MTSS1 curtails lung adenocarcinoma immune evasion by promoting AIP4-mediated PD-L1 monoubiquitination and lysosomal degradation.

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.

Cardiovascular health profiles, systemic inflammation, and physical function in older adults: A population-based study.

We examined the association of modifiable cardiovascular health (CVH) metrics with physical function among rural older adults in China and the potential role of inflammatory mechanisms in the association. This study included 3733 stroke- and dementia-free participants (age ≥65 years; 56.9% women) in the baseline survey of a multimodal intervention study in rural China. From March-September 2018, data were collected via face-to-face interviews, clinical assessments, and laboratory tests. The Short Performance Physical Battery (SPPB) test was performed to assess physical function. We defined six modifiable CVH metrics according to the modified American Heart Association's recommendations. Serum interleukin (IL)-6 was measured in a subsample (n = 1156). Data were analyzed with multiple general linear and logistic regression models and structural equation modeling. Poor physical function (SPPB score ≤9) was defined in 1443 participants. Ideal CVH (vs. poor CVH) was associated with multivariable-adjusted odds ratio of 0.60 (95%CI 0.48-0.75) for poor physical function. Ideal CVH was significantly associated with higher scores on balance, chair stand, and walking speed tests (all p < 0.05). Moreover, ideal CVH profile was associated with lower serum IL-6 (multivariable-adjusted ß=-0.04; 95% CI -0.06, -0.01). Mediation analysis revealed that serum IL-6 accounted for 14% of the association of CVH with total SPPB score and 10% of the association with walking speed score (p < 0.05). This study suggests that an ideal CVH profile is associated with better physical function among stroke- and dementia-free older adults, partly via inflammatory mechanisms. The preventive implications of these findings warrant further investigation in cohort studies.

The joint effect between fetal growth and health behaviors on the risk of cardiovascular diseases in young adulthood.

PURPOSE: To investigate the individual and the joint effect of impaired fetal growth and adult health behaviors on the risk of cardiovascular diseases (CVDs). METHODS: A total of 15,618 individuals were included from three sub-cohorts of the Stockholm Public Health Cohort. Data on participants' birthweight and gestational age were retrieved from the Medical Birth Register. Data on the diagnoses of CVDs were extracted from the Swedish National Patient Register and the Cause of Death Register. Data on health behaviors were identified from self-reported questionnaires, and health behavioral profile was defined based on the recommendations of the American Health Association. The associations of fetal growth and health behaviors with the risk of CVDs were analyzed using Cox proportional hazard model. RESULTS: Individuals born small for gestational age (SGA) had a higher risk of CVDs than those born appropriate for gestational age (AGA), and the adjusted hazard ratio (HR) and 95% confidence interval (CI) was 1.88 (1.44, 2.47). Participants born SGA and having poor health behavioral profile in adulthood had a higher risk of CVDs than those born AGA and having ideal health behaviors with adjusted HR (95% CI) being 3.58 (1.95, 6.56). CONCLUSIONS: Impaired fetal growth was associated with an increased risk of CVDs in adulthood, and the risk was highest in individuals with both impaired fetal growth and poor health behaviors in adulthood.

Genome-wide identification and expression reveal the involvement of the FCS-like zinc finger (FLZ) gene family in Gossypium hirsutum at low temperature.

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.

Comorbidity in patients with first-ever ischemic stroke: Disease patterns and their associations with cognitive and physical function.

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%, P < 0.001). Exploratory factor analysis identified three patterns of comorbidity, i.e., patterns of degenerative-cardiopulmonary, heart-gastrointestinal-psychiatric, and metabolic-kidney diseases. The number of comorbidities was significantly associated with a higher likelihood of moderate-to-severe physical dependence [odds ratio (95% CI) = 1.15 (1.06-1.25) for BI and 1.12 (1.04-1.21) for mRS, all P < 0.01] and cognitive impairment [odds ratio (95% CI) = 1.11 (1.02-1.20), P = 0.017], after adjusting for multiple covariates. Almost all the three comorbidity patterns were associated with increased likelihoods of physical dependence (range for odds ratios: 1.26-1.33) and cognitive impairment (range for odds ratios: 1.25-1.34). No significant association was found between degenerative-cardiopulmonary pattern and mRS. These findings suggest that comorbidity is associated with poor physical and cognitive functioning during the acute phase of ischemic stroke. Routine assessments of comorbidity and cognitive and physical function among patients with acute ischemic stroke should be considered in stroke research and clinical practice.

IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer.

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 ß (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.

Whole Transcriptome Sequencing Reveals Drought Resistance-Related Genes in Upland Cotton.

