUDY DESIGN: We innovatively created a combined strategy of network pharmacology, transcriptomics, proteomics and molecular biology to study the active ingredients and mechanisms of YQTL. We performed a network pharmacology study of active ingredients absorbed by the brain to explore the targets, biological processes and pathways of YQTL against CIRI. We also conducted further mechanistic analyses at the gene and protein levels using transcriptomics, proteomics, and molecular biology techniques. RESULTS: YQTL significantly decreased the infarction volume percentage and improved the neurological function of mice with CIRI, inhibited hippocampal neuronal death, and suppressed apoptosis. Fifteen active ingredients of YQTL were detected in the brains of rats. Network pharmacology combined with multi-omics revealed that the 15 ingredients regulated 19 pathways via 82 targets. Further analysis suggested that YQTL protected against CIRI via the PI3K-Akt signaling pathway, MAPK signaling pathway, and cAMP signaling pathway. CONCLUSION: We confirmed that YQTL protected against CIRI by inhibiting nerve cell apoptosis enhanced by the PI3K-Akt signaling pathway.

Construction of Zn-doped RuO2 nanowires for efficient and stable water oxidation in acidic media.

Oxygen evolution reaction catalysts capable of working efficiently in acidic media are highly demanded for the commercialization of proton exchange membrane water electrolysis. Herein, we report a Zn-doped RuO2 nanowire array electrocatalyst with outstanding catalytic performance for the oxygen evolution reaction under acidic conditions. Overpotentials as low as 173, 304, and 373 mV are achieved at 10, 500, and 1000 mA cm-2, respectively, with robust stability reaching to 1000 h at 10 mA cm-2. Experimental and theoretical investigations establish a clear synergistic effect of Zn dopants and oxygen vacancies on regulating the binding configurations of oxygenated adsorbates on the active centers, which then enables an alternative Ru-Zn dual-site oxide path of the reaction. Due to the change of reaction pathways, the energy barrier of rate-determining step is reduced, and the over-oxidation of Ru active sites is alleviated. As a result, the catalytic activity and stability are significantly enhanced.

excluderanges: exclusion sets for T2T-CHM13, GRCm39, and other genome assemblies.

SUMMARY: Exclusion regions are sections of reference genomes with abnormal pileups of short sequencing reads. Removing reads overlapping them improves biological signal, and these benefits are most pronounced in differential analysis settings. Several labs created exclusion region sets, available primarily through ENCODE and Github. However, the variety of exclusion sets creates uncertainty which sets to use. Furthermore, gap regions (e.g. centromeres, telomeres, short arms) create additional considerations in generating exclusion sets. We generated exclusion sets for the latest human T2T-CHM13 and mouse GRCm39 genomes and systematically assembled and annotated these and other sets in the excluderanges R/Bioconductor data package, also accessible via the BEDbase.org API. The package provides unified access to 82 GenomicRanges objects covering six organisms, multiple genome assemblies, and types of exclusion regions. For human hg38 genome assembly, we recommend hg38.Kundaje.GRCh38_unified_blacklist as the most well-curated and annotated, and sets generated by the Blacklist tool for other organisms. AVAILABILITY AND IMPLEMENTATION: https://bioconductor.org/packages/excluderanges/. Package website: https://dozmorovlab.github.io/excluderanges/.

Fast and Sensitive Detection of Protein Markers Using an All-Printing Photonic Crystal Microarray via Fingertip Blood.

With the demand for point-of-care testing (POCT) in cardiovascular diseases, the detection of biomarkers in trace blood samples is of great significance in emergency medicine settings. Here, we demonstrated an all-printed photonic crystal microarray for POCT of protein markers (named "P4 microarray"). The paired nanobodies were printed as probes to target the soluble suppression of tumorigenicity 2 (sST2) as a certified cardiovascular protein marker. Benefiting from photonic crystal-enhanced fluorescence and integrated microarrays, quantitative detection of sST2 is 2 orders of magnitude lower than that of a traditional fluorescent immunoassay. The limit of detection is down to 10 pg/mL with the coefficient of variation being less than 8%. Detection of sST2 via fingertip blood is achieved in 10 min. Moreover, the P4 microarray after 180 days of storage at room temperature showed excellent stability for detection. This P4 microarray, as a convenient and reliable immunoassay for rapid and quantitative detection of protein markers in trace blood samples, has high sensitivity and strong storage stability, which hold great potential to advance cardiovascular precision medicine.

A fluorescent nano vector for early diagnosis and enhanced Interleukin-33 therapy of thoracic aortic dissection.

