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Medications acting on the central nervous system (CNS) are common causes of medication-related unintentional poisoning. Little is known about the short-term effects of CNS medications on unintentional poisoning.This study aims to determine the short-term association between newly prescribed CNS drugs and unintentional poisoning.We conducted a register-based case-crossover study of 9354 patients (age ≥ 50 years) with first-time hospitalization for unintentional poisoning in Sweden between 1 July, 2006 and 30 September, 2018. Newly initiated CNS medication was identified based on dispensations from the Swedish Prescribed Drug Register during 28 days prior to the unintentional poisoning event and compared with dispensations during an equally long control period. Conditional logistic regression was used to estimate the odds ratio and 95% confidence intervals.After a newly initiated CNS treatment, we found an increased risk of unintentional poisoning during the following 2 weeks with an odds ratio (95%) being 2.52 (1.98-3.21) and 1.47 (1.08-2.00) for the first and second week, respectively. The risk was elevated in all sub-groups but to a different degree with odds ratio ranges of 1.73-2.47 by age, 1.91-2.21 by sex, 1.40-2.30 by Charlson Comorbidity Index, 2.00-2.07 by neuropsychiatric comorbidity, and 1.63-2.82 by number of other medications.The risk of unintentional poisoning doubles in 2 weeks following a new initiation of CNS drugs and the risk is increased across a range of population groups. Clinicians should carefully monitor signs of poisoning after such initiation among not only multimorbid older adults but also those with less comorbidity and polypharmacy.

Fig. S1. CSC abundance, expression of ABC transporters and cancer cell chemoresistance after MTDH knockdown or overexpression. Fig. S2. Expression of EMT marker proteins after MTDH knockdown or overexpression. Fig. S3. CSC abundance and in vivo tumorigencity of DU145 cells after MTDH knockdown. Fig. S4. TWIST1 expression was regulated by histone acetylation. Fig. S5. The CBP homolog p300 was not involved in MTDH regulation of TWIST1. Fig. S6. TWIST1+ cells are co-localized with MTDH+ cells at invasive tumor front (ITF). Table S1: The sequences of primers and shRNA constructs used in the study.

The canonical estimation of distribution algorithm (EDA) easily falls into a local optimum with an ill-shaped population distribution, which leads to weak convergence performance and less stability when solving global optimization problems. To overcome this defect, we explore a novel EDA variant with an ensemble of three distribution modification strategies, i.e., archive-based population updating (APU), multileader-based search diversification (MSD), and the triggered distribution shrinkage (TDS) strategy, named E3-EDA. The APU strategy utilizes historical population information to rebuild the search scope and avoid ill-shaped distributions. Moreover, it continuously updates the archive to avoid overfitting the distribution model. The MSD makes full use of the location differences among populations to evolve the sampling toward promising regions. TDS is triggered when the search stagnates, shrinking the distribution scope to achieve local exploitation. Additionally, the E3-EDA performance is evaluated using the CEC 2014 and CEC 2018 test suites on 10-dimensional, 30-dimensional, 50-dimensional and 100-dimensional problems. Moreover, several prominent EDA variants and other top methods from CEC competitions are comprehensively compared with the proposed method. The competitive performance of E3-EDA in solving complex problems is supported by the nonparametric test results.

Immune checkpoint blockade (ICB) therapy targeting PD-1/PD-L1 has shown durable clinical benefits in lung cancer. However, many patients respond poorly to ICB treatment, underscoring an incomplete understanding of PD-L1 regulation and therapy resistance. Here, we find that MTSS1 is downregulated in lung adenocarcinoma, leading to PD-L1 upregulation, impairment of CD8+ lymphocyte function, and enhanced tumor progression. MTSS1 downregulation correlates with improved ICB efficacy in patients. Mechanistically, MTSS1 interacts with the E3 ligase AIP4 for PD-L1 monoubiquitination at Lysine 263, leading to PD-L1 endocytic sorting and lysosomal degradation. In addition, EGFR-KRAS signaling in lung adenocarcinoma suppresses MTSS1 and upregulates PD-L1. More importantly, combining AIP4-targeting via the clinical antidepressant drug clomipramine and ICB treatment improves therapy response and effectively suppresses the growth of ICB-resistant tumors in immunocompetent mice and humanized mice. Overall, our study discovers an MTSS1-AIP4 axis for PD-L1 monoubiquitination and reveals a potential combinatory therapy with antidepressants and ICB.

Purpose: To determine and compare the prevalence of depression and depressive symptoms in 2010 and 2021 in an adult population living in Stockholm at start of participation, Sweden, and study the possible impact of the Covid-19 pandemic. Methods: Data were used from 2010 (n=6,641) and 2021 (n=8,863) based on a longitudinal population-based study with the aim to study risk and protective factors for mental health. Self-reported depression was assessed using Major Depression Inventory and in 2021 questions on effects of the Covid-19 pandemic were added. Prevalence was calculated and presented with 95% confidence intervals. Results: Depression and depressive symptoms had increased in 2021 compared with 2010. The highest prevalence was found in women and in the youngest age-group. There was no difference after adjusting for Covid-19 infection in any of the age-groups. Women who experienced life changes related to the pandemic situation had higher rates of depression as well as those who lost their job during the pandemic. Conclusion: During the Covid-19 pandemic, it seems both depression and depressive symptoms become more common. However, we did not find support for a direct effect related to a Covid-19 infection but our results suggest that part of the increase may be due to secondary social and economic consequences of the pandemic.

BACKGROUND Both young and advanced maternal age have been associated with higher risks of neonatal mortality, but most studies are from high-income countries and the evidence from low- and middle-income countries (LMICs) is scarce. OBJECTIVE To investigate the association between maternal age at delivery and neonatal mortality in LMICs. METHODS This is a cross-sectional study using data from 159 Demographic and Health Surveys in 67 LMICs between 2000 and 2018. Maternal age at the time of the birth was the exposure variable, and neonatal mortality was the outcome. Multivariable logistic regression model taking into consideration complex survey design was performed with adjustments for maternal education level, paternal education level, rural/urban residence, country, and survey year. Subgroup analyses were performed by time of death, sex, the country's World Bank income classification, the World Health Organization region, and survey year. RESULTS A total of 1 395 746 mother-neonate pairs were included. Overall, compared with neonates born to mothers aged 25-29 years, those born to younger mothers aged 20-24, 16-19 and 12-15 years were at an increased risk of mortality (adjusted odds ratio [OR] 1.24, 95% confidence interval [CI] 1.17, 1.30; OR 1.81, 95% CI 1.71, 1.93; OR 2.29, 95% CI 1.96, 2.67, respectively). Neonates born to mothers aged 30-34, 35-39, 40-44, and ≥45 years were also at an increased risk of mortality (OR 1.09, 95% CI 1.03, 1.15; OR 1.30, 95% CI 1.21, 1.39; OR 1.50, 95% CI 1.38, 1.64; OR 1.84, 95% CI 1.54, 2.20, respectively). The results were consistent across most subgroup analyses. CONCLUSIONS Neonates born to younger (