China, particularly the cotton-growing province of Xinjiang, is experiencing acute agricultural water shortages, stifling the expansion of the cotton sector. Discovering drought resistance genes in cotton and generating high-quality, drought-resistant cotton varieties through molecular breeding procedures are therefore critical to the cotton industry's success. The drought-resistant cotton variety Xinluzhong No. 82 and the drought-sensitive cotton variety Kexin No. 1 were utilised in this study to uncover a batch of drought-resistant candidate genes using whole transcriptome sequencing. The following are the key research findings: A competing endogenous RNA network (ceRNA) was built using complete transcriptional sequencing to screen the core genes in the core pathway, and two drought-related candidate genes were discovered. It was found that γ-aminobutyric acid aminotransferase (GhGABA-T, Gohir.A11G156000) was upregulated at 0 h vs. 12 h and downregulated at 12 h vs. 24 h. L-Aspartate oxidase (GhAO, Gohir.A07G220600) was downregulated at 0 h vs. 12 h and upregulated at 12 h vs. 24 h. GABA-T is analogous to a pyridoxal phosphate-dependent transferase superfamily protein (POP2) in Arabidopsis thaliana and influences plant drought resistance by controlling γ-aminobutyric acid (GABA) concentration. The analogue of GhAO in A. thaliana is involved in the early steps of nicotinamide adenine dinucleotide (NAD) production as well as in plant antioxidant responses. This study revealed that gene expression regulatory networks can be used for rapid screening of reliable drought resistance genes and then utilised to validate gene function.

Metabolic syndrome in patients with first-ever ischemic stroke: prevalence and association with coronary heart disease.

The metabolic syndrome (MetS) has been well linked with coronary heart disease (CHD) in the general population, but studies have rarely explored their association among patients with stroke. We examine prevalence of MetS and its association with CHD in patients with first-ever ischemic stroke. This hospital-based study included 1851 patients with first-ever ischemic stroke (mean age 61.2 years, 36.5% women) who were hospitalized into two university hospitals in Shandong, China (January 2016-February 2017). Data were collected through interviews, physical examinations, and laboratory tests. MetS was defined following the National Cholesterol Education Program (NCEP) criteria, the International Diabetes Federation (IDF) criteria, and the Chinese Diabetes Society (CDS) criteria. CHD was defined following clinical criteria. Data were analyzed using binary logistic regression models. The overall prevalence of MetS was 33.4% by NECP criteria, 47.2% by IDF criteria, and 32.5% by CDS criteria, with the prevalence being decreased with age and higher in women than in men (p < 0.05). High blood pressure, high triglycerides, and low HDL-C were significantly associated with CHD (multi-adjusted odds ratio [OR] range 1.27-1.38, p < 0.05). The multi-adjusted OR of CHD associated with MetS defined by the NECP criteria, IDF criteria, and CDS criteria (vs. no MetS) was 1.27 (95% confidence interval 1.03-1.57), 1.44 (1.18-1.76), and 1.27 (1.03-1.57), respectively. In addition, having 1-2 abnormal components (vs. none) of MetS was associated with CHD (multi-adjusted OR range 1.66-1.72, p < 0.05). MetS affects over one-third of patients with first-ever ischemic stroke. MetS is associated with an increased likelihood of CHD in stroke patients.

Short-Term Risk of Unintentional Poisoning After New Initiation of Central Nervous System Medications in Swedish Older Adults: A Register-Based Case-Crossover Study.

INTRODUCTION: 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. OBJECTIVE: This study aims to determine the short-term association between newly prescribed CNS drugs and unintentional poisoning. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Association of Cardiovascular Health Metrics with Dementia in Rural Chinese Older Adults: A Population-Based Study.

Purpose: We explore the associations of individual and composite cardiovascular health metrics with all-cause dementia, Alzheimer's disease, and vascular dementia among rural-dwelling older adults and the potential age variations in their associations. Patients and Methods: This community-based cross-sectional study included 4980 older adults (age ≥65 years; 57.23% women) from the baseline examination of MIND-China. In March-September 2018, data were collected via face-to-face interviews, clinical examinations, and laboratory test. We defined six cardiovascular health metrics according to the modified American Heart Association's recommendations. We diagnosed dementia and its subtypes following the international criteria. Data were analyzed using logistic regression models. Results: Of all the participants, 250 were diagnosed with dementia, including 165 with Alzheimer's disease and 75 with vascular dementia. Ideal composite global cardiovascular health metrics (vs poor composite metrics) were associated with a multi-adjusted odds ratio (95% confidence interval) of 0.62 (0.42-0.93) for dementia, 0.88 (0.52-1.48) for Alzheimer's disease, and 0.31 (0.16-0.60) for vascular dementia. Moreover, ideal biological cardiovascular health metrics were associated with multi-adjusted odds ratio of 0.52 (0.28-0.95) for dementia and 0.21 (0.06-0.77) for vascular dementia in young-old adults (65-74 years), whereas ideal behavioral cardiovascular health metrics were associated with multi-adjusted odds ratio of 0.48 (0.26-0.89) for dementia and 0.16 (0.06-0.43) for vascular dementia in old-old adults (≥75 years). Conclusion: Our results suggest that ideal cardiovascular health metrics are cross-sectionally associated with a low likelihood of dementia and vascular dementia among rural-dwelling older Chinese adults. The associations vary with age, components of cardiovascular health metrics, and dementia subtypes.

