Live birth of chimeric monkey with high contribution from embryonic stem cells.

A formal demonstration that mammalian pluripotent stem cells possess preimplantation embryonic cell-like (naive) pluripotency is the generation of chimeric animals through early embryo complementation with homologous cells. Whereas such naive pluripotency has been well demonstrated in rodents, poor chimerism has been achieved in other species including non-human primates due to the inability of the donor cells to match the developmental state of the host embryos. Here, we have systematically tested various culture conditions for establishing monkey naive embryonic stem cells and optimized the procedures for chimeric embryo culture. This approach generated an aborted fetus and a live chimeric monkey with high donor cell contribution. A stringent characterization pipeline demonstrated that donor cells efficiently (up to 90%) incorporated into various tissues (including the gonads and placenta) of the chimeric monkeys. Our results have major implications for the study of primate naive pluripotency and genetic engineering of non-human primates.

Exploiting public databases of genomic variation to quantify evolutionary constraint on the branch point sequence in 30 plant and animal species.

The branch point sequence is a degenerate intronic heptamer required for the assembly of the spliceosome during pre-mRNA splicing. Disruption of this motif may promote alternative splicing and eventually cause phenotype variation. Despite its functional relevance, the branch point sequence is not included in most genome annotations. Here, we predict branch point sequences in 30 plant and animal species and attempt to quantify their evolutionary constraints using public variant databases. We find an implausible variant distribution in the databases from 16 of 30 examined species. Comparative analysis of variants from whole-genome sequencing shows that variants submitted from exome sequencing or false positive variants are widespread in public databases and cause these irregularities. We then investigate evolutionary constraint with largely unbiased public variant databases in 14 species and find that the fourth and sixth position of the branch point sequence are more constrained than coding nucleotides. Our findings show that public variant databases should be scrutinized for possible biases before they qualify to analyze evolutionary constraint.

PE-STOP: A versatile tool for installing nonsense substitutions amenable for precise reversion.

The rapid advances in genome editing technologies have revolutionized the study of gene functions in cell or animal models. The recent generation of double-stranded DNA cleavage-independent base editors has been suitably adapted for interrogation of protein-coding genes on the basis of introducing premature stop codons or disabling the start codons. However, such versions of stop/start codon-oriented genetic tools still present limitations on their versatility, base-level precision, and target specificity. Here, we exploit a newly developed prime editor (PE) that differs from base editors by its adoption of a reverse transcriptase activity, which enables incorporation of various types of precise edits templated by a specialized prime editing guide RNA. Based on such a versatile platform, we established a prime editing-empowered method (PE-STOP) for installation of nonsense substitutions, providing a complementary approach to the present gene-targeting tools. PE-STOP is bioinformatically predicted to feature substantially expanded coverage in the genome space. In practice, PE-STOP introduces stop codons with good efficiencies in human embryonic kidney 293T and N2a cells (with medians of 29% [ten sites] and 25% [four sites] editing efficiencies, respectively), while exhibiting minimal off-target effects and high on-target precision. Furthermore, given the fact that PE installs prime editing guide RNA-templated mutations, we introduce a unique strategy for precise genetic rescue of PE-STOP-dependent nonsense mutation via the same PE platform. Altogether, the present work demonstrates a versatile and specific tool for gene inactivation and for functional interrogation of nonsense mutations.

CircTRIM1 encodes TRIM1-269aa to promote chemoresistance and metastasis of TNBC via enhancing CaM-dependent MARCKS translocation and PI3K/AKT/mTOR activation.

