Descending dopaminergic pathway facilitates itch signal processing via activating spinal GRPR+ neurons.

A11 dopaminergic neurons regulate somatosensory transduction by projecting from the diencephalon to the spinal cord, but the function of this descending projection in itch remained elusive. Here, we report that dopaminergic projection neurons from the A11 nucleus to the spinal dorsal horn (dopaminergicA11-SDH ) are activated by pruritogens. Inhibition of these neurons alleviates itch-induced scratching behaviors. Furthermore, chemogenetic inhibition of spinal dopamine receptor D1-expressing (DRD1+ ) neurons decreases acute or chronic itch-induced scratching. Mechanistically, spinal DRD1+ neurons are excitatory and mostly co-localize with gastrin-releasing peptide (GRP), an endogenous neuropeptide for itch. In addition, DRD1+ neurons form synapses with GRP receptor-expressing (GRPR+ ) neurons and activate these neurons via AMPA receptor (AMPAR). Finally, spontaneous itch and enhanced acute itch induced by activating spinal DRD1+ neurons are relieved by antagonists against AMPAR and GRPR. Thus, the descending dopaminergic pathway facilitates spinal itch transmission via activating DRD1+ neurons and releasing glutamate and GRP, which directly augments GRPR signaling. Interruption of this descending pathway may be used to treat chronic itch.

LIPUS regulates the progression of knee osteoarthritis in mice through primary cilia-mediated TRPV4 channels.

Osteoarthritis (OA) is a common disease in middle-aged and elderly people. An imbalance in calcium ion homeostasis will contribute to chondrocyte apoptosis and ultimately lead to the progression of OA. Transient receptor potential channel 4 (TRPV4) is involved in the regulation of intracellular calcium homeostasis. TRPV4 is expressed in primary cilia, which can sense mechanical stimuli from outside the cell, and its abnormal expression is closely related to the development of OA. Low-intensity pulsed ultrasound (LIPUS) can alleviate chondrocyte apoptosis while the exact mechanism is unclear. In this project, with the aim of revealing the mechanism of action of LIPUS, we proposed to use OA chondrocytes and animal models, LIPUS intervention, inhibition of primary cilia, use TRPV4 inhibitors or TRPV4 agonist, and use Immunofluorescence (IF), Immunohistochemistry (IHC), Western Blot (WB), Quantitative Real-time PCR (QP) to detect the expression of cartilage synthetic matrix and endoplasmic reticulum stress markers. The results revealed that LIPUS altered primary cilia expression, promoted synthetic matrix metabolism in articular chondrocytes and was associated with primary cilia. In addition, LIPUS exerted a active effect on OA by activating TRPV4, inducing calcium inward flow, and facilitating the entry of NF-κB into the nucleus to regulate synthetic matrix gene transcription. Inhibition of TRPV4 altered primary cilia expression in response to LIPUS stimulation, and knockdown of primary cilia similarly inhibited TRPV4 function. These results suggest that LIPUS mediates TRPV4 channels through primary cilia to regulate the process of knee osteoarthritis in mice.

Polyphyllin I Sensitizes Cisplatin-Resistant Human Cervical Cancer Cells to Cisplatin Treatment.

Cervical cancer (CC) is a common gynecological malignancy, and improving cisplatin sensitivity has become a hot topic in CC chemotherapy research. Polyphyllin I (PPI), a potent bioactive compound found in Rhizoma Paridis, known for its anticancer properties, remains underexplored in CC resistance. In this study, we evaluated PPI's impact on cisplatin-resistant CC cells and elucidated its underlying mechanism. Our findings reveal that PPI enhances the sensitivity of cisplatin-resistant CC cells to the drug, promotes apoptosis, and inhibits cell migration. Mechanistically, PPI was found to regulate p53 expression and its target genes, and suppressing p53 expression reverses PPI's sensitizing effect in drug-resistant CC cells. In conclusion, PPI showed promise in sensitizing cisplatin-resistant human CC cells to cisplatin treatment, suggesting that it could serve as a potent adjunct therapy for cervical cancer, particularly for cases that have developed resistance to cisplatin, thereby providing a promising basis for further clinical investigation into PPI for enhancing the efficacy of existing chemotherapy regimens in resistant cervical cancer.