Newly initiated cardiovascular medication and short-term risk of unintentional poisoning among Swedish middle-aged and older adults: A national register-based case-crossover study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Migraine, Cognitive Decline, and Dementia in Older Adults: A Population-Based Study.

BACKGROUND: The potential impact of migraine on cognitive aging among older adults remains controversial. OBJECTIVE: To examine the relationship of migraine and subtypes with cognitive decline and dementia in an older Swedish population. METHODS: This population-based study included 3,069 participants (age ≥ 60 years) from the Swedish National study on Aging and Care in Kungsholmen, Stockholm. Baseline examination was conducted in 2001-2004, and participants were followed every 3 or 6 years until 2013-2016. Data were collected through face-to-face interviews, clinical examinations, laboratory tests, and linkage with registers. Global cognitive function was measured with the Mini-Mental State Examination (MMSE). Dementia was diagnosed according to the DSM-IV criteria. Migraine and subtypes were defined following the international classification system. Data were analyzed using logistic regression, Cox regression, and linear mixed-effects models. RESULTS: At baseline, 305 participants were defined with non-migraine headache and 352 with migraine. The cross-sectional analysis showed that the multivariable-adjusted odds ratio (95% confidence interval) of prevalent dementia was 0.49 (0.20-1.21) for migraine and 0.66 (0.26-1.66) for migraine without aura. The longitudinal analysis showed that the multivariable-adjusted hazard ratios of incident dementia associated with migraine and subtypes ranged 0.68-0.89 (p > 0.05). Furthermore, migraine and subtypes were not significantly associated with either baseline MMSE score or MMSE changes during follow-ups (p > 0.05). The nonsignificant associations did not vary substantially by age, APOEɛ4 allele, cerebrovascular disease, and antimigraine treatment (p for interactions > 0.05). CONCLUSION: This study shows no evidence supporting the associations of migraine and its subtypes with cognitive decline and dementia among older adults.

Geriatric syndromes and subsequent health-care utilization among older community dwellers in Stockholm.

Little is known about the long-term effect of geriatric syndromes on health-care utilization. This study aims to determine the association between geriatric syndromes and health-care utilization during a four-year period among older community dwellers. Based on the Stockholm Public Health Cohort study, a total number of 6700 community dwellers aged ≥65 years were included. From a baseline survey in 2006, geriatric syndromes were defined as having at least one of the following: insomnia, functional decline, urinary incontinence, depressive symptoms and vision impairment. Health-care utilization was identified by linkages at individual level with register data with a four-year follow-up. Cox regression was performed to estimate the associations. Compared to those without geriatric syndromes, participants with any geriatric syndromes had a higher prevalence of frequent hospitalizations, long hospital stays, frequent outpatient visits and polypharmacy in each of the follow-up years. After controlling for covariates, having any geriatric syndromes was associated with higher levels of utilization of inpatient and outpatient care as well as polypharmacy. The association was stable over time, and the fully adjusted hazard ratio (95% confidence interval) remained stable in frequent hospitalizations (from 1.89 [1.31, 2.73] in year 1 to 1.70 [1.23, 2.35] in year 4), long hospital stay (from 1.75 [1.41, 2.16] to 1.49 [1.24, 1.78]), frequent outpatient visits (from 1.40 [1.26, 1.54] to 1.33 [1.22, 1.46]) and polypharmacy (from 1.63 [1.46, 1.83] to 1.53 [1.37, 1.71]). Having any geriatric syndromes is associated with higher levels of health-care utilization among older community dwellers, and the impact of geriatric syndromes is stable over a four-year period. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at. 10.1007/s10433-021-00600-2.

Association of Preeclampsia and Perinatal Complications With Offspring Neurodevelopmental and Psychiatric 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.

Geriatric Syndromes and Incident Chronic Health Conditions Among 9094 Older Community-Dwellers: Findings from the Lifelines Cohort Study.

