Governments around the world have implemented non-pharmaceutical interventions to limit the transmission of COVID-19. While lockdowns and physical distancing have proven effective for reducing COVID-19 transmission, there is still limited understanding of how NPI measures are reflected in indicators of human mobility. Further, there is a lack of understanding about how findings from high-income settings correspond to low and middle-income contexts.

Pancreatic ductal adenocarcinoma (PDAC) is a type of malignant tumor with a five-year survival rate of less than 10%. Gemcitabine (GEM) is the most commonly used drug for PDAC chemotherapy. However, a vast majority of patients with PDAC develop resistance after GEM treatment.

Researchers have shown that 25-hydroxyvitamin D (25[OH] D), a kind of active vitamin D in the human body, plays a role in cardiovascular disease (CVD). Low serum 25(OH) D levels have been found to be associated with elevated blood pressure (BP) in adults. However, measurement of 25(OH) D in hypertensive children has not been documented. The aim of this study was to investigate the relationship between 25(OH) D and target organ damage (TOD) in children with essential hypertension. We recruited a total of 346 children with essential hypertension and analyzed the correlation between serum 25(OH) D and TOD. Serum 25(OH) D concentration was significantly lower in the TOD than in the no-TOD group (t = 2.416, P = 0.016), as well as significantly lower in the two-organ damage than in the single-organ damage group (t = 3.140, P = 0.002). Pearson's correlation coefficient (PCC) indicated that serum 25(OH) D levels were negatively correlated with left ventricular mass index (LVMI; r = -0.110, P = 0.041) and albuminuria (r = -0.120, P = 0.026). Linear- regression analysis showed that 25(OH) D was a risk factor for left ventricular hypertrophy (LVH; β ± s.e. =-0.074 ± 0.036; 95% confidence interval [CI], - 0.145 to -0.003; P < 0.001) and renal damage (β ± s.e.= -0.018 ± 0.008; 95% CI, - 0.035 to -0.002; P = 0.004). In total, our data revealed that serum 25(OH) D was independently associated with hypertensive cardiac and renal damage, meaning that it was a risk factor for LVH and albuminuria in childhood hypertension.

Earlier studies have shown the neuroprotective role of TWIK-related K+ channel 1 (TREK-1) in global cerebral and spinal cord ischemia, while its function in focal cerebral ischemia has long been debated. This study used TREK-1-deficient mice to directly investigate the role of TREK-1 after focal cerebral ischemia. First, immunofluorescence assays in the mouse cerebral cortex indicated that TREK-1 expression was mostly abundant in astrocytes, neurons, and oligodendrocyte precursor cells but was low in myelinating oligodendrocytes, microglia, or endothelial cells. TREK-1 deficiency did not affect brain weight and morphology or the number of neurons, astrocytes, or microglia but did increase glial fibrillary acidic protein (GFAP) expression in astrocytes of the cerebral cortex. The anatomy of the major cerebral vasculature, number and structure of brain micro blood vessels, and blood-brain barrier integrity were unaltered. Next, mice underwent 60 min of focal cerebral ischemia and 72 h of reperfusion induced by the intraluminal suture method. TREK-1-deficient mice showed less neuronal death, smaller infarction size, milder blood-brain barrier (BBB) breakdown, reduced immune cell invasion, and better neurological function. Finally, the specific pharmacological inhibition of TREK-1 also decreased infarction size and improved neurological function. These results demonstrated that TREK-1 might play a detrimental rather than beneficial role in focal cerebral ischemia, and inhibition of TREK-1 would be a strategy to treat ischemic stroke in the clinic.

Fusobacterium nucleatum, found in the oral cavity, influences the progression of gastrointestinal cancers. Additionally, our previous results suggested that F. nucleatum is associated with poor patient prognosis in esophageal squamous cell carcinoma (ESCC). However, the mechanism by which F. nucleatum affects aggressive tumor behavior has yet to be elucidated. We have conducted this clinical, in vitro, and in vivo study to clarify the mechanism of ESCC progression induced by F. nucleatum. Transmission electron microscopy revealed that F. nucleatum invaded and occupied ESCC cells and impacted gene and protein expression. Comprehensive mRNA expression and pathway enrichment analyses of F. nucleatum-treated ESCC cells identified the "NF-κB" and "NOD-like receptor" signaling pathways as enriched. We confirmed the relationship between the presence of F. nucleatum and NF-κB activation in resected ESCC tissues. Furthermore, F. nucleatum-treated ESCC cells demonstrated enhanced growth ability, and NF-κB activation, as well as overexpression of NOD1 and phosphorylated RIPK2. Furthermore, treated cells showed accelerated tumor growth, with NF-κB activation in xenograft models. F. nucleatum invaded ESCC cells and induced the NF-κB pathway through the NOD1/RIPK2 pathway, leading to tumor progression.