Comparative analysis of hospitalization risk for incident heart failure in non-Hispanic Black versus non-Hispanic White individuals with type 2 diabetes on empagliflozin (Empa-AA): Insights from real-world data.

AIM: There are limited data to evaluate hospitalization for heart failure (hHF) in non-Hispanic Black (hereafter Black) or non-Hispanic White (hereafter White) individuals without previous hHF. Our goal was to evaluate the risk of hHF among Black versus White patients with type 2 diabetes (T2DM) who were initially prescribed empagliflozin using real-world data. METHODS: This multicentre retrospective cohort study included participants aged ≥18 years who had T2DM, were either Black or White, had no previous hHF, and were prescribed empagliflozin between August 2014 and December 2019. Our primary outcome was time to first hHF after the initial prescription of empagliflozin. A propensity-score (PS)-weighted analysis was performed to balance characteristics by race. The inverse probability treatment weighting method based on PS was used to make treatment comparisons. To compare Black with White, a PS-weighted Cox's cause-specific hazards model was used. RESULTS: In total, 8789 participants were eligible for inclusion (Black = 3216 vs. White = 5573). The Black cohort was significantly younger, had a higher proportion of females, and had a higher prevalence of chronic kidney disease, hypertension and diabetic retinopathy, while the White cohort had a higher prevalence of coronary artery disease. After adjustment for confounding factors such as age, gender, coronary artery disease, hypertension and diabetic retinopathy, the hazard ratio for first-time hHF was not significantly different between the two racial groups [hazard ratio (95% confidence interval) = 1.09 (0.84-1.42), p = .52]. CONCLUSION: This study showed no significant difference in incident hHF among Black versus White individuals with T2DM following a prescription for empagliflozin.

Racial Differences in Stage IV Colorectal Cancer Molecular Profiling and Mutation Rates.

INTRODUCTION: Despite advances in colorectal cancer (CRC) treatment, racial disparities persist. The primary aims of the study were to: evaluate differences in molecular testing rates over time by race; and measure the incidence of tumor mutations by race in patients with metastatic CRC. METHODS: A retrospective cohort study was performed of all adult patients with stage IV CRC (2008-2018) identified within the cancer registry of a large regional health system. Demographic/clinical characteristics were collected through primary data abstraction of the electronic health record. Molecular profiling results were obtained directly from Caris Molecular Intelligence and electronic health record. RESULTS: Three hundred eighty-three patients were included: 40.5% (n = 155) were Black and 59.5% (n = 228) were White. Significant increases were observed in microsatellite instability (MSI), KRAS, and BRAF testing rates during the study period (P < 0.0001). The odds of testing over time increased more significantly in Black compared to White patients for MSI testing (White: odds ratio [OR] 1.26 [95% confidence interval [CI] 1.12-1.41], Black: OR 1.69 [95% CI 1.41-2.02], P = 0.005) and BRAF testing (White: OR 1.42 [95% CI 1.26-1.62], Black: OR 1.89 [95% CI 1.51-2.36], P = 0.027). An increase in KRAS testing over time was observed for both cohorts and was independent of race (P = 0.58). Mutation rates did not differ by race: KRAS (Black 55.8% versus White 45.6%, P = 0.13) and BRAF (Black 4.8% versus White 10.0%, P = 0.33). CONCLUSIONS: Within a large regional health system, molecular testing rates in patients with metastatic CRC increased significantly following National Comprehensive Cancer Network guideline changes for both Black and White patients. Black and White patients who underwent molecular testing had similar rates of MSI, KRAS, and BRAF mutations.

Built environment and loneliness in later life: productive engagement as the pathway.