The present study examined the prevalence and pattern of comorbidity among Chinese patients with first-ever acute ischemic stroke, and assessed the associations of specific comorbidity patterns with physical and cognitive functioning after stroke occurrence. A hospital-based cross-sectional study was conducted among 2,151 patients with first-ever ischemic stroke (age ≥40 years; 64.2% men) who were admitted to two university hospitals in Shandong, China between 2016 and 2017. Data on demographics, lifestyles, chronic health conditions, and use of medications were collected through in-person interviews, clinical examinations, and laboratory tests. Physical functioning was assessed by the Barthel index (BI) and the modified Rankin Scale (mRS) while cognitive functioning was assessed by the Montreal Cognitive Assessment test. The results showed that comorbidity was present in 90.9% of the stroke patients (women vs. men: 95.2 vs. 88.7%

Key Points Question Is maternal preeclampsia, alone or together with perinatal complications (preterm birth and/or small birth size) associated with an increased risk of neurodevelopmental and psychiatric disorders in offspring? Findings In this cohort study of 1 012 723 singleton live births in Finland, exposure to both maternal preeclampsia and perinatal complications was associated with higher risks of specific neurodevelopmental disorders as well as attention-deficit/hyperactivity disorder and conduct disorders in offspring compared with exposure to either preeclampsia or perinatal complications alone. Meaning These results suggest that children exposed to both preeclampsia in utero and perinatal complications have modestly increased risks of developing specific neurodevelopmental disorders as well as attention-deficit/hyperactivity disorder and conduct disorders., Importance Maternal preeclampsia has been reported to increase the risk of autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability in offspring. However, the association between maternal preeclampsia combined with perinatal complications and neurodevelopmental and psychiatric disorders in offspring is less well documented. Objective To examine the association of maternal preeclampsia, separately and together with perinatal complications, with neurodevelopmental and psychiatric disorders in offspring. Design, Setting, and Participants This population-based cohort study used data from nationwide registries in Finland to assess all singleton live births (N = 1 012 723) between January 1, 1996, and December 31, 2014. Offspring were followed up until December 31, 2018 (when the oldest reached age 22 years). Exclusion criteria were maternal inpatient psychiatric diagnoses and pregestational diabetes. The study and data analysis were conducted from May 1, 2020, to June 1, 2021. Exposures Preeclampsia and perinatal complications (delivery earlier than 34 weeks’ gestation and/or small for gestational age). Main Outcomes and Measures The primary outcomes were neurodevelopmental and psychiatric diagnoses and dispensation of psychotropic drugs among offspring until December 31, 2018. Cox proportional hazards regression analyses were performed to assess the associations. Results Of 1 012 723 singleton live births (51.1% boys; mean [SD] maternal age at birth, 30.0 [5.4] years; specific data on race and ethnicity were not available in the data set), 21 010 children (2.1%) were exposed to preeclampsia alone, 33 625 children (3.3%) were exposed to perinatal complications alone, and 4891 children (0.5%) were exposed to both preeclampsia and perinatal complications. A total of 93 281 children (9.2%) were diagnosed with a neurodevelopmental or psychiatric disorder. Offspring exposed to both preeclampsia and perinatal complications had an increased risk of any neurodevelopmental or psychiatric disorder after adjusting for potential confounding (adjusted hazard ratio [aHR], 2.11; 95% CI, 1.96-2.26) compared with those not exposed to either preeclampsia or perinatal complications; this risk was higher than exposure to either preeclampsia alone (aHR, 1.18; 95% CI, 1.12-1.23) or perinatal complications alone (aHR, 1.77; 95% CI, 1.72-1.82). Sibling pair analyses did not detect any increase in the risk of neurodevelopmental or psychiatric disorders after exposure to preeclampsia alone, but offspring exposed to both preeclampsia and perinatal complications had increased risks of intellectual disabilities (aHR, 3.24; 95% CI, 1.05-10.06), specific developmental disorders (aHR, 3.56; 95% CI, 2.35-5.41), ADHD and conduct disorders (aHR, 2.42; 95% CI, 1.09-5.39), and other behavioral and emotional disorders (aHR, 2.45; 95% CI, 1.17-5.13). The risk estimates for specific developmental disorders (aHR, 2.82; 95% CI, 2.60-3.05) and ADHD and conduct disorders (aHR, 1.88; 95% CI, 1.65-2.14) were higher among offspring exposed to both preeclampsia and perinatal complications compared with those exposed to perinatal complications alone (aHR, 2.26 [95% CI, 2.18-2.33] and 1.60 [95% CI, 1.52-1.68], respectively). Conclusions and Relevance In this study, exposure to both maternal preeclampsia and perinatal complications was associated with intellectual disabilities, specific developmental disorders, ADHD and conduct disorders, and other behavioral and emotional disorders in offspring. For specific developmental disorders and ADHD and conduct disorders, the risk estimates were higher among offspring exposed to both preeclampsia and perinatal complications compared with those exposed to perinatal complications only., This cohort study uses data from national registers in Finland to examine the association between exposure to maternal preeclampsia, alone and together with exposure to perinatal complications, and the risk of neurodevelopmental and psychiatric disorders in offspring.

FCS-like zinc finger (FLZ) is a plant-specific gene family that plays an important regulatory role in plant growth and development and its response to stress. However, studies on the characteristics and functions of cotton FLZ family genes are still lacking. This study systematically identified members of the cotton FLZ gene family based on cotton genome data. The cotton FLZ family genes were systematically analyzed by bioinformatics, and their expression patterns in different tissues and under low-temperature stress were analyzed by transcriptome and qRT–PCR. The G. hirsutum genome contains 56 FLZ genes distributed on 20 chromosomes, and most of them are located in the nucleus. According to the number and evolution analysis of FLZ family genes, FLZ family genes can be divided into five subgroups in cotton. The G. hirsutum FLZ gene has a wide range of tissue expression types, among which the expression is generally higher in roots, stems, leaves, receptacles and calyx. Through promoter analysis, it was found that it contained the most cis-acting elements related to methyl jasmonate (MeJA) and abscisic acid (ABA). Combined with the promoter and qRT–PCR results, it was speculated that GhFLZ11, GhFLZ25, GhFLZ44 and GhFLZ55 were involved in the response of cotton to low-temperature stress. Taken together, our findings suggest an important role for the FLZ gene family in the cotton response to cold stress. This study provides an important theoretical basis for further research on the function of the FLZ gene family and the molecular mechanism of the cotton response to low temperature.