Hepatocellular carcinoma has been identified to be among the most prevalent malignancies in the world and has an unfavorable prognosis. Immune checkpoints perform an essential function in many biological processes and are associated with the survival of cancer patients. The function of immune checkpoints remains unknown.

The main aim of the study was to illustrate the association between urinary polycyclic aromatic hydrocarbons (PAHs) and their metabolites with cardiovascular diseases (CVDs), including congestive heart failure (CHF), coronary heart disease (CHD), angina, heart attack, and stroke among the US population.

Males and females often exhibit differences in behaviour, life histories, and ecology, many of which are typically reflected in their brains. Neuronal protection and maintenance include complex processes led by the microglia, which also interacts with metabolites such as hormones or immune components. Despite increasing interest in sex-specific brain function in laboratory animals, the significance of sex-specific immune activation in the brain of wild animals along with the variables that could affect it is widely lacking. Here, we use the Kentish plover (Charadrius alexandrinus) to study sex differences in expression of immune genes in the brain of adult males and females, in two wild populations breeding in contrasting habitats: a coastal sea-level population and a high-altitude inland population in China. Our analysis yielded 379 genes associated with immune function. We show a significant male-biased immune gene upregulation. Immune gene expression in the brain did not differ in upregulation between the coastal and inland populations. We discuss the role of dosage compensation in our findings and their evolutionary significance mediated by sex-specific survival and neuronal deterioration. Similar expression profiles in the coastal and inland populations suggest comparable genetic control by the microglia and possible similarities in pathogen pressures between habitats. We call for further studies on gene expression of males and females in wild population to understand the implications of immune function for life-histories and demography in natural systems.

To investigate the effect of liraglutide on the browning of white fat and the suppression of obesity via regulating microRNA (miR)-27b in vivo and in vitro.

SCL/TAL1 Interrupting locus (STIL) is a ciliary-related gene involved in regulating the cell cycle and duplication of centrioles in dividing cells. STIL has been found disordered in multiple cancers and driven carcinogenesis. However, the molecular mechanisms and biological functions of STIL in cancers remain ambiguous. Here, we systematically analyzed the genetic alterations, molecular mechanisms, and clinical relevance of STIL across >10,000 samples representing 33 cancer types in The Cancer Genome Atlas (TCGA) dataset. We found that STIL expression is up-regulated in most cancer types compared with their adjacent normal tissues. The expression dysregulation of STIL was affected by copy number variation, mutation, and DNA methylation. High STIL expression was associated with worse outcomes and promoted the progression of cancers. Gene Ontology (GO) enrichment analysis and Gene Set Variation Analysis (GSVA) further revealed that STIL is involved in cell cycle progression, Mitotic spindle, G2M checkpoint, and E2F targets pathways across cancer types. STIL expression was negatively correlated with multiple genes taking part in ciliogenesis and was positively correlated with several genes which participated with centrosomal duplication or cilia degradation. Moreover, STIL silencing could promote primary cilia formation and inhibit cell cycle protein expression in prostate and kidney cancer cell lines. The phenotype and protein expression alteration due to STIL silencing could be reversed by IFT88 silencing in cancer cells. These results revealed that STIL could regulate the cell cycle through primary cilia in tumor cells. In summary, our results revealed the importance of STIL in cancers. Targeting STIL might be a novel therapeutic approach for cancers.

The epigenomic abnormality of pancreatic ductal adenocarcinoma (PDAC) has rarely been investigated due to its strong heterogeneity. Here, we used single-cell multiomics sequencing to simultaneously analyze the DNA methylome, chromatin accessibility and transcriptome in individual tumor cells of PDAC patients. We identified normal epithelial cells in the tumor lesion, which have euploid genomes, normal patterns of DNA methylation, and chromatin accessibility. Using all these normal epithelial cells as controls, we determined that DNA demethylation in the cancer genome was strongly enriched in heterochromatin regions but depleted in euchromatin regions. There were stronger negative correlations between RNA expression and promoter DNA methylation in cancer cells compared to those in normal epithelial cells. Through in-depth integrated analyses, a set of novel candidate biomarkers were identified, including ZNF667 and ZNF667-AS1, whose expressions were linked to a better prognosis for PDAC patients by affecting the proliferation of cancer cells. Our work systematically revealed the critical epigenomic features of cancer cells in PDAC patients at the single-cell level.