Peptides and proteins encoded by noncanonical open reading frames (ORFs) of circRNAs have recently been recognized to play important roles in disease progression, but the biological functions and mechanisms of these peptides and proteins are largely unknown. Here, we identified a potential coding circular RNA, circTRIM1, that was upregulated in doxorubicin-resistant TNBC cells by intersecting transcriptome and translatome RNA-seq data, and its expression was correlated with clinicopathological characteristics and poor prognosis in patients with TNBC. CircTRIM1 possesses a functional IRES element along with an 810 nt ORF that can be translated into a novel endogenously expressed protein termed TRIM1-269aa. Functionally, we demonstrated that TRIM1-269aa, which is involved in the biological functions of circTRIM1, promoted chemoresistance and metastasis in TNBC cells both in vitro and in vivo. In addition, we found that TRIM1-269aa can be packaged into exosomes and transmitted between TNBC cells. Mechanistically, TRIM1-269aa enhanced the interaction between MARCKS and calmodulin, thus promoting the calmodulin-dependent translocation of MARCKS, which further initiated the activation of the PI3K/AKT/mTOR pathway. Overall, circTRIM1, which encodes TRIM1-269aa, promoted TNBC chemoresistance and metastasis by enhancing MARCKS translocation and PI3K/AKT/mTOR activation. Our investigation has yielded novel insights into the roles of protein-coding circRNAs and supported circTRIM1/TRIM1-269aa as a novel promising prognostic and therapeutic target for patients with TNBC.

YAP-LAMB3 axis dictates cellular resistance of pancreatic ductal adenocarcinoma cells to gemcitabine.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with poor prognosis and inadequate response to treatment, such as gemcitabine (Gem), the first-line chemotherapeutic drug. Understanding the molecular determinants that control drug resistance to Gem is critical to predict potentially responsive patients and improve the benefits of Gem therapy. Emerging evidence suggests that certain developmental pathways, such as Hippo signaling, are aberrated and play important roles in Gem resistance in cancers. Although Hippo signaling has been reported to play a role in chemoresistance in cancers, it has not been clarified which specific target gene(s) functionally mediates the effect. In the present study, we found that YAP serves as a potent barrier for the cellular sensitivity of PDAC cells to Gem. We then identified and characterized laminin subunit beta 3 (LAMB3) as a bona fide target of YAP-TEAD4 to amplify YAP signaling via a feedback loop. Such a YAP-LAMB3 axis is critical to induce epithelial-mesenchymal transition and mediate Gem resistance. Taken together, we uncovered that YAP-LAMB3 axis is an important regulator of Gem, thus providing potential therapeutic targets for overcoming Gem resistance in PDAC.

Gut microbiota regulates chronic ethanol exposure-induced depressive-like behavior through hippocampal NLRP3-mediated neuroinflammation.

Chronic ethanol exposure (CEE), which can lead to neuroinflammation, is an increasing risk factor for depression disorder, but the underlying mechanism is not clear. Recent observations have revealed the associations among psychiatric disorders, ethanol exposure and alterations of the gut microbiota. Here, we found that CEE induced depressive-like behavior, which could be alleviated by probiotics and transferred from donor to recipient mice by fecal microbiota transplantation (FMT). Neuroinflammation and the activation of the NLRP3 inflammasome were also observed in recipient mice. The downregulation of NLRP3 in the hippocampus mitigated CEE-induced depressive-like behavior and neuroinflammation but had no significant effect on FMT recipient mice. Moreover, elevated serum inflammatory factors in recipient mice showed a significant mediation effect between the gut microbiota and depressive-like behavior. Together, our study findings indicate that the gut microbiota contributes to both hippocampal NLRP3-mediated neuroinflammation and depressive-like behavior induced by CEE, which may open avenues for potential interventions against CEE-associated psychiatric disorders.

KCNE4 is a crucial host factor for Orf virus infection by mediating viral entry.

The orf virus (ORFV) poses a serious threat to the health of domestic small ruminants (i.e., sheep and goats) and humans on a global scale, causing around $150 million in annual losses to livestock industry. However, the host factors involved in ORFV infection and replication are still elusive. In this study, we compared the RNA-seq profiles of ORFV-infected or non-infected sheep testicular interstitial cells (STICs) and identified a novel host gene, potassium voltage-gated channel subfamily E member 4 (KCNE4), as a key host factor involved in the ORFV infection. Both RNA-seq data and RT-qPCR assay revealed a significant increase in the expression of KCNE4 in the infected STICs from 9 to 48 h post infection (hpi). On the other hand, the RT-qPCR assay detected a decrease in ORFV copy number in both the STICs transfected by KCNE4 siRNA and the KCNE4 knockout (KO) HeLa cells after the ORFV infection, together with a reduced fluorescence ratio of ORFV-GFP in the KO HeLa cells at 24 hpi, indicating KCNE4 to be critical for the ORFV infection. Furthermore, the attachment and internalization assays showed decreased ORFV attachment, internalization, replication, and release by the KO HeLa cells, demonstrating a potential inhibition of ORFV entry into the cells by KCNE4. Pretreatment with the KCNE4 inhibitors such as quinidine and fluoxetine significantly repressed the ORFV infection. All our findings reveal KCNE4 as a novel host regulator of the ORFV entry and replication, shedding new insight into the interactive mechanism of ORFV infection. The study also highlights the K+ channels as possible druggable targets to impede viral infection and disease.