Thoracic aortic dissection (TAD) is the most devastating complication of vascular disease. The accuracy of the clinical diagnosis and treatment of TAD at the early stage is still limited. Herein, we report a nano-delivery strategy for early diagnosis and the first case of interleukin-33 (IL-33) based therapy for the effective intervention of TAD. A targeted fluorescent nano vector (FNV) is designed to co-assemble with IL-33, which protects IL-33 and prolongs its half-life. With specific targeting ability to the thoracic aorta, FNV can diagnose TAD at its early stage through fluorescent imaging. FNV@IL-33 nanocomplex presents better therapeutic effects on mice TAD progression compared with that of IL-33 alone by reducing smooth muscle apoptosis. Administration of FNV@IL-33 two weeks before onset, the development of TAD is greatly intervened. Our study provides a novel approach for early diagnosis and effective IL-33 therapy of TAD, which opens attractive opportunities for clinical prevention of cardiovascular diseases.

Combination of panax ginseng and ginkgo biloba extracts attenuate cerebral ischemia injury with modulation of NLRP3 inflammasome and CAMK4/CREB pathway.

Stroke is a major cause of death and disability throughout the world. A combination of Panax Ginseng and Ginkgo biloba extracts (CGGE) is an effective treatment for nervous system diseases, but the neuroprotective mechanism underlying CGGE remains unclear. Both network analysis and experimental research were employed to explore the potential mechanism of CGGE in treating ischemic stroke (IS). Network analysis identified a total number of 133 potential targets for 34 active ingredients and 239 IS-related targets. What's more, several processes that might involve the regulation of CGGE against IS were identified, including long-term potentiation, cAMP signaling pathway, neurotrophin signaling pathway, and Nod-like receptor signaling pathway. Our studies in animal models suggested that CGGE could reduce inflammatory response by inhibiting the activity of Nod-like receptor, pyrin containing 3 (NLRP3) inflammasome, and maintain the balance of glutamate (Glu)/gamma-aminobutyric acid (GABA) via activating calmodulin-dependent protein kinase type Ⅳ (CAMK4)/cyclic AMP-responsive element-binding protein (CREB) pathway. These findings indicated the neuroprotective effects of CGGE, possibly improving neuroinflammation and excitotoxicity by regulating the NLRP3 inflammasome and CAMK4/CREB pathway.

Cerebral Small Vessel Disease: Neuroimaging Features, Biochemical Markers, Influencing Factors, Pathological Mechanism and Treatment.

Cerebral small vessel disease (CSVD) is the most common chronic vascular disease involving the whole brain. Great progress has been made in clinical imaging, pathological mechanism, and treatment of CSVD, but many problems remain. Clarifying the current research dilemmas and future development direction of CSVD can provide new ideas for both basic and clinical research. In this review, the risk factors, biological markers, pathological mechanisms, and the treatment of CSVD will be systematically illustrated to provide the current research status of CSVD. The future development direction of CSVD will be elucidated by summarizing the research difficulties.

GenomicDistributions: fast analysis of genomic intervals with Bioconductor.

BACKGROUND: Epigenome analysis relies on defined sets of genomic regions output by widely used assays such as ChIP-seq and ATAC-seq. Statistical analysis and visualization of genomic region sets is essential to answer biological questions in gene regulation. As the epigenomics community continues generating data, there will be an increasing need for software tools that can efficiently deal with more abundant and larger genomic region sets. Here, we introduce GenomicDistributions, an R package for fast and easy summarization and visualization of genomic region data. RESULTS: GenomicDistributions offers a broad selection of functions to calculate properties of genomic region sets, such as feature distances, genomic partition overlaps, and more. GenomicDistributions functions are meticulously optimized for best-in-class speed and generally outperform comparable functions in existing R packages. GenomicDistributions also offers plotting functions that produce editable ggplot objects. All GenomicDistributions functions follow a uniform naming scheme and can handle either single or multiple region set inputs. CONCLUSIONS: GenomicDistributions offers a fast and scalable tool for exploratory genomic region set analysis and visualization. GenomicDistributions excels in user-friendliness, flexibility of outputs, breadth of functions, and computational performance. GenomicDistributions is available from Bioconductor ( https://bioconductor.org/packages/release/bioc/html/GenomicDistributions.html ).

BYHW Decoction Improves Cognitive Impairments in Rats with Cerebral Microinfarcts via Activation of the PKA/CREB Pathway.