BACKGROUND There are limited studies on the effects of cholesterol homeostasis in populations at high risk for cardiovascular disease. We aimed to use gas chromatography and flame-ionization detection (GC-FID) of non-cholesterol sterols as indicators of cholesterol absorption and synthesis. Sterol indicators of cholesterol absorption included campesterol, stigmasterol, and sitosterol. Sterol indicators of cholesterol synthesis included squalene, 7-lathosterol, and desmosterol. MATERIAL AND METHODS A total of 158 participants were enrolled in 3 groups: healthy control (n=64), hyperlipidemia (n=69), and familial hypercholesterolemia (FH, n=25). Age, sex, blood pressure, blood glucose, and lipoprotein were collected, and cholesterol absorption and synthesis markers were determined by GC-FID. RESULTS All 6 cholesterol concentration indicators, except squalene, were significantly different among the 3 groups (all P<0.05); whereas in the ratio to cholesterol (%, sterols/cholesterol), only desmosterol and lathosterol were significantly different (P<0.05). Multifactorial regression analysis showed that triglycerides, total cholesterol, and desmosterol were independent risk factors affecting the development of hyperlipidemia (P<0.05). The efficacy of the ROC curve for the diagnosis of dyslipidemia was also higher for all 3 indices (Model 1, AUC=0.960). Model 1 was superior to Model 2 for the 6 indicators of cholesterol. For the FH and dyslipidemia groups, the 6-indicator model (Model 3) was shown to have a good diagnostic value (AUC=1.000). CONCLUSIONS The 6 sterol indicators of cholesterol absorption and synthesis had a dynamic course in all study participants. Desmosterol was an indicator of dyslipidemia. The combined use of the 6 sterol indicators differentiated between healthy individuals and patients with dyslipidemia and FH.

Mosses compose one of the three lineages of bryophytes. Today, about 13,000 species of mosses are recognized from across the globe, and at least one-third of this diversity composes the Hypnales, a lineage characterized by an early rapid radiation. We sequenced and de novo assembled the genomes of two hypnalean mosses, namely Entodon seductrix and Hypnum curvifolium, based on the 10x genomics and Hi-C data. The genome assemblies of E. seductrix and H. curvifolium comprise 348.4 and 262.0 Mb, respectively, estimated by k-mer analyses to represent 93.3% and 97.2% of their total genome size. Both genomes were assembled at the chromosome level, with scaffold N50 of 30.0 and 20.7 Mb, respectively. The annotated genome of E. seductrix comprises 25,801 protein-coding genes and that of H. curvifolium 29,077, estimated to represent 96.8% and 97.2%, respectively, of the total gene spaces based on BUSCO (Benchmarking Universal Single-Copy Ortholog) assessment. For both genomes, most contigs were anchored to the largest 11 pseudomolecules, corresponding to the 11 chromosomes of the two species, and each with a putative sex-related chromosome characterized by low gene density. The chromosomes of E. seductrix and H. curvifolium are highly syntenic, suggests limited architectural shifts occurred following the rapid radiation of the Hypnales. We compared their genomic features to the model moss Physcomitrium patens. The hypnalean moss genomes lack signatures of recent whole-genome duplication. The presented high-quality moss genomes provide new resources for comparative genomics to potentially unveil the genomic evolution of derived moss lineages.

Advances in microbiome science are being driven in large part due to our ability to study and infer microbial ecology from genomes reconstructed from mixed microbial communities using metagenomics and single-cell genomics. Such omics-based techniques allow us to read genomic blueprints of microorganisms, decipher their functional capacities and activities, and reconstruct their roles in biogeochemical processes. Currently available tools for analyses of genomic data can annotate and depict metabolic functions to some extent; however, no standardized approaches are currently available for the comprehensive characterization of metabolic predictions, metabolite exchanges, microbial interactions, and microbial contributions to biogeochemical cycling.

Spinal cord injury (SCI) is caused by spinal fracture after the displacement of the spine or broken bone fragments protruding into the spinal canal, resulting in different degrees of injury to the spinal cord or spinal nerves. Expression levels of miR-99a and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in cerebrospinal fluid of SCI patients were analyzed. Rat adrenal gland pheochromocytoma cell line PC-12 were stimulated with lipopolysaccharide (LPS) to mimic the in vitro environment of SCI. A rat mode of SCI was established by laminectomy. Reactive oxygen species (ROS) levels were measured by 2',7'-Dichlorodihydrofluorescein diacetate staining assay. Western blot was conducted to evaluate the expression levels of apoptotic indexes and proinflammatory cytokines. The interaction between miR-99a and NOX4 was verified by dual-luciferase reporter assay. The expression level of miR-99a was reduced while NOX4 expression was upregulated in cerebrospinal fluid of SCI patients and LPS-treated PC-12 cells. LPS impeded cell viability and promoted inflammation, apoptosis and ROS levels of PC-12 cells. Overexpression of miR-99a significantly promoted cell viability and reduced inflammation, apoptosis and oxidative stress in LPS-stimulated PC-12 cells. Dual-luciferase reporter assays verified that NOX4 was a target of miR-99a. Moreover, the expression of NOX4 was reduced in PC-12 cells after transfection with miR-99a mimic. Overexpression of NOX4 partly abolished the protective effect of miR-99a in LPS-treated PC-12 cells. To sum up, miR-99a suppresses NOX4 expression to relieve the LPS-induced inflammation, apoptosis and the progression of oxidative stress in SCI.