Micro- and Mesoporous Structural Effects of Beta Zeolites for Volatile Organic Compound Sorption.

To fully exploit pore engineering in the design of more efficient zeolite adsorbents for volatile organic compound (VOC) treatment, the roles of meso- and micropores need to be clarified to provide the theoretical basis and feasible measures. In this work, the three VOC sorption properties of conventional and hierarchical porous beta zeolites were comparatively investigated to study the roles of meso- and micropores. There is a division of functions between micro- and mesopores, with micropores being the main VOC adsorption sites and mesopores greatly enhancing VOC diffusion and adsorbent reusability. On the one hand, micropores should be preserved as much as possible because obtaining mesopores by sacrificing micropores (i.e., alkali treatment) results in 28-60% decreases in adsorption capacities. On the other hand, mesopore introduction is highly desirable, which results in an enhancement of VOC intraparticle diffusion rates by 1.3-2.3 times (at the VOC concentration of 600 ppm) and chlorobenzene adsorption capacity on the 20th cycle increasing from 78% of the initial value to 89 and 93%. The findings may provide valuable information about zeolite-based adsorbents for adsorption removal or recovery of VOCs.

Traditional Chinese medicine and plant-derived natural products in regulating triglyceride metabolism: Mechanisms and therapeutic potential.

The incidence of cardiometabolic disease is increasing globally, with a trend toward younger age of onset. Among these, atherosclerotic cardiovascular disease is a leading cause of mortality worldwide. Despite the efficacy of traditional lipid-lowering drugs, such as statins, in reducing low-density lipoprotein cholesterol levels, a significant residual risk of cardiovascular events remains, which is closely related to unmet triglyceride (TG) targets. The clinical application of current TG-lowering Western medicines has certain limitations, necessitating alternative or complementary therapeutic strategies. Traditional Chinese medicine (TCM) and plant-derived natural products, known for their safety owing to their natural origins and diverse biological activities, offer promising avenues for TG regulation with potentially fewer side effects. This review systematically summarises the mechanisms of TG metabolism and subsequently reviews the regulatory effects of TCM and plant-derived natural products on TG metabolism, including the inhibition of TG synthesis (via endogenous and exogenous pathways), promotion of TG catabolism, regulation of fatty acid absorption and transport, enhancement of lipophagy, modulation of the gut microbiota, and other mechanisms. In conclusion, through a comprehensive analysis of recent studies, this review consolidates the multifaceted regulatory roles of TCM and plant-derived natural products in TG metabolism and elucidates their potential as safer, multi-target therapeutic agents in managing hypertriglyceridemia and mitigating cardiovascular risk, thereby providing a basis for new drug development.

The role of DNA and RNA guanosine oxidation in cardiovascular diseases.

Cardiovascular diseases (CVD) persist as a prominent cause of mortality worldwide, with oxidative stress constituting a pivotal contributory element. The oxidative modification of guanosine, specifically 8-oxoguanine, has emerged as a crucial biomarker for oxidative stress, providing novel insights into the molecular underpinnings of CVD. 8-Oxoguanine can be directly generated at the DNA (8-oxo-dG) and RNA (8-oxo-G) levels, as well as at the free nucleotide level (8-oxo-dGTP or 8-oxo-GTP), which are produced and can be integrated through DNA replication or RNA transcription. When exposed to oxidative stress, guanine is more readily produced in RNA than in DNA. A burgeoning body of research surrounds 8-oxoguanine, exhibits its accumulation playing a pivotal role in the development of CVD. Therapeutic approaches targeting oxidative 8-Oxoguanine damage to DNA and RNA, encompassing the modulation of repair enzymes and the development of small molecule inhibitors, are anticipated to enhance CVD management. In conclusion, we explore the noteworthy elevation of 8-oxoguanine levels in patients with various cardiac conditions and deliberate upon the formation and regulation of 8-oxo-dG and 8-oxo-G under oxidative stress, as well as their function in CVD.