In 2017, the American Academy of Pediatrics (AAP) updated the clinical practice guideline for high blood pressure (BP) in the pediatric population. In this study, we compared the difference in prevalence of elevated and hypertensive BP values defined by the 2017 AAP guideline and the 2004 Fourth Report and estimated the cardiovascular risk associated with the reclassification of BP status defined by the AAP guideline. A total of 47 200 children and adolescents aged 6 to 17 years from 6 countries (China, India, Iran, Korea, Poland, and Tunisia) were included in this study. Elevated BP and hypertension were defined according to 2 guidelines. In addition, 1606 children from China, Iran, and Korea who were reclassified upward by the AAP guideline compared with the Fourth Report and for whom laboratory data were available were 1:1 matched with children from the same countries who were normotensive by both guidelines. Compared with the Fourth Report, the prevalence of elevated BP defined by the AAP guideline was lower (14.9% versus 8.6%), whereas the prevalence of stages 1 and 2 hypertension was higher (stage 1, 6.6% versus 14.5%; stage 2, 0.4% versus 1.7%). Additionally, comparison of laboratory data in the case-control study showed that children who were reclassified upward were more likely to have adverse lipid profiles and high fasting blood glucose compared with normotensive children. In conclusion, the prevalence of elevated BP and hypertension varied significantly between both guidelines. Applying the new AAP guideline could identify more children with hypertension who are at increased cardiovascular risk.

Blood pressure (BP) trajectories among older adults, especially among the oldest-old, are still poorly characterized.To investigate the longitudinal trajectories of four BP components with age and their potential influential factors.This population-based prospective cohort study included 3315 participants (age 60-105 years, 64.6% women) who were regularly examined from 2001 to 2004 through 2013-2016. The longitudinal trajectories of systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP), and mean arterial pressure (MAP) with age were estimated using linear mixed-effects models.Overall, SBP and PP increased with age until ∼80 years and then declined, whereas DBP and MAP decreased constantly after 60 years of age. The age-related BP trajectories varied by survival time, birth cohort, use of antihypertensive drugs, and heart disease. Specifically, people who survived2 years after the last visit showed higher levels of BP components before ∼80 years, followed by steeper declines in SBP and PP. At the same age, people who were born earlier showed higher BP than those who were born later. People who used antihypertensive drugs had higher BP than those who did not until ∼80-90 years old, thereafter BP showed no significant difference. After ∼80 years old, people with heart disease showed steeper declines in SBP and PP than those without.The late-life longitudinal BP trajectories with age vary with demographics, clinical conditions, and contextual factors. These findings may help better understand the age-dependent relationship of BP with health outcomes as well as help achieve optimal BP control in older people.Competency in medical knowledge: Understanding the age-related blood pressure trajectories and potential influential factors may help improve blood pressure management in older people. Translational outlook 1: Blood pressure trajectories with age in older adults vary by birth cohort, survival time, antihypertensive therapy, and heart disease. The age-related blood pressure trajectories by birth cohorts are featured with lower blood pressure levels at the same age in more recent birth cohorts, which may partially reflect the improvement of blood pressure control over time. Translational outlook 2: The age-related blood pressure trajectories in the oldest old (e.g., age ≥ 85 years) are characterized by steeper and faster blood pressure declines associated with heart disease and short survival (e.g.,2 years). This may have implications for the optimal management of blood pressure as well as for the interpretation of the relationships between blood pressure and health outcomes (e.g., death) among the oldest old.

Bone is a common site of metastasis in lung cancer, but the regulatory mechanism remains incompletely understood. Osteoclasts are known to play crucial roles in osteolytic bone metastasis by digesting bone matrix and indirectly enhancing tumor colonization. In this study, we found that IL receptor 20 subunit β (IL-20RB) mediated a direct tumoral response to osteoclasts. Tumoral expression of IL-20RB was associated with bone metastasis of lung cancer, and functionally, IL-20RB promoted metastatic growth of lung cancer cells in bone. Mechanistically, tumor cells induced osteoclasts to secrete the IL-20RB ligand IL-19, and IL-19 stimulated IL-20RB-expressing tumor cells to activate downstream JAK1/STAT3 signaling, leading to enhanced proliferation of tumor cells in bone. Importantly, blocking IL-20RB with a neutralizing antibody significantly suppressed bone metastasis of lung cancer. Overall, our data revealed a direct protumor role of osteoclastic niche in bone metastasis and supported IL-20RB-targeting approaches for metastasis treatment.

China, especially the Xinjiang cotton area, is facing severe agricultural water shortages, which seriously restrain the development of the cotton industry. Discovering cotton drought resistance genes and cultivating high-quality and drought-resistant cotton materials through molecular breeding methods are of great significance to the development of the cotton industry. In this study, the drought-resistant cotton material Xinluzhong NO.82 and the drought-sensitive cotton material Kexin NO.1 were used to identify a batch of drought-resistant candidate genes through whole transcriptome sequencing. The main research results obtained were as follows: the ceRNA (competing endogenous RNAs) network was constructed using full transcriptional sequencing to screen the core genes in the core pathway; two drought-related candidate genes were obtained. Gohir.A11G156000 was upregulated at 0 h vs 12 h and downregulated at 12 h vs 24 h. Gohir.A07G220600 was downregulated at 0 h vs 12 h and upregulated at 12 h vs 24 h. The results for drought-resistant materials and drought-sensitive materials were similar. Gohir.A11G156000, encoding GABA-T, which is homologous to POP2 in Arabidopsis thaliana, affects the drought resistance of plants by regulating the GABA content. Gohir.A07G220600 encodes L-aspartate oxidase, which is homologous to AO in Arabidopsis thaliana, and is involved in the early steps of NAD biosynthesis and in plant antioxidant reactions. This study confirmed that the use of gene expression regulatory networks can quickly screen reliable drought-resistance genes and can be used for subsequent gene function verification.

Cardiovascular diseases (CVDs) have a high disease burden both globally and in South Africa. They have also been found to be temperature-sensitive globally. The association between temperature and CVD morbidity has previously been demonstrated, but little is known about it in South Africa. It is important to understand how changes in temperature in South Africa will affect CVD morbidity, especially in rural regions, to inform public health interventions and adaptation strategies. This study aimed to determine the short-term effect of apparent temperature (T(app)) on CVD hospital admissions in Mopani District, Limpopo province, South Africa. A total of 3124 CVD hospital admissions records were obtained from two hospitals from 1 June 2009 to 31 December 2016. Daily T(app) was calculated using nearby weather station measurements. The association was modelled using a distributed lag non-linear model with a negative binomial regression over a 21-day lag period. The fraction of morbidity attributable to non-optimal T(app), i.e., cold (6-25 degrees C) and warm (27-32 degrees C) T(app) was reported. We found an increase in the proportion of admissions due to CVDs for warm and cold T(app) cumulatively over 21 days. Increasing CVD admissions due to warm T(app) appeared immediately and lasted for two to four days, whereas the lag-structure for the cold effect was inconsistent. A proportion of 8.5% (95% Confidence Interval (CI): 3.1%, 13.7%) and 1.1% (95% CI: -1.4%, 3.5%) of the total CVD admissions was attributable to cold and warm temperatures, respectively. Warm and cold T(app) may increase CVD admissions, suggesting that the healthcare system and community need to be prepared in the context of global temperature changes.