Besides its well-known benefits on human health, calcitriol, the hormonally active form of vitamin D3, has been being evaluated in clinical trials as an anticancer agent. However, currently available results are contradictory and not fundamentally deciphered. To the best of our knowledge, hypercalcemia caused by high-dose calcitriol administration and its low bioavailability limit its anticancer investigations and translations. Here, we show that the one-step self-assembly of calcitriol and amphiphilic cholesterol-based conjugates leads to the formation of a stable minimalist micellar nanosystem. When administered to mice, this nanosystem demonstrates high calcitriol doses in breast tumor cells, significant tumor growth inhibition and antimetastasis capability, as well as good biocompatibility. We further reveal that the underlying molecular antimetastatic mechanisms involve downregulation of proteins facilitating metastasis and upregulation of paxillin, the key protein of focal adhesion, in primary tumors.

Multiple sclerosis (MS) is a chronic autoimmune disease driven by T and B lymphocytes. The remyelination failure and neurodegeneration results in permanent clinical disability in MS patients. A desirable therapy should not only modulate the immune system, but also promote neuroprotection and remyelination. To investigate the neuroprotective effect of CD52 antibody in MS, both C57BL/6J and SJL mice with experimental autoimmune encephalomyelitis (EAE) were treated with CD52 antibody at the peak of disease. Treatment with CD52 antibody depleted T but not B lymphocytes in the blood, reduced the infiltration of T lymphocytes and microglia/macrophages in the spinal cord. Anti-CD52 therapy attenuated EAE scores during the recovery phase. It protected neurons immediately after treatment (within 4 days) as shown by reducing the accumulation of amyloid precursor proteins. It potentially promoted remyelination as it increased the number of olig2/CC-1-positive mature oligodendrocytes and prevented myelin loss in the following days (e.g., 14 days post treatment). In further experiments, EAE mice with a conditional knockout of BDNF in neurons were administered with CD52 antibodies. Neuronal deficiency of BDNF attenuated the effect of anti-CD52 treatment on reducing EAE scores and inflammatory infiltration but did not affect anti-CD52 treatment-induced improvement of myelin coverage in the spinal cord. In summary, anti-CD52 therapy depletes CD4-positive T lymphocytes, prevents myelin loss and protects neurons in EAE mice. Neuronal BDNF regulates neuroprotective and anti-inflammatory effect of CD52 antibody in EAE mice.

Distance metastasis is the leading cause of death for breast cancer patients, and circulating tumor cells (CTCs) play a key role in cancer metastasis. There have been few studies on CTCs at the molecular level due to their rarity, and the heterogeneity of CTCs may provide special information for solid tumor analysis.

The genus Paris is an excellent source of steroidal saponins that exhibit various bioactivities. Paris mairei is a unique species and has been widely used as folk medicine in Southwest China for a long time. With the help of chemical methods and modern spectra analysis, five new steroidal saponins, pamaiosides A-E (1-5), along with five known steroidal saponins 6-10, were isolated from the rhizomes of Paris mairei. The cytotoxicity of all the new saponins was evaluated against human pancreatic adenocarcinoma PANC-1 and BxPC3 cell lines.

Pancreatic islets respond to metabolic and inflammatory stress by producing hormones and other factors that induce adaptive cellular and systemic responses. Here we show that intracellular Ca2+ ([Ca2+]i) and ROS signals generated by high glucose and cytokine-induced ER stress activate calcineurin (CN)/NFATc2 and PI3K/AKT to maintain β-cell identity and function. This was attributed in part by direct induction of the endocrine differentiation gene RFX6 and suppression of several β-cell "disallowed" genes, including MCT1. CN/NFATc2 targeted p300 and HDAC1 to RFX6 and MCT1 promoters to induce and suppress gene transcription, respectively. In contrast, prolonged exposure to stress, hyperstimulated [Ca2+]i, or perturbation of CN/NFATc2 resulted in downregulation of RFX6 and induction of MCT1. These findings reveal that CN/NFATc2 and PI3K/AKT maintain β-cell function during acute stress, but β-cells dedifferentiate to a dysfunctional state upon loss or exhaustion of Ca2+/CN/NFATc2 signaling. They further demonstrate the utility of targeting CN/NFATc2 to restore β-cell function.