OBJECTIVES: The built environment is increasingly recognized as being associated with late-life loneliness. However, the pathway remains understudied. This study investigated the mediating effects of productive engagement in relationships between the built environment and loneliness. METHODS: We conducted a cross-sectional analysis of data from 4,409 community-dwelling people aged 65 years and above in China. We employed the Chinese version of the De Jong Gierveld Loneliness Scale to assess loneliness. The built environment comprises residential density, street connectivity, park-based and vegetation-based green space, land use mix, and the number of and distance to the nearest recreational, health, shopping and community services within 300-meter and 500-meter buffer areas. Structural equation modeling was used. RESULTS: Only green space (parks) had a direct effect on loneliness. Residential density and green space (parks) had an indirect effect on loneliness through volunteering. The number of recreational services had an indirect effect on loneliness through recreational and sporting activities, although distance to the nearest recreational services did not. All the significant results were only found within 300-meter rather than 500-meter buffers. CONCLUSIONS: Our findings have implications for environmental gerontology theory and practice. Providing more green space and recreational services can significantly improve older adults' helping behavior, social activities and sporting activities, which can further reduce older adults' loneliness.

Seeds Priming with Melatonin Improves Root Hydraulic Conductivity of Wheat Varieties under Drought, Salinity, and Combined Stress.

Drought and salinity stress reduce root hydraulic conductivity of plant seedlings, and melatonin application positively mitigates stress-induced damage. However, the underlying effect of melatonin priming on root hydraulic conductivity of seedlings under drought-salinity combined remains greatly unclear. In the current report, we investigated the influence of seeds of three wheat lines' 12 h priming with 100 µM of melatonin on root hydraulic conductivity (Lpr) and relevant physiological indicators of seedlings under PEG, NaCl, and PEG + NaCl combined stress. A previous study found that the combined PEG and NaCl stress remarkably reduced the Lpr of three wheat varieties, and its value could not be detected. Melatonin priming mitigated the adverse effects of combined PEG + NaCl stress on Lpr of H4399, Y1212, and X19 to 0.0071 mL·h-1·MPa-1, 0.2477 mL·h-1·MPa-1, and 0.4444 mL·h-1·MPa-1, respectively, by modulating translation levels of aquaporin genes and contributed root elongation and seedlings growth. The root length of H4399, Y1212, and X19 was increased by 129.07%, 141.64%, and 497.58%, respectively, after seeds pre-treatment with melatonin under PEG + NaCl combined stress. Melatonin -priming appreciably regulated antioxidant enzyme activities, reduced accumulation of osmotic regulators, decreased levels of malondialdehyde (MDA), and increased K+ content in stems and root of H4399, Y1212, and X19 under PEG + NaCl stress. The path investigation displayed that seeds primed with melatonin altered the modification of the path relationship between Lpr and leaf area under stress. The present study suggested that melatonin priming was a strategy as regards the enhancement of root hydraulic conductivity under PEG, NaCl, and PEG + NaCl stress, which efficiently enhanced wheat resistant to drought-salinity stress.

Betaine Alleviates High-Fat Diet Induced Excessive Lipid Deposition in Gibel Carp Hepatopancreas and L8824 Cells by Enhancing VLDL Secretion through HNF4α/MTTP Pathway.

Betaine, a methyl donor, plays a crucial role in lipid metabolism. Previous studies have shown that appropriate betaine supplementation in a high-fat diet reduces triglycerides (TG) of serum and hepatopancreas in fish. However, the underlying mechanism remains unclear. This study examined whether betaine can enhance the secretion of very low-density lipoprotein (VLDL) and sought to identify the specific mechanisms through which this enhancement occurs. A lipid accumulation model was established in gibel carp and L8824 cells using a high-fat diet and oleic acid, respectively. Different doses of betaine (1, 4, and 16 g/kg in the diet; 400 µmol in cell culture) were administered, and measurements were taken for lipid deposition, gene expression of HNF4α, MTTP, and ApoB, as well as the regulation of Mttp and Apob promoters by HNF4α. The results showed that betaine supplementation mitigated lipid droplet accumulation, TG levels, and VLDL production induced by the high-fat diet in gibel carp hepatopancreas and L8824 cells. Moreover, betaine not only increased VLDL content in the cell culture supernatant but also reversed the inhibitory effects of the high-fat diet on protein expression of MTTP, ApoB, and HNF4α in both gibel carp hepatopancreas and L8824 cells. Additionally, HNF4α exhibits transactivating activity on the promoter of Mttp in gibel carp. These findings suggest that betaine supplementation exerts its effects through the HNF4α/MTTP/ApoB pathway, promoting the assembly and secretion of VLDL and effectively reducing lipid accumulation in the hepatopancreas of farmed gibel carp fed a high-fat diet.