Cerebral microinfarcts (CMIs) are characterized by sporadic obstruction of small vessels leading to neurons death. They are associated with increased risk of cognitive impairments and may have different risk factors compared with macroinfarcts. CMIs have a high incidence and result in heavy social burden; thus, it is essential to provide reasonable treatment in clinical practice. However, there are relatively few researches on the mechanism and treatment of CMIs, and the literature is composed almost exclusively of community-or hospital based on autopsy or imageological studies focusing on elderly patients. The Bu Yang Huan Wu (BYHW) decoction, a traditional Chinese herbal formula, has long been used to treat stroke and stroke-related diseases, including cognitive impairments. We applied microsphere-induced CMI model in rats to investigate the behavioral and molecular consequences of CMIs and to determine how they were ameliorated by BYHW decoction treatment. We then used the Morris water maze, quantitative proteomics, immunohistochemistry, and other molecular assays and found that activation of the PKA/CREB pathway by BYHW decoction treatment may reverse mitochondrial dysfunction, inhibit apoptosis of hippocampal neurons, and ameliorate CMI-induced cognitive impairments in rats. Collectively, these findings confirmed the therapeutic potential of the BYHW decoction in treating cognitive impairments induced by CMIs and demonstrated a viable mechanism for its action.

Jiedu Tongluo Granules Ameliorates Post-stroke Depression Rat Model via Regulating NMDAR/BDNF Signaling Pathway.

Post-stroke depression (PSD) is one of the most common stroke complications, which seriously affects stroke's therapeutic effect and brings great pain for patients. The pathological mechanism of PSD has not been revealed. Jiedu Tongluo granules (JDTLG) is an effective traditional Chinese medicine for PSD treatment which is widely used in clinical treatment. JDTLG has a significant therapeutic effect against PSD, but the mechanism is still unclear. The PSD rat model was established by carotid artery embolization combined with chronic sleep deprivation followed by treating with JDTLG. Neurobehavioral and neurofunctional experiments were engaged in studying the neural function of rats. Histomorphology, proteomics, and western blotting researches were performed to investigate the potential molecular mechanisms related to JDTLG therapy. Oral treatment of JDTLG could significantly improve the symptoms of neurological deficit and depression symptoms of PSD rats. Proteomic analysis identified several processes that may involve the regulation of JDTLG on the PSD animal model, including energy metabolism, nervous system, and N-methyl-D-aspartate receptor (NMDAR)/brain-derived neurotrophic factor (BDNF) signal pathway. Our results showed that JDTLG could reduce glutamate (Glu) level and increase gamma-aminobutyric acid (GABA) level via regulating the NMDAR/BDNF pathway, which may play a vital role in the occurrence and development of PSD.

Identity and compatibility of reference genome resources.

Genome analysis relies on reference data like sequences, feature annotations, and aligner indexes. These data can be found in many versions from many sources, making it challenging to identify and assess compatibility among them. For example, how can you determine which indexes are derived from identical raw sequence files, or which annotations share a compatible coordinate system? Here, we describe a novel approach to establish identity and compatibility of reference genome resources. We approach this with three advances: first, we derive unique identifiers for each resource; second, we record parent-child relationships among resources; and third, we describe recursive identifiers that determine identity as well as compatibility of coordinate systems and sequence names. These advances facilitate portability, reproducibility, and re-use of genome reference data. Available athttps://refgenie.databio.org.

KinPred: A unified and sustainable approach for harnessing proteome-level human kinase-substrate predictions.

Tyrosine and serine/threonine kinases are essential regulators of cell processes and are important targets for human therapies. Unfortunately, very little is known about specific kinase-substrate relationships, making it difficult to infer meaning from dysregulated phosphoproteomic datasets or for researchers to identify possible kinases that regulate specific or novel phosphorylation sites. The last two decades have seen an explosion in algorithms to extrapolate from what little is known into the larger unknown-predicting kinase relationships with site-specific substrates using a variety of approaches that include the sequence-specificity of kinase catalytic domains and various other factors, such as evolutionary relationships, co-expression, and protein-protein interaction networks. Unfortunately, a number of limitations prevent researchers from easily harnessing these resources, such as loss of resource accessibility, limited information in publishing that results in a poor mapping to a human reference, and not being updated to match the growth of the human phosphoproteome. Here, we propose a methodological framework for publishing predictions in a unified way, which entails ensuring predictions have been run on a current reference proteome, mapping the same substrates and kinases across resources to a common reference, filtering for the human phosphoproteome, and providing methods for updating the resource easily in the future. We applied this framework on three currently available resources, published in the last decade, which provide kinase-specific predictions in the human proteome. Using the unified datasets, we then explore the role of study bias, the emergent network properties of these predictive algorithms, and comparisons within and between predictive algorithms. The combination of the code for unification and analysis, as well as the unified predictions are available under the resource we named KinPred. We believe this resource will be useful for a wide range of applications and establishes best practices for long-term usability and sustainability for new and existing predictive algorithms.

[Yiqi Tongluo Particles improve Qi-deficiency and blood stasis in multiple cerebral infarction rats by promoting angiogenesis].