Extreme high temperatures are threatening cotton production around the world due to the intensification of global warming. To cope with high-temperature stress, heat-tolerant cotton cultivars have been bred, but the heat-tolerant mechanism remains unclear. This study selected heat-tolerant (‘Xinluzao36′) and heat-sensitive (‘Che61-72′) cultivars of cotton treated with high-temperature stress as plant materials and performed comparative nanopore sequencing transcriptome analysis to reveal the potential heat-tolerant mechanism of cotton. Results showed that 120,605 nonredundant sequences were generated from the raw reads, and 78,601 genes were annotated. Differentially expressed gene (DEG) analysis showed that a total of 19,600 DEGs were screened; the DEGs involved in the ribosome, heat shock proteins, auxin and ethylene signaling transduction, and photosynthesis pathways may be attributed to the heat tolerance of the heat-tolerant cotton cultivar. This study also predicted a total of 5118 long non-coding RNAs (lncRNAs)and 24,462 corresponding target genes. Analysis of the target genes revealed that the expression of some ribosomal, heat shock, auxin and ethylene signaling transduction-related and photosynthetic proteins may be regulated by lncRNAs and further participate in the heat tolerance of cotton. This study deepens our understandings of the heat tolerance of cotton.

Giant cell tumor of bone (GCTB) is an aggressive osteolytic bone tumor characterized by the within-tumor presence of osteoclast-like multinucleated giant cells (MGCs), which are induced by the neoplastic stromal cells and lead to extensive bone destruction. However, the underlying mechanism of the pathological process of osteoclastogenesis in GCTB is poorly understood. Here we show that the proteoglycan Serglycin (SRGN) secreted by neoplastic stromal cells plays a crucial role in the formation of MGCs and tumorigenesis in GCTB. Upregulated SRGN expression and secretion are observed in GCTB tumor cells and patients. Stromal-derived SRGN promotes osteoclast differentiation from monocytes. SRGN knockdown in stromal cells inhibits tumor growth and bone destruction in a patient-derived orthotopic xenograft model of mice. Mechanistically SRGN interacts with CD44 on the cell surface of monocytes and thus activates focal adhesion kinase (FAK), leading to osteoclast differentiation. Importantly, blocking CD44 with a neutralizing antibody reduces the number of MGCs and suppresses tumorigenesis in vivo. Overall, our data reveal a mechanism of MGC induction in GCTB and support CD44-targeting approaches for GCTB treatment.

Soil salinization is the main abiotic stress factor affecting agricultural production worldwide, and salt stress has a significant impact on plant growth and development. Cotton is one of the most salt-tolerant crops. Its salt tolerance varies greatly depending on the variety, growth stage, organs, and soil salt types. Therefore, the selection and utilization of excellent salt-tolerant germplasm resources and the excavation of excellent salt-tolerant salt and salt resistance genes play important roles in improving cotton production in saline-alkali soils. In this study, we analysed the population structure and genetic diversity of 144 elite Gossypium hirsutum cultivar accessions collected from around the world, and especially from China. Illumina Cotton SNP 70K was used to obtain genome-wide single-nucleotide polymorphism (SNP) data for 149 experimental materials, and 18,432 highly consistent SNP loci were obtained by filtering. PCA (principal component analysis) indicated that 149 upland cotton materials could be divided into 2 subgroups, including subgroup 1 with 78 materials and subgroup 2 with 71 materials. Using the obtained SNP and other marker genotype test results, under salt stress, the salt tolerance traits 3d_Germination_potential, 3d_Bud_length_drop_rate, 7d_Germination_rate, 7d_Bud_length_drop_rate, 7d_Germination_weight, 3d_Bud_length, 7d_Bud_length, relative_germination_potential, Relative_germination_rate, 7d_Bud_weight_drop_rate, Salt tolerance index 3d_Germination_potential_index, 3d_Bud_length_index, 7d_Bud_length_index, 7d_Bud_weight_index, and 7d_Germination_rate_index were evaluated by genome association analysis. A total of 27 SNP markers closely related to salt tolerance traits and 15 SNP markers closely related to salt tolerance index were detected. At the SNP locus associated with the traits of the bud length decline rate at 7 days, alleles Gh_A01G0034 and Gh_D01G0028 related to plant salt tolerance were detected, and they are related to intracellular transport, membrane microtubule formation and actin network. This study provides a theoretical basis for the selection and breeding of salt-tolerant upland cotton varieties.

Great efforts have been made on the algorithms that deal with RNA-seq data to enhance the accuracy and efficiency of differential expression (DE) analysis. However, no consensus has been reached on the proper threshold values of fold change and adjusted p-value for filtering differentially expressed genes (DEGs). It is generally believed that the more stringent the filtering threshold, the more reliable the result of a DE analysis. Nevertheless, by analyzing the impact of both adjusted p-value and fold change thresholds on DE analyses, with RNA-seq data obtained for three different cancer types from the Cancer Genome Atlas (TCGA) database, we found that, for a given sample size, the reproducibility of DE results became poorer when more stringent thresholds were applied. No matter which threshold level was applied, the overlap rates of DEGs were generally lower for small sample sizes than for large sample sizes. The raw read count analysis demonstrated that the transcript expression of the same gene in different samples, whether in tumor groups or in normal groups, showed high variations, which resulted in a drastic fluctuation in fold change values and adjustedp-values when different sets of samples were used. Overall, more stringent thresholds did not yield more reliable DEGs due to high variations in transcript expression; the reliability of DEGs obtained with small sample sizes was more susceptible to these variations. Therefore, less stringent thresholds are recommended for screening DEGs. Moreover, large sample sizes should be considered in RNA-seq experimental designs to reduce the interfering effect of variations in transcript expression on DEG identification.

Genetic diversity, kinship and population genetic structure analyses of Gossypium hirsutum germplasm can provide a better understanding of the origin and evolution of G. hirsutum biodiversity. In this study, 1313331 SNP molecular markers were used to construct a phylogenetic tree of each sample using MEGAX, to perform population structure analysis by ADMIXTURE software and principal component analysis (PCA) by EIGENSOFT software, and to estimate relatedness using SPAGeDi. ADMIXTURE software divided the experimental cotton population into 16 subgroups, and the Gossypium hirsutum samples could be roughly clustered according to source place, but there were some overlapping characteristics among samples. The experimental cotton population was divided into six groups according to source to calculate the genetic diversity index (H), and the obtained value (0.306) was close to that for germplasm collected by others in China. Cluster 4 had a relatively high genetic diversity level (0.390). The degrees of genetic differentiation within the experimental cotton population groups were low (the population differentiation indexes ranged from 0.02368 to 0.10664). The genetic distance among cotton accessions varied from 0.000332651 to 0.562664014, with an average of 0.25240429. The results of this study may provide a basis for mining elite alleles and using them for subsequent association analysis.