Ciona embryonic tail bending is driven by asymmetrical notochord contractility and coordinated by epithelial proliferation.

Ventral bending of the embryonic tail within the chorion is an evolutionarily conserved morphogenetic event in both invertebrates and vertebrates. However, the complexity of the anatomical structure of vertebrate embryos makes it difficult to experimentally identify the mechanisms underlying embryonic folding. This study investigated the mechanisms underlying embryonic tail bending in chordates. To further understand the mechanical role of each tissue, we also developed a physical model with experimentally measured parameters to simulate embryonic tail bending. Actomyosin asymmetrically accumulated at the ventral side of the notochord, and cell proliferation of the dorsal tail epidermis was faster than that in the ventral counterpart during embryonic tail bending. Genetic disruption of actomyosin activity and inhibition of cell proliferation dorsally caused abnormal tail bending, indicating that both asymmetrical actomyosin contractility in the notochord and the discrepancy of epidermis cell proliferation are required for tail bending. In addition, asymmetrical notochord contractility was sufficient to drive embryonic tail bending, whereas differential epidermis proliferation was a passive response to mechanical forces. These findings showed that asymmetrical notochord contractility coordinates with differential epidermis proliferation mechanisms to drive embryonic tail bending.This article has an associated 'The people behind the papers' interview.

Regulatory effects of silicon nanoparticles on the growth and photosynthesis of cotton seedlings under salt and low-temperature dual stress.

BACKGROUND: Silicon nanoparticles (SiO2-NPs) play a crucial role in plants mitigating abiotic stress. However, the regulatory mechanism of SiO2-NPs in response to multiple stress remains unclear. The objectives of this study were to reveal the regulatory mechanism of SiO2-NPs on the growth and photosynthesis in cotton seedlings under salt and low-temperature dual stress. It will provide a theoretical basis for perfecting the mechanism of crop resistance and developing the technology of cotton seedling preservation and stable yield in arid and high salt areas. RESULTS: The results showed that the salt and low-temperature dual stress markedly decreased the plant height, leaf area, and aboveground biomass of cotton seedlings by 9.58%, 15.76%, and 39.80%, respectively. While SiO2-NPs alleviated the damage of the dual stress to cotton seedling growth. In addition to reduced intercellular CO2 concentration, SiO2-NPs significantly improved the photosynthetic rate, stomatal conductance, and transpiration rate of cotton seedling leaves. Additionally, stomatal length, stomatal width, and stomatal density increased with the increase in SiO2-NPs concentration. Notably, SiO2-NPs not only enhanced chlorophyll a, chlorophyll b, and total chlorophyll content, but also slowed the decrease of maximum photochemical efficiency, actual photochemical efficiency, photochemical quenching of variable chlorophyll, and the increase in non-photochemical quenching. Moreover, SiO2-NPs enhanced the activities of ribulose-1,5-bisphosphate carboxylase/oxygenase and phosphoenolpyruvate carboxylase, improved leaf water potential, and decreased abscisic acid and malondialdehyde content. All the parameters obtained the optimal effects at a SiO2-NPs concentration of 100 mg L- 1, and significantly increased the plant height, leaf area, and aboveground biomass by 7.68%, 5.37%, and 43.00%, respectively. Furthermore, significant correlation relationships were observed between photosynthetic rate and stomatal conductance, stomatal length, stomatal width, stomatal density, chlorophyll content, maximum photochemical efficiency, actual photochemical efficiency, photochemical quenching of variable chlorophyll, and Rubisco activity. CONCLUSION: The results suggested that the SiO2-NPs improved the growth and photosynthesis of cotton seedlings might mainly result from regulating the stomatal state, improving the light energy utilization efficiency and electron transport activity of PSII reaction center, and inducing the increase of Rubisco activity to enhance carbon assimilation under the salt and low-temperature dual stress.