Impact of adrenalectomy on hypertension in patients with nonfunctional adrenal tumors: a retrospective study.

OBJECTIVE: To investigate the impact of adrenalectomy on hypertension in patients with nonfunctional adrenal tumors. SUBJECTS AND METHODS: Between January 2020 and October 2022, patients with adrenal lesions were retrospectively screened for nonfunctional adrenal tumors at the Zhongnan Hospital of Wuhan University. All patients underwent detailed endocrinological examination and computed tomography to characterize the lesions. One year after discharge, follow-up blood pressure (BP) was assessed and compared to the blood pressure on admission. Univariate analysis and multivariate regression analysis were performed to determine factors predicting favorable hypertension outcomes after adrenalectomy. RESULTS: A total of 309 patients were found to be eligible, including 123 who underwent adrenalectomy. Patients who underwent adrenalectomy were stratified into two groups: (Bancos I (2022) Adrenal Incidentalomas: Insights Into Prevalence. Ann Intern Med 175:1481-1482. https://doi.org/10.7326/M22-2600 ) those with improved hypertension (n = 71), and (Fassnacht M, Tsagarakis S, Terzolo M, Tabarin A, Sahdev A, Newell-Price J et al. (2023) European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 189:G1-42. https://doi.org/10.1093/ejendo/lvad066 ) those without improved hypertension (n = 52). In contrast, the blood pressure levels of conservatively treated patients remained relatively stable 1 year after discharge. Univariate analysis and multivariate regression analysis showed that body mass index (BMI) and duration of hypertension were significantly different between the hypertension improvement group and the non-improvement group (p < 0.05). CONCLUSION: Adrenalectomy has been shown to be effective in improving hypertension in certain patients with nonfunctional adrenal tumors. BMI and duration of hypertension were independent factors associated with favorable hypertension outcomes after adrenalectomy.

Design and synthesis 1H-Pyrrolo[2,3-b]pyridine derivatives as FLT3 inhibitors for the treatment of Acute myeloid Leukemia.

Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyridine derivatives CM1-CM24, as FLT3 inhibitors based on F14, which we previously reported, that can target the hydrophobic FLT3 back pocket. Among these derivates, CM5 showed significant inhibition of FLT3 and FLT3-ITD, with inhibitory percentages of 57.72 % and 53.77 % respectively at the concentration of 1 µΜ. Furthermore, CM5 demonstrated potent inhibition against FLT3-dependent human AML cell lines MOLM-13 and MV4-11 (both harboring FLT3-ITD mutant), with IC50 values of 0.75 µM and 0.64 µM respectively. In our cellular mechanistic studies, CM5 also effectively induces apoptosis by arresting cell cycle progression in the G0/G1 phase. In addition, the amide and urea linker function were discussed in detail based on computational simulations studies. CM5 will serve as a novel lead compound for further structural modification and development of FLT3 inhibitors specifically targeting AML with FLT3-ITD mutations.

ARTN-GFRA3 axis induces epithelial-mesenchymal transition phenotypes, migration, and invasion of gastric cancer cells via KRAS signaling.