Background Exercise can protect myocardial infarction (MI) and downregulate cardiac Homeodomain-Interacting Protein Kinase 2 (HIPK2). However, the role of HIPK2 in MI is unclear. Methods HIPK2–/– mice and miR-222–/– rats, HIPK2 inhibitor (PKI1H) and adeno-associated virus serotype 9 (AAV9) carrying miR-222 were applied in the study. Animals were subjected to running, swimming, acute MI or post-MI remodeling. HIPK2 inhibition and P53 activator were used in neonatal rat cardiomyocytes (NRCMs) and human embryonic stem cell-derived cardiomyocytes (hESC-CMs) subjected to oxygen glucose deprivation/reperfusion (OGD/R). Serum miR-222 levels were analyzed in healthy people and MI patients that were survival or readmitted to the hospital and/or died. Findings Cardiac HIPK2 protein levels were reduced by exercise while increased in MI. In vitro, HIPK2 suppression by lentiviral vectors or inhibitor prevented apoptosis induced by OGD/R in NRCMs and hESC-CMs. HIPK2 inhibitor-treated mice and HIPK2–/– mice reduced infarct size after acute MI, and preserved cardiac function in MI remodeling. Mechanistically, protective effect against apoptosis by HIPK2 suppression was reversed by P53 activators. Furthermore, increasing levels of miR-222, targeting HIPK2, protected post-MI cardiac dysfunction, whereas cardiac dysfunction post-MI was aggravated in miR-222–/– rats. Moreover, serum miR-222 levels were significantly reduced in MI patients, as well as in MI patients that were readmitted to the hospital and/or died compared to those not. Interpretation Exercise-induced HIPK2 suppression attenuates cardiomyocytes apoptosis and protects MI by decreasing P-P53. Inhibition of HIPK2 represents a potential novel therapeutic intervention for MI. Funding This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to JJ Xiao), National Natural Science Foundation of China (82020108002, 81722008, and 81911540486 to JJ Xiao, 81400647 to MJ Xu, 81800265 to YJ Liang), Innovation Program of Shanghai Municipal Education Commission (2017-01-07-00-09-E00042 to JJ Xiao), the grant from Science and Technology Commission of Shanghai Municipality (18410722200 and 17010500100 to JJ Xiao), the “Dawn” Program of Shanghai Education Commission (19SG34 to JJ Xiao), Shanghai Sailing Program (21YF1413200 to QL Zhou). JS is supported by Horizon2020 ERC-2016-COG EVICARE (725229).

Heat shock transcription factors (HSFs) are involved in environmental stress response and plant development, such as heat stress and flowering development. According to the structural characteristics of the HSF gene family, HSF genes were classified into three major types (HSFA, HSFB, and HSFC) in plants. Using conserved domains of HSF genes, we identified 621 HSF genes among 13 cotton genomes, consisting of eight diploid and five tetraploid genomes. Phylogenetic analysis indicated that HSF genes among 13 cotton genomes were grouped into two different clusters: one cluster contained all HSF genes of HSFA and HSFC, and the other cluster contained all HSF genes of HSFB. Comparative analysis of HSF genes in Arabidopsis thaliana, Gossypium herbaceum (A1), Gossypium arboreum (A2), Gossypium raimondii (D5), and Gossypium hirsutum (AD1) genomes demonstrated that four HSF genes were inherited from a common ancestor, A0, of all existing cotton A genomes. Members of the HSF gene family in G. herbaceum (A1) genome indicated a significant loss compared with those in G. arboretum (A2) and G. hirsutum (AD1) A genomes. However, HSF genes in G. raimondii (D5) showed relative loss compared with those in G. hirsutum (AD1) D genome. Analysis of tandem duplication (TD) events of HSF genes revealed that protein-coding genes among different cotton genomes have experienced TD events, but only the two-gene tandem array was detected in Gossypium thurberi (D1) genome. The expression analysis of HSF genes in G. hirsutum (AD1) and Gossypium barbadense (AD2) genomes indicated that the expressed HSF genes were divided into two different groups, respectively, and the expressed HSF orthologous genes between the two genomes showed totally different expression patterns despite the implementation of the same abiotic stresses. This work will provide novel insights for the study of evolutionary history and expression characterization of HSF genes in different cotton genomes and a widespread application model for the study of HSF gene families in plants.

It is well established that obesity is associated with an increased risk of elevated and high blood pressure (BP) in children and adolescents. However, it is uncertain whether there is an increase in the risk of elevated and high BP associated with an increase of body mass index (BMI) among children and adolescents whose BMI is in the accepted normal range. Data were available for 58 899 children and adolescents aged 6–17 years from seven national cross-sectional surveys in China, India, Iran, Korea, Poland, Tunisia, and the United States. The subjects were divided into eight percentile subgroups according to their BMI levels based on the World Health Organization recommendations. Elevated BP and high BP were defined using the 2016 international child BP criteria. Compared with the reference subgroup of the 5th–24th percentiles, the odds ratios (ORs) for high BP were 1.27 (95% confidence interval [CI], 1.14–1.41; P

The common point of traditional BRB parameters training methods is taking the training process as an optimization problem, which may result in overfitting problem when training data is insufficient or contains strong noises. To solve the problems, we propose a novel method based on Bayesian estimation to update parameters of BRB online. While the optimization methods consider BRB parameters as unknown but determinate values, the Bayesian estimation regards BRB parameters as random variables. Instead of finding single optimal values of parameters, the proposed method is to estimate the posterior distribution of BRB parameters and produce prediction outputs by considering all possible parameters. Since the posterior distribution of BRB parameters cannot be calculated by analytical methods due to the nonlinearity of BRB models, the Sequential Monte Carlo (SMC) sampling technique is adopted to on-line approximate the posterior distribution of BRB parameters. A numerical function and a practical case on pipeline leak detection are studied to verify the performance of proposed algorithm.

To overcome the premature convergence caused by the ill-distribution of solutions in the basic Gaussian estimation of distribution algorithm (GEDA), this paper explores a novel GEDA variant with random walk strategies, namely RW-GEDA. In RW-GEDA, the weighted maximum likelihood estimation method is used to estimate the Gaussian distribution. The new candidates are sampled using a shifted mean to enhance exploration performance. When the algorithm stagnates, two random walk strategies, namely, Gaussian random walk and Lévy walk, are activated to enrich the population diversity. Moreover, RW-GEDA is executed in an Eigen coordinate framework to promote the evolution towards the dominant region. The performance of RW-GEDA is evaluated by using the CEC 2014 test suite and compared with other top algorithms from different communities as well as promising GEDA extensions. The statistical results demonstrate the competitive performance of our proposed RW-GEDA in terms of efficiency and accuracy. In addition, RW-GEDA is applied to solve the optimal missile guidance handover problem. To fill the gap in solving this problem, a novel missile guidance advantage model is established, and the optimal missile guidance handover is determined by optimizing the control variables of unmanned combat aerial vehicles. The validity and practicability of the problem model as well as the accuracy and efficiency of RW-GEDA are demonstrated by the experimental results.