Downregulation of HHLA2 inhibits ovarian cancer progression via the NF-κB signaling pathway and suppresses the expression of CA9.

HHLA2 has been recently demonstrated to play multifaceted roles in several types of cancers. However, its underlying mechanism in the progression of human ovarian cancer (OC) remains largely unexplored. In the present study, we aimed to determine whether downregulation of HHLA2 inhibited malignant phenotypes of human OC cells and explore its specific mechanism. Our results revealed that downregulation of HHLA2 by transfection with a lentiviral vector significantly suppressed the viability, invasion, and migration of OC cells. Interaction study showed that downregulation of HHLA2 in OC cells reduced the expression of CA9 and increased the expressions of p-IKKß and p-RelA. Conversely, the viability, invasion, and migration of HHLA2-depleted OC cells were increased when CA9 was upregulated. In vivo, we found that downregulation of HHLA2 significantly inhibited tumor growth, which was reversed by CA9 overexpression. In addition, downregulation of HHLA2 inhibited the OC progression via activating the NF-κB signaling pathway and decreasing the expression of CA9. Collectively, our data suggested a link between HHLA2 and NF-κB axis in the pathogenesis of OC, and these findings might provide valuable insights into the development of novel potential therapeutic targets for OC.

Long-term effects of childhood adversity on the subjective well-being of older adults in urban China: the mediating effect of elder abuse.

Adverse childhood experiences (ACEs) have negative impacts on individuals' subjective well-being (SWB) in later life. This article investigates the relationships between the ACEs and SWB of Chinese older adults and examines how elder abuse victimization mediates the pathways in these relationships.We used retrospective cross-sectional survey data collected in Beijing, China, in 2019. The study sample consists of 1002 older adults aged 65 years and over. The survey measured individual types, number, and various categories of ACEs of older adults and their elder abuse victimization experiences, along with their SWB (i.e. depression and life satisfaction). We tested the potential mediating role of elder abuse victimization in the relationships between ACEs and SWB.After controlling for socio-demographic factors and self-rated health, the results suggest a full mediating effect of elder abuse on the relationship between both several individual types and multiple categories of ACEs (i.e. childhood victimization, the family's economic difficulties, and a family member's episodes of illness) and depression, in addition to a partial mediating effect of elder abuse between number of ACEs and depression. A full mediating effect of elder abuse was found in regard to the relationship between a family's economic difficulties and life satisfaction.This study provides evidence for a long-term impact of ACEs on the SWB of older adults in China. In analyzing and understanding elder abuse victimization as a pathway linking ACEs and SWB, we stress the importance of the prevention of interpersonal violence across the life course.Supplemental data for this article is available online at https://doi.org/10.1080/13607863.2022.2040427 .

Association between internet use and depressive symptoms among older adults: mediating role of daytime napping and moderating role of productive engagement.

OBJECTIVES: This study investigated the mediating role of daytime napping in the relationship between internet use and depressive symptoms among older adults. Further the moderating effect of productive engagement was assessed on the linkage between internet use and depressive symptoms. METHODS: We surveyed 956 Chinese community-dwelling older adults. Respondents reported their internet use for different purposes (social, informational, and instrumental use), rated their levels of depressive symptoms and of daytime napping, and reported different types of/overall productive engagement. We conducted mediation and moderation analyses to test the potential pathways of associations among those factors. RESULTS: Daytime napping mediated the association between social and informational internet use and depressive symptoms. Family caregiving, sporting activities, and overall productive engagement each moderated the relationship between internet use and depressive symptoms. CONCLUSION: Internet use can increase the risk of depressive symptoms in older adults by increasing daytime napping. However, the benefits of internet use can be particularly salient for those who have a low level of productive engagement. The findings have implications for policies and practices that are designed to help older adults access the internet to enhance well-being.