Neural invasion underlies the local spread of gastric cancer and is associated with poor prognosis. This process has been receiving increasing attention in recent years. However, the relationship between neural invasion and the malignant phenotypes of gastric cancer cells, as well as the molecular mechanism involved in this process, remain unclear. In this study, bioinformatics analysis was performed using a dataset obtained from The Cancer Genome Atlas-Stomach Adenocarcinoma. The results revealed that high expression of GDNF family receptor alpha 3 (GFRA3) was associated with a poor prognosis of patients with gastric cancer. GFRA3 is a receptor for artemin (ARTN), a glial cell line-derived neurotrophic factor (GDNF). This association was indicated by short overall/disease-free survival, as well as the presence of high-stage and high-grade disease. Gene set enrichment analysis showed that two cancer-associated pathways, namely KRAS signaling and epithelial-mesenchymal transition (EMT), were activated when GFRA3 was highly expressed in gastric cancer. Further studies confirmed that GFRA3 activated KRAS downstream signaling phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) or extracellular signal-regulated kinase (ERK) and induced EMT markers, as well as promoted the migration and invasion of gastric cancer cells. As a ligand of GFRA3, ARTN induced the EMT, migration, and invasion of gastric cancer cells via GFRA3. Notably, the effects of the ARTN-GFRA3 axis were attenuated by treatment with a KRAS inhibitor. The present findings indicated that, during the neural invasion of gastric cancer, ARTN-mediated activation of GFRA3 induces EMT phenotypes, migration, and invasion of gastric cancer cells via KRAS signaling.

Disease burden of AIDS in last 30-year period and its predicted level in next 25-years based on the global burden disease 2019.

BACKGROUND: This study examines global trends in acquired immune deficiency syndrome (AIDS) incidence, mortality, and disability-adjusted life years (DALYs) from 1990 to 2019, focusing on regional disparities in AIDS incidence, mortality, and DALYs across various levels of socio-demographic index (SDI). It also investigates variations in AIDS incidence, mortality, and DALYs across different age groups, and projects specific trends for the next 25 years. METHODS: Comprehensive data on AIDS from 1990 to 2019 in 204 countries and territories was obtained from a GBD study. This included information on AIDS incidence, mortality, DALYs, and age-standardized rates (ASRs). Projections for AIDS incidence and mortality over the next 25 years were generated using the Bayesian age-period-cohort model. RESULTS: From 1990 to 2019, the global incidence of HIV cases increased from 1,989,282 to 2,057,710, while the age-standardized incidence rate (ASIR) decreased from 37.59 to 25.24 with an estimated annual percentage change (EAPC) of -2.38. The ASIR exhibited an upward trend in high SDI and high-middle SDI regions, a stable trend in middle SDI regions, and a downward trend in low-middle SDI and low SDI regions. In regions with higher SDI, the ASIR was higher in males than in females, while the opposite was observed in lower SDI regions. Throughout 1990 to 2019, the age-standardized death rate (ASDR) and age-standardized DALY rate remained stable, with EAPCs of 0.24 and 0.08 respectively. Countries with the highest HIV burden affecting women and children under five years of age are primarily situated in lower SDI regions, particularly in sub-Saharan Africa. Projections indicate a significant continued decline in the age-standardized incidence and mortality rates of AIDS over the next 25 years, for both overall and by gender. CONCLUSIONS: The global ASIR decreased from 1990 to 2019. Higher incidence and death rates were observed in the lower SDI region, indicating a greater susceptibility to AIDS among women and < 15 years old. This underscores the urgent need for increased resources to combat AIDS in this region, with focused attention on protecting women and < 15 years old as priority groups. The AIDS epidemic remained severe in sub-Saharan Africa. Projections for the next 25 years indicate a substantial and ongoing decline in both age-standardized incidence and mortality rates.

Ultrasonic optic nerve sheath diameter can be used as a diagnostic measure after accidental dural puncture during cesarean section: a case report.