Although some studies have shown the average side effects of cardiovascular medication, the short-term effect after newly initiated cardiovascular medications has not been studied in any detail. We aim to determine the effect of newly initiated cardiovascular medications resulting in unintentional poisoning and to identify those at high risk.A case-crossover design was used. From the Swedish National Patient Register, a total of 9,354 persons aged ≥ 50 and hospitalized with a first event of unintentional poisoning between July 2006 and September 2018 were identified. Through linkage to the Prescribed Drug Register, exposure to newly initiated cardiovascular medication during the case period (1-28 days prior to the onset date of unintentional poisoning) was compared with that in a corresponding control period (113-140 days prior to the onset date). Conditional logistic regression was used to determine the associations in total, for different time periods as well as by age, sex, underlying comorbidity, and use of other medications.Newly initiated cardiovascular medications were associated with a higher risk of unintentional poisoning, especially during the first week after initiation (odds ratio [OR]=1.39), (95% confidence interval [CI]=1.08-1.79). The risk of unintentional poisoning was comparable across age groups, sex, underlying comorbidities, and medications with OR (95% CI) ranging from 1.15 (0.75-1.74) to 2.00 (1.15-3.47).This large population-based case-crossover study showed that newly initiated cardiovascular medication is associated with an increased risk of unintentional poisoning, particularly during the first week after initiation. The risk is comparable across age, sex, underlying comorbidity, and medications.

Processing attribute reduction plays a key role in the fault diagnosis of incomplete decision information system (IDIS), and it improves the efficiency and accuracy of fault diagnosis. Tolerance relation-based attribute reduction is widely used in the IDIS. However, the fuzziness of relation-based classification always exists in the practical attribute reduction problems of fault diagnosis as the incompleteness and uncertainty of data information, and the traditional tolerance relation-based attribute reduction methods are not suitable for fault diagnosis of IDIS. Therefore, this paper proposes a hybrid hierarchical fault diagnosis method with the combination of tolerance relation-based attribute reduction method and integrated logarithmic fuzzy preference programming (LFPP) based methodology. The method utilizes both qualitative and quantitative data information and constructs the hierarchical structure of fault diagnosis in IDIS. The integrated LFPP based methodology obtains the unique normalized optimal significance priorities vector for attribute fuzzy pairwise comparison matrices simultaneously and directly as the sorting part of proposed method. The tolerance relation-based attribute reduction method decomposes the fault attributes reduction problem into multiple sub-problems, which is the decomposing part of proposed method. Hence, the proposed hybrid method can handle the fuzziness of relation-based classification and mitigate complexity attribute reduction for fault diagnosis of IDIS. Finally, an engineering case for strategy reduction of fault diagnosis is provided to demonstrate the feasibility of the proposed method and obtain the reduction diagnosis strategies. Another test case is given for verifying the validity of the reduction results and for comparison between the proposed method and other different methods, which shows that the method is indeed efficient and has greater advantages at producing higher accuracy, reducing difficulty and mitigating complexity in fault diagnosis.

To investigate the associations between cardiovascular health (CVH) metrics and health-related quality of life (HRQL) among patients with ischemic stroke in China, and further explore the role of physical and cognitive function in their associations.This hospital-based study included 1714 patients with first-ever acute ischemic stroke (age ≥ 40 years; 36.7% women) who were admitted to two university hospitals in Shandong, China. We collected information on seven CVH metrics (smoking, body mass index, diet, physical activity, blood pressure, total cholesterol, and fasting blood glucose) through interviews, clinical examinations, and laboratory tests. EQ-5D-3L was used to assess HRQL. Cognitive and physical functioning was assessed by the Montreal Cognitive Assessment test and Barthel index, respectively. Data were analyzed using the general linear regression models.The average score (SD) was 0.746 (0.23) for HRQL index and 72.7 (15.8) for self-rated health. Optimal levels of four individual CVH metric components (diet, physical activity, blood pressure, and blood glucose) and a higher composite CVH score were significantly associated with a greater HRQL index and better self-rated health (p 0.05 for all). Physical dependence and cognitive impairment were associated with a lower HRQL index and poorer self-rated health status (p 0.001). Furthermore, the relationships between CVH metrics and HRQL index varied by functional status, such that their associations were statistically significant only among people who had physical dependence or cognitive impairment.Achieving a better cardiovascular health profile is associated with better quality of life among ischemic stroke survivors, primarily in those with physical or cognitive impairment.

Additional file 1: Supplementary Material S1. Definitions of cardiovascular health metrics.

Intervention studies often assume that changes in an outcome are homogenous across the population, however this assumption might not always hold. This article describes how latent class growth modelling (LCGM) can be performed in intervention studies, using an empirical example, and discusses the challenges and potential implications of this method. The analysis included 110 young adults with mobility disability that had participated in a parallel randomized controlled trial and received either a mobile app program (n = 55) or a supervised health program (n = 55) for 12 weeks. The primary outcome was accelerometer measured moderate to vigorous physical activity (MVPA) levels in min/day assessed at baseline, 6 weeks, 12 weeks, and 1-year post intervention. The mean change of MVPA from baseline to 1-year was estimated using paired t-test. LCGM was performed to determine the trajectories of MVPA. Logistic regression models were used to identify potential predictors of trajectories. There was no significant difference between baseline and 1-year MVPA levels (4.8 min/day, 95% CI: −1.4, 10.9). Four MVPA trajectories, ‘Normal/Decrease’, ‘Normal/Increase’, ‘Normal/Rapid increase’, and ‘High/Increase’, were identified through LCGM. Individuals with younger age and higher baseline MVPA were more likely to have increasing trajectories of MVPA. LCGM uncovered hidden trajectories of physical activity that were not represented by the average pattern. This approach could provide significant insights when included in intervention studies. For higher accuracy it is recommended to include larger sample sizes. Electronic supplementary material The online version of this article (10.1007/s10865-021-00216-y) contains supplementary material, which is available to authorized users.