OBJECTIVES: To determine the association between geriatric syndromes and any specific incident chronic health conditions among older community-dwellers. DESIGN: Population-based cohort study over a median follow-up period of 43 months. SETTING AND PARTICIPANTS: Participants from the Lifelines Cohort Study aged 60 years and older without presence of the studied chronic health conditions at baseline (n = 9094). METHODS: Baseline assessment took place between November 2006 and December 2013 and included information on socioeconomic (age, sex, level of education and income), social contact, and health-related factors [eg, self-rated health, body mass index, chronic health conditions, and health behavior (alcohol consumption and smoking)]. Participants also reported the presence of geriatric syndromes (ie, included falls, incontinence, vision impairment, hearing impairment, depressive symptoms, and frailty at baseline). Three follow-up questionnaires were used to examine the incidence of any and specific chronic health conditions (ie, pulmonary and cardiovascular diseases, diabetes, cancer, and neurological diseases). Cox regression was used to analyze the longitudinal associations between geriatric syndromes and incident chronic health conditions. RESULTS: Older community-dwelling individuals with at least one geriatric syndrome (44.7%, n = 4038) had an increased risk of developing any new chronic health condition [hazard ratio (HR) 1.35; 95% confidence interval (CI) 1.21-1.51]. The association was attenuated but remained significant after adjustment for socioeconomic factors, social contact, health status, and health behavior (HR 1.27; 95% CI 1.12-1.43). Analyses for specific chronic health conditions showed that compared with older community-dwellers without geriatric syndromes, those with geriatric syndromes had an increased risk to develop a cardiovascular health condition (HR 1.42; 95% CI 1.13-1.79) or diabetes (HR 1.53; 95% CI 1.11-2.11). They had no increased risk to develop pulmonary conditions, cancer, or neurological conditions. CONCLUSION AND IMPLICATIONS: The presence of geriatric syndromes is associated with incident chronic health conditions, specifically cardiovascular conditions and diabetes. Increased awareness is needed among older people with geriatric syndromes and their physicians. Comprehensive assessments of geriatric syndromes may help to prevent or at least delay the development of chronic health conditions.

Analysis of the genetic structure and diversity of upland cotton groups in different planting areas based on SNP markers.

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, adopt 273 elite upland cotton cultivar accessions collected from around the world, and especially from China to get 1,313,331 SNP molecular markers, it 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.

The Association between Apparent Temperature and Hospital Admissions for Cardiovascular Disease in Limpopo Province, South Africa.

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 (Tapp) 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 Tapp 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 Tapp, i.e., cold (6-25 °C) and warm (27-32 °C) Tapp was reported. We found an increase in the proportion of admissions due to CVDs for warm and cold Tapp cumulatively over 21 days. Increasing CVD admissions due to warm Tapp 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 Tapp may increase CVD admissions, suggesting that the healthcare system and community need to be prepared in the context of global temperature changes.

CST6 protein and peptides inhibit breast cancer bone metastasis by suppressing CTSB activity and osteoclastogenesis.

Background: Bone metastasis is a frequent symptom of breast cancer and current targeted therapy has limited efficacy. Osteoclasts play critical roles to drive osteolysis and metastatic outgrowth of tumor cells in bone. Previously we identified CST6 as a secretory protein significantly downregulated in bone-metastatic breast cancer cells. Functional analysis showed that CST6 suppresses breast-to-bone metastasis in animal models. However, the functional mechanism and therapeutic potential of CST6 in bone metastasis is unknown. Methods: Using in vitro osteoclastogenesis and in vivo metastasis assays, we studied the effect and mechanism of extracellular CST6 protein in suppressing osteoclastic niches and bone metastasis of breast cancer. A number of peptides containing the functional domain of CST6 were screened to inhibit bone metastasis. The efficacy, stability and toxicity of CST6 recombinant protein and peptides were evaluated in preclinical metastasis models. Results: We show here that CST6 inhibits osteolytic bone metastasis by inhibiting osteoclastogenesis. Cancer cell-derived CST6 enters osteoclasts by endocytosis and suppresses the cysteine protease CTSB, leading to up-regulation of the CTSB hydrolytic substrate SPHK1. SPHK1 suppresses osteoclast maturation by inhibiting the RANKL-induced p38 activation. Importantly, recombinant CST6 protein effectively suppresses bone metastasis in vitro and in vivo. We further identified several peptides mimicking the function of CST6 to suppress cancer cell-induced osteoclastogenesis and bone metastasis. Pre-clinical analyses of CTS6 recombinant protein and peptides demonstrated their potentials in treatment of breast cancer bone metastasis. Conclusion: These findings reveal the CST6-CTSB-SPHK1 signaling axis in osteoclast differentiation and provide a promising approach to treat bone diseases with CST6-based peptides.

Nanopore-Based Comparative Transcriptome Analysis Reveals the Potential Mechanism of High-Temperature Tolerance in Cotton (Gossypium hirsutum L.).

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.

Exercise downregulates HIPK2 and HIPK2 inhibition protects against myocardial infarction.

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).