BACKGROUND: Parturients are prone to postdural puncture headache (PDPH) after epidural puncture. Cerebral venous sinus thrombosis (CVST) is a fatal complication of PDPH. The main symptom of both is headache, however, the mechanism is not similar. For persistent PDPH, early differential diagnosis from CVST is essential. Optic nerve sheath diameter (ONSD) measurements can be used to identify changes in intracranial pressure as an auxiliary tool to distinguish the cause of headache. CASE PRESENTATION: The dura of a 32-year-old woman undergoing cesarean section was accidentally penetrated while administering epidural anesthesia, and the patient developed PDPH the subsequent day. The patient refused epidural blood patch (EBP) treatment and was discharged after conservative treatment. Fourteen days post-discharge, she was readmitted for a seizure. Magnetic resonance imaging (MRI) and Magnetic resonance angiography (MRA) indicated low cranial pressure syndrome and superior sagittal sinus thrombosis with acute infarction. The next morning, the EBP was performed with 15 ml autologous blood. Subsequently, the headache symptoms decreased during the day and worsened at night. ONSD measurement suggested dilation of the optic nerve sheath, and subsequently, the patient showed intracranial hypertension with papilledema. After dehydration and anticoagulant treatment, the patient's symptoms were relieved and she was discharged from the hospital 49 days later. CONCLUSIONS: Headache is the main symptom of PDPH and cerebral venous thrombosis, which are difficult to distinguish. ONSD measurement may help to estimate the intracranial pressure, and early measurement may be helpful for women with PDPH to avoid serious complications, such as CVST.

Voacangine protects hippocampal neuronal cells against oxygen-glucose deprivation/reoxygenation-caused oxidative stress and ferroptosis by activating the PI3K-Akt-FoxO signaling.

Voacangine, a naturally occurring alkaloid, has been testified to display beneficial effects on a variety of human diseases, but its role in ischemic stroke is unclear. The impacts of voacangine on oxygen-glucose deprivation/reoxygenation (OGD/R)-tempted hippocampal neuronal cells are investigated. The bioinformatics analysis found that voacangine is a bioactive ingredient that may have good effects on ischemic stroke. KEGG pathways analysis found that voacangine may regulate ischemic stroke through modulating the PI3K-Akt-FoxO signaling pathway. Voacangine could mitigate OGD/R-tempted cytotoxicity in HT22 cells. Voacangine mitigated OGD/R-tempted oxidative stress in HT22 cells by diminishing reactive oxygen species level and enhancing superoxide dismutase level. Voacangine mitigated OGD/R-tempted ferroptosis in HT22 cells. Voacangine promoted activation of the PI3K-Akt-FoxO signaling in OGD/R-induced HT22 cells. Inactivation of the PI3K-Akt-FoxO signaling pathway reversed the protective effects of voacangine against OGD/R-tempted oxidative stress, cytotoxicity, and ferroptosis in HT22 cells. In conclusion, voacangine protects hippocampal neuronal cells against OGD/R-caused oxidative stress and ferroptosis by activating the PI3K-Akt-FoxO signaling.

Neurosurgical clipping versus endovascular coiling for patients with ruptured anterior circulation aneurysms: A systematic review and meta-analysis.

To compare the safety and efficacy of clipping and coiling in patients with ruptured anterior circulation aneurysms. A systematic search of four databases (PubMed, Web of Science, Cochrane Library, and Embase) was conducted to identify comparative articles on endovascular coiling and surgical clipping in patients with ruptured anterior circulation aneurysms. Meta-analyses were conducted using random-effects models. Nineteen studies, including 1983 patients, were included. The meta-analysis showed that neurosurgical clipping was associated with a lower incidence of retreatment (OR:0.28, 95% CI (0.11, 0.70), P = 0.006) than endovascular coiling, which seemed to be a result of incomplete occlusion (OR:0.22, 95% CI (0.11, 0.45), P < 0.001). Neurosurgical clipping was associated with lower mortality (OR:0.45, 95% CI (0.25, 0.82), P = 0.009) at short-term follow-up than endovascular coiling. However, neurosurgical clipping showed a higher incidence of ischemic infarction (OR:2.28, 95% CI (1.44, 3.63), P < 0.001) and a longer length of stay (LOS) (WMD:6.12, 95% CI (4.19, 8.04), P < 0.001) after surgery than endovascular coiling. Furthermore, the pooled results showed no statistically significant differences between the two groups regarding poor outcome, long-term mortality, rebleeding, vasospasm, and hydrocephalus. Evidence from this systematic review illustrates that neurosurgical clipping may be superior to endovascular coiling for ruptured anterior circulation aneurysms. Large-scale RCTs should be conducted to verify these outcomes and provide results according to patient status.

May Measurement Month 2021: an analysis of blood pressure screening results from China.