Disseminated tumor cells often fall into a long term of dormant stage, characterized by decreased proliferation but sustained survival, in distant organs before awakening for metastatic growth. However, the regulatory mechanism of metastatic dormancy and awakening is largely unknown. Here, we show that the epithelial-like and mesenchymal-like subpopulations of breast cancer stem-like cells (BCSCs) demonstrate different levels of dormancy and tumorigenicity in lungs. The long non-coding RNA (lncRNA) NR2F1-AS1 (NAS1) is up-regulated in the dormant mesenchymal-like BCSCs, and functionally promotes tumor dissemination but reduces proliferation in lungs. Mechanistically, NAS1 binds to NR2F1 mRNA and recruits the RNA-binding protein PTBP1 to promote internal ribosome entry site (IRES)-mediated NR2F1 translation, thus leading to suppression of ΔNp63 transcription by NR2F1. Furthermore, ΔNp63 downregulation results in epithelial-mesenchymal transition, reduced tumorigenicity and enhanced dormancy of cancer cells in lungs. Overall, the study links BCSC plasticity with metastatic dormancy, and reveals the lncRNA as an important regulator of both processes., Disseminated tumor cells often become dormant before awakening for metastatic growth. Here, the authors report that the lncRNA, NR2F1-AS1, is upregulated in dormant mesenchymal-like breast cancer stem-like cells and promotes dissemination but inhibits proliferation, leading to metastatic dormancy.

Summary Background Tobacco use is a leading preventable cause of morbidity and mortality worldwide. Little is known about recent prevalence and trends in tobacco use among adolescents globally. We aimed to assess the recent global prevalence of tobacco use in young adolescents and the secular trends in prevalence between 1999 and 2018. Methods We used the most recent Global Youth Tobacco Surveys data on adolescents aged 13–15 years from 143 countries or territories that had done at least one survey between Jan 1, 2010, and Dec 31, 2018, to assess the recent prevalence of tobacco use; and data from 140 countries that had done two or more surveys between Jan 1, 1999, and Dec 31, 2018, to assess the trends in the prevalence of tobacco use. Findings 530 234 adolescents were included from the 143 countries that had done at least one survey between 2010 and 2018. 1 192 312 adolescents were included from the 140 countries that had done two or more surveys between 1999 and 2018. The most recent global prevalence of cigarette smoking was 11·3% (95% CI 10·3–12·3) in boys and 6·1% (5·6–6·6) in girls, based on cigarette smoking on at least 1 day during the past 30 days, 6·0% (5·5–6·6) and 2·6% (2·4–2·9) based on smoking on at least 3 days, and 4·2% (3·8–4·6) and 1·6% (1·4–1·8) based on smoking on at least 6 days. The most recent prevalence of the use of tobacco products other than cigarettes (eg, chewing tobacco, snuff, dip, cigars, cigarillos, pipe, electronic cigarettes) on at least 1 day during the past 30 days was 11·2% (9·9–12·6) in boys and 7·0% (6·4–7·7) in girls. The most recent prevalence of any tobacco use on at least 1 day during the past 30 days was 17·9% (16·1–19·6) in boys and 11·5% (10·5–12·4) in girls. The prevalence of cigarette smoking on at least 1 day during the past 30 days decreased between the first and last surveys in 80 (57·1%) of 140 countries, was unchanged in 39 countries (27·9%), and increased in 21 countries (15·0%). However, the prevalence of the use of tobacco products other than cigarettes was unchanged or increased in 81 (59·1%) of 137 countries. Interpretation The global prevalence of tobacco use among adolescents aged 13–15 years was substantial. Although the prevalence of cigarette smoking decreased over time in the majority of countries, the prevalence of the use of other tobacco products increased or did not change in the majority of countries during the past two decades. These findings re-emphasise the need to strengthen tobacco control efforts among young adolescents globally. Funding Shandong University.

ObjectiveThis study aimed to assess using Doppler ultrasound for analyzing stability of deep venous thrombosis (DVT) of the lower extremities.MethodsPatients with DVT of the lower extremities who were treated from August 2017 to December 2019 were selected. The patients were divided into stable and unstable groups according to whether thrombus was collected in a filter. Related ultrasound and blood test results were analyzed and compared.ResultsA total of 126 patients with DVT of the lower extremities were included, of whom 74 were in the stable group and 52 were in the unstable group. There were significant differences in the prothrombin time (PT), and lipoprotein alpha, D-dimer, and triglyceride levels between the groups. D-dimer levels >2800 ug/L, smoking, history of venous thrombosis, PT >13.15 s, and body mass index >24.45 kg/m2were independent risk factors for stability of DVT of the lower extremities. The area under the curve with combined detection of DVT was significantly higher than that for body mass index, PT, and D-dimer alone.ConclusionDoppler ultrasound may be reliable for analyzing the stability of DVT of the lower extremities. Related strategies targeting risk factors are required for reducing DVT of the lower extremities.

Objective Several longitudinal studies have investigated the association between elevated blood pressure (BP) in childhood and hypertension in adulthood but the strength of the association has not been always consistent. This study aimed at quantitatively assessing the strength of the association between elevated BP in childhood and hypertension in adulthood based on both a meta-analysis and a systematic review. Methods We identified eligible studies using PubMed and Embase databases up to 1 November, 2019 and by manually searching the reference lists of all identified studies. All longitudinal studies on the association between elevated BP in childhood and hypertension in adulthood were included. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model in this meta-analysis. Results Eleven articles (N = 39 714) were included in our meta-analysis and five additional articles were used for systematic review (two providing ORs without 95% CIs, one not using standard cut-offs for elevated BP in childhood, and two not using standard criteria for adult hypertension). Elevated BP in childhood (3--18 years in the included studies) was significantly associated with hypertension in adulthood (18--57 years in the included studies), with a summary OR of 2.02 (95% CI 1.62--2.53). We also found that an increase of 1 standard deviation in systolic BP and diastolic BP, respectively, in childhood (3--19 years in the included studies) was associated with hypertension in adulthood (21--49 years in the included studies), with summary ORs of 1.71 (1.50-1.95) and 1.57 (1.37-1.81). Our systematic review of the five additional articles not eligible for meta-analysis also suggested a significant association between elevated BP in childhood and hypertension in adulthood. Conclusion This meta-analysis and systematic review demonstrated a significant association between elevated BP in childhood and hypertension in adulthood. The findings support measures to promote healthy BP during childhood to reduce the risk of hypertension later in life.