This research was aimed to evaluate the protective effect and potential mechanism of Yiqi Tongluo Particles(YQTLs).Firstly,an animal model of multiple cerebral infarction(MCI) with Qi deficiency and blood stasis was established.Rats were randomly divided into six groups:SHAM group,Vehicle group,Buyang Huanwu decoction original group(BYHWO),EGb761 group,high and low dose of YQTLs group.Rats underwent sleep deprivation after one week of MCI and the tongues and pulses of rats after six weeks of sleep deprivation were detected,followed by collecting blood to analysis the blood coagulation.Differential expression of angiogenesis associated proteins was examined using proteomic research and verified by immunohistochemical.RESULTS: showed that neurological function score was obviously declined,G and B value of tongue surface was increased significantly and the pulse distension,the activated partial thromboplatin time(APTT) as well as prothrombin time(PT) were recovered following YQTLs 7.56 g·kg-1 treatment.Furthermore,G value of tongue surface,APTT and PT were also improved by YQTLs 3.78 g·kg-1.The results of proteomic technology showed that proteins associated with angiogenesis were reversed compared with Vehicle group.Moreover,the expression of VEGFR2 from immunohistochemical was promoted after YQTLs treatment.The MCI with Qi deficiency and blood stasis was alleviated obviously following YQTLs treatment and the possible mechanism was that YQTLs may enhance angiogenesis during cerebral ischemia.

Astragaloside IV Protects Primary Cerebral Cortical Neurons from Oxygen and Glucose Deprivation/Reoxygenation by Activating the PKA/CREB Pathway.

Stroke is one of the major leading causes of death and disability worldwide, and post-stroke cognitive impairment is a major contributor to this disability. Astragaloside IV (AST-IV) is a primary bioactive compound of Radix Astragali, which is widely used in traditional Chinese medicine to treat stroke. AST-IV was found to possess cognition-enhancing properties against ischemic stroke; however, the mechanisms underlying this effect remain largely elusive. Mitochondrial health is critical to cell viability after ischemic injury. Cyclic AMP response element-binding protein (CREB) is a transcription factor that can be activated by protein kinase A (PKA) to preserve mitochondria, regulate memory and cognitive functions. We used an in vitro model of ischemic injury via oxygen and glucose deprivation (OGD) of cultured neurons, which led to PKA inactivation and decreased CREB phosphorylation, reduced cell viability, and increased neuronal apoptosis. We hypothesized that AST-IV could protect OGD-exposed cerebral cortical neurons by modulating the PKA/CREB signaling pathway and preserving mitochondrial function. We found that the mitochondrial and cellular injuries induced by OGD were reversed following treatment with AST-IV. The activity of neuronal mitochondria was evaluated by measuring the mitochondrial potential and the levels of reactive oxygen species (ROS) and adenosine triphosphate (ATP). AST-IV significantly enhanced PKA and CREB phosphorylation and prevented OGD-induced mitochondrial dysfunction, thereby protecting neurons exposed to OGD from injury and death. Furthermore, the effects of AST-IV were partially blocked by a PKA inhibitor. Collectively, these data elucidated the molecular mechanisms underlying the protective effects of AST-IV against ischemic injury in cortical neurons.

Proteomic analysis of rat serum revealed the effects of chronic sleep deprivation on metabolic, cardiovascular and nervous system.

Sleep is an essential and fundamental physiological process that plays crucial roles in the balance of psychological and physical health. Sleep disorder may lead to adverse health outcomes. The effects of sleep deprivation were extensively studied, but its mechanism is still not fully understood. The present study aimed to identify the alterations of serum proteins associated with chronic sleep deprivation, and to seek for potential biomarkers of sleep disorder mediated diseases. A label-free quantitative proteomics technology was used to survey the global changes of serum proteins between normal rats and chronic sleep deprivation rats. A total of 309 proteins were detected in the serum samples and among them, 117 proteins showed more than 1.8-folds abundance alterations between the two groups. Functional enrichment and network analyses of the differential proteins revealed a close relationship between chronic sleep deprivation and several biological processes including energy metabolism, cardiovascular function and nervous function. And four proteins including pyruvate kinase M1, clusterin, kininogen1 and profilin-1were identified as potential biomarkers for chronic sleep deprivation. The four candidates were validated via parallel reaction monitoring (PRM) based targeted proteomics. In addition, protein expression alteration of the four proteins was confirmed in myocardium and brain of rat model. In summary, the comprehensive proteomic study revealed the biological impacts of chronic sleep deprivation and discovered several potential biomarkers. This study provides further insight into the pathological and molecular mechanisms underlying sleep disorders at protein level.