We reported findings from participants screened during the May Measurement Month 2021 in China, which aimed to raise awareness of raised blood pressure (BP), and to investigate the risk factors of BP. The study participants were adults (≥18 years), ideally in whom BP had not been measured in the previous year. Blood pressure was measured three times consecutively with 1 min intervals in the sitting position, using a validated upper-arm cuff automated BP monitor (Omron HEM-7081IT), and transmitted to a central cloud database via a smartphone app. The measurement was performed in 218 844 participants in 183 sites across 31 China provinces. The mean (standard deviation) age was 47.0 (15.7) years, and 51.8% (n = 113 466) were women. The mean systolic/diastolic BP was 120.2/77.5 mmHg. Among 57 178 (26.1%) participants with hypertension, the awareness, treatment, and control rates of hypertension were 30.4% (n = 17 354), 28.7% (n = 16 369), and 17.1% (n = 9743), respectively. After adjustment for age, sex, and use of antihypertensive medication, both systolic and diastolic BP were significantly (P ≤ 0.01) higher in current smokers (n = 22 344, +0.4/+0.7 mmHg) and with moderate (n = 4780, +1.4/+4.2 mmHg) or daily alcohol intake (n = 2427, +1.3/+2.5 mmHg). Blood pressure was lower in those reporting regular exercise (n = 32 328, -2.2/-1.4 mmHg). In addition, individuals with previous COVID-19 vaccination had lower systolic and diastolic BP (n = 88 945, -1.8/-1.5 mmHg, P ≤ 0.001). In conclusion, our study showed that long-term large-scale screening for hypertension is feasible, and there is a strong association between BP and major lifestyle factors.

Deep learning-based state prediction of the Lorenz system with control parameters.

Nonlinear dynamical systems with control parameters may not be well modeled by shallow neural networks. In this paper, the stable fixed-point solutions, periodic and chaotic solutions of the parameter-dependent Lorenz system are learned simultaneously via a very deep neural network. The proposed deep learning model consists of a large number of identical linear layers, which provide excellent nonlinear mapping capability. Residual connections are applied to ease the flow of information and a large training dataset is further utilized. Extensive numerical results show that the chaotic solutions can be accurately forecasted for several Lyapunov times and long-term predictions are achieved for periodic solutions. Additionally, the dynamical characteristics such as bifurcation diagrams and largest Lyapunov exponents can be well recovered from the learned solutions. Finally, the principal factors contributing to the high prediction accuracy are discussed.

Study of the PI3K/Akt/mTOR signaling pathway in vitro and molecular docking analysis of periplocin inhibits cell cycle progression and induces apoptosis in MDA-MB-231.

Breast cancer mainly affects women and is the second leading cause of cancer-related deaths worldwide. Breast cancer affects women aged 15-59. The current study explored periplocin's anticancer activities against breast cancer MDA-MB-231 cells by down-regulating the PI3K/Akt/mTOR pathway. The MTT assay assessed control-treated and periplocin (2.5-50 µM) treated MDA-MB-231 cell viability. ROS accumulation and apoptosis levels in periplocin-treated cells were examined using DAPI, dual staining, and Annexin V-FITC/PI assays. Caspase enzymes were studied using assay kits. Flow cytometry was used to measure cell cycle distributions. Periplocin-treated cells were analyzed using RT-PCR assays and insilico analyses for the expression of PI3K/Akt/mTOR molecules. The periplocin treatment remarkably reduced the viability of the MDA-MB-231 cells, with an IC50 concentration of 7.5 µM. The fluorescent staining assays revealed a substantial increase in ROS levels and apoptotic events in the periplocin-treated cells. The flow cytometry analysis revealed that periplocin triggered apoptosis and arrested the cell cycle in G0/G1 phases. Periplocin increased the caspase-3, -8, and -9 enzyme activities. In MDA-MB-231 cells, Periplocin decreased PI3K/Akt/mTOR activity, and in silico analysis, Periplocin was inhibited by CDK8-Cyclin C interactions. Periplocin has anticancer properties against breast cancer and may be an effective therapeutic agent for treating breast cancer.