Background Prevention and control of cardiometabolic conditions and cardiovascular disease (CVD) in China may contribute to sustainable CVD reduction globally, given the fact that one-fifth of the worldwide population is in China. Knowing the distribution of behavioral risk factors (e.g., smoking and physical inactivity), especially at a national level in China, would be extremely relevant to the field of public health and CVD prevention. The objectives of this study were to investigate the nationwide prevalence of obesity, smoking, heavy drinking, and physical inactivity in Chinese adults, and further explore whether cardiometabolic conditions would modify the distribution of behavioral risk factors. Methods This population-based study is based on the China Health and Retirement Longitudinal Study (2011–2012), including 17,302 adults (≥45 years, mean age 59.67 years, female 51.66%) from 25 provinces in China. Data on demographics, lifestyle factors, health status and history of diseases were collected via structured interviews and laboratory tests. Smoking, heavy drinking, obesity, and physical inactivity were defined following standard guidelines. We performed descriptive analysis and logistic regressions in this study. Results The overall prevalence of heavy drinking, obesity, current smoking, and physical inactivity among middle-aged and older adults was 7.23% (95% confidence interval 6.53—7.29%), 11.53% (10.43—12.62%), 27.46% (26.30—28.62%), and 44.06% (41.19—46.92%), respectively. The prevalence varied between rural and urban areas as well as among geographic areas, with higher prevalence in the Northern and Northeastern regions. Heavy drinking and obesity were significantly associated with incident hypertension, diabetes, and high cholesterol; while current smoking was significantly associated with incident hypertension. Compared with healthy individuals, participants who self-reported a diagnosis of hypertension, high cholesterol, or diabetes were less likely to smoke currently and drink alcohol heavily, but more likely to be physically inactive and obese. Conclusions Among Chinese middle-aged and older adults, the prevalence of behavioral risk factors varies by geographic region. Further effort is required to improve physical activity and fitness for Chinese adults, especially those with cardiometabolic conditions.

Background: Cardiovascular health (CVH) metrics among Chinese older adults are poorly understood. We investigated gender disparities in CVH metrics and their management among rural-dwelling older adults in China.Methods: This community-based study included 5026 participants (age ≥65 years; 57.2% women) in the baseline survey of a multimodal intervention study in rural China. Data were collected through face-to-face interviews, clinical examinations, and laboratory tests in March-September 2018. We defined six CVH metrics (three behavioral factors—smoking, body mass index, and physical activity; three biological factors—blood pressure, total cholesterol, and blood glucose) following the modified American Heart Association’s recommendations. We performed descriptive analysis separately for men and women.Results: Of all participants, only 0.8% achieved ideal levels in all six CVH metrics. Men were more likely than women to have ideal levels in all CVH metrics but smoking. Women had higher prevalence of ideal global CVH metrics (9.7% in women vs. 7.8% in men) and behavioral CVH metrics (18.3% vs. 9.5%) (ppp for trendpConclusions: The CVH metrics among older adults living in the rural communities in China are characterized by an extremely low proportion of optimal global CVH metrics and distinct gender differences, alongside poor management of major biological risk factors.Trial registration: ChiCTR1800017758.

Summary Global warming has reduced the productivity of many field‐grown crops, as the effects of high temperatures can lead to male sterility in such plants. Genetic regulation of the high temperature (HT) response in the major crop cotton is poorly understood.We determined the functionality and transcriptomes of the anthers of 218 cotton accessions grown under HT stress. By analyzing transcriptome divergence and implementing a genome‐wide association study (GWAS), we identified three thermal tolerance associated loci which contained 75 protein coding genes and 27 long noncoding RNAs, and provided expression quantitative trait loci (eQTLs) for 13 132 transcripts.A transcriptome‐wide association study (TWAS) confirmed six causal elements for the HT response (three genes overlapped with the GWAS results) which are involved in protein kinase activity. The most susceptible gene, GhHRK1, was confirmed to be a previously uncharacterized negative regulator of the HT response in both cotton and Arabidopsis.These functional variants provide a new understanding of the genetic basis for HT tolerance in male reproductive organs.

Lung metastasis is the major cause of breast cancer-related mortality. The neutrophil-associated inflammatory microenvironment aids tumor cells in metastatic colonization in lungs. Here, we show that tumor-secreted protease cathepsin C (CTSC) promotes breast-to-lung metastasis by regulating recruitment of neutrophils and formation of neutrophil extracellular traps (NETs). CTSC enzymatically activates neutrophil membrane-bound proteinase 3 (PR3) to facilitate interleukin-1β (IL-1β) processing and nuclear factor κB activation, thus upregulating IL-6 and CCL3 for neutrophil recruitment. In addition, the CTSC-PR3-IL-1β axis induces neutrophil reactive oxygen species production and formation of NETs, which degrade thrombospondin-1 and support metastatic growth of cancer cells in the lungs. CTSC expression and secretion are associated with NET formation and lung metastasis in human breast tumors. Importantly, targeting CTSC with compound AZD7986 effectively suppresses lung metastasis of breast cancer in a mouse model. Overall, our findings reveal a mechanism of how tumor cells regulate neutrophils in metastatic niches and support CTSC-targeting approaches for cancer treatment.

Aim To investigat the association between paternal age at birth and offspring's under-5 mortality in low- and middle-income countries (LIMCs). Methods Data from 159 population-based surveys in 67 LIMCs between 2000 and 2018 were obtained from the Demographic and Health Surveys. Cox proportional hazard regression models in consideration of complex survey design were performed to examine the associations. Results In the pooled analysis, compared with children born to fathers aged 25-29 years, those born to younger fathers aged 20-24, 16-19 and 12-15 years, respectively, were at increased risk of under-5 mortality (hazard ratio (HR) = 1.09, 95% confidence interval (CI) = 1.06-1.13; HR = 1.48, 95% CI = 1.42-1.55; HR = 1.70, 95% CI = 1.56-1.84, respectively). In addition, children born to older fathers aged 40-44 and ≥ 45 years, also had increased risk of under-5 mortality (HR = 1.08, 95% CI = 1.03-1.15; HR = 1.12, 95% CI = 1.07-1.18, respectively). Conclusions Our findings show that children born to both younger and older fathers are at higher risk of offspring's under-5 mortality in LIMCs.

BACKGROUND: Several studies have investigated the association of breastfeeding status with offspring mortality in Africa, but most studies were from one center only or had limited statistical power to draw robust conclusions. METHODS: Data came from 75 nationally representative cross-sectional Demographic and Health Surveys in 35 countries in sub-Saharan Africa conducted between 2000 and 2016. Our study relied on 217 112 individuals aged 4 days to 23 months for breastfeeding pattern analysis, 161 322 individuals aged 6 to 23 months for breastfeeding history analysis, and 104 427 individuals aged 12 to 23 months for breastfeeding duration analysis. RESULTS: Compared with children aged 4 days to 23 months exclusively breastfed in the first 3 days of life, those not breastfed had a high risk of mortality at CONCLUSIONS: Our findings support exclusive breastfeeding during the first 6 months of life and continued breastfeeding up to 2 years of age recommended by the World Health Organization for reducing mortality of children

Additional file 1: Supplementary Table 1. Geographic prevalence (95% confidence interval) of smoking, drinking, obesity and physical inactivity. Supplementary Fig. 1. Province-specific prevalence of current smoking, heavy drinking, physical inactivity and obesity by urban and rural areas. Supplementary Table 2. Association between behavioral risk factors and cardiometabolic conditions. Supplementary Table 3. Association between behavioral risk factors and cardiometabolic conditions among those without history of cardiovascular disease.