Identification and Characterization of 5-HT Receptor 1 from Scylla paramamosain: The Essential Roles of 5-HT and Its Receptor Gene during Aggressive Behavior in Crab Species.

Biogenic amines (BAs) play an important role in the aggressive behavior of crustaceans. In mammals and birds, 5-HT and its receptor genes (5-HTRs) are characterized as essential regulators involved in neural signaling pathways during aggressive behavior. However, only one 5-HTR transcript has been reported in crabs. In this study, the full-length cDNA of the 5-HTR1 gene, named Sp5-HTR1, was first isolated from the muscle of the mud crab Scylla paramamosain using the reverse-transcription polymerase chain reaction (RT-PCR) and rapid-amplification of cDNA ends (RACE) methods. The transcript encoded a peptide of 587 amino acid residues with a molecular mass of 63.36 kDa. Western blot results indicate that the 5-HTR1 protein was expressed at the highest level in the thoracic ganglion. Furthermore, the results of quantitative real-time PCR show that the expression levels of Sp5-HTR1 in the ganglion at 0.5, 1, 2, and 4 h after 5-HT injection were significantly upregulated compared with the control group (p < 0.05). Meanwhile, the behavioral changes in 5-HT-injected crabs were analyzed with EthoVision. After 0.5 h of injection, the speed and movement distance of the crab, the duration of aggressive behavior, and the intensity of aggressiveness in the low-5-HT-concentration injection group were significantly higher than those in the saline-injection and control groups (p < 0.05). In this study, we found that the Sp5-HTR1 gene plays a role in the regulation of aggressive behavior by BAs, including 5-HT in the mud crab. The results provide reference data for the analysis of the genetic mechanism of aggressive behaviors in crabs.

Ginsenoside Rh2 Ameliorates Neuropathic Pain by inhibition of the miRNA21-TLR8-mitogen-activated protein kinase axis.

Ginsenoside Rh2 is one of the major bioactive ginsenosides in Panax ginseng. Although Rh2 is known to enhance immune cells activity for treatment of cancer, its anti-inflammatory and neuroprotective effects have yet to be determined. In this study, we investigated the effects of Rh2 on spared nerve injury (SNI)-induced neuropathic pain and elucidated the potential mechanisms. We found that various doses of Rh2 intrathecal injection dose-dependently attenuated SNI-induced mechanical allodynia and thermal hyperalgesia. Rh2 also inhibited microglia and astrocyte activation in the spinal cord of a murine SNI model. Rh2 treatment inhibited SNI-induced increase of proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1 and IL-6. Expression of miRNA-21, an endogenous ligand of Toll like receptor (TLR)8 was also decreased. Rh2 treatment blocked the mitogen-activated protein kinase (MAPK) signaling pathway by inhibiting of phosphorylated extracellular signal-regulated kinase expression. Finally, intrathecal injection of TLR8 agonist VTX-2337 reversed the analgesic effect of Rh2. These results indicated that Rh2 relieved SNI-induced neuropathic pain via inhibiting the miRNA-21-TLR8-MAPK signaling pathway, thus providing a potential application of Rh2 in pain therapy.

Metagenomic analysis of rhizosphere microbiome provides insights into occurrence of iron deficiency chlorosis in field of Asian pears.

BACKGROUND: Fe-deficiency chlorosis (FDC) of Asian pear plants is widespread, but little is known about the association between the microbial communities in the rhizosphere soil and leaf chlorosis. The leaf mineral concentration, leaf subcellular structure, soil physiochemical properties, and bacterial species community and distribution had been analysed to gain insights into the FDC in Asian pear plant. RESULTS: The total Fe in leaves with Fe-deficiency was positively correlated with total K, Mg, S, Cu, Zn, Mo and Cl contents, but no differences of available Fe (AFe) were detected between the rhizosphere soil of chlorotic and normal plants. Degraded ribosomes and degraded thylakloid stacks in chloroplast were observed in chlorotic leaves. The annotated microbiome indicated that there were 5 kingdoms, 52 phyla, 94 classes, 206 orders, 404 families, 1,161 genera, and 3,043 species in the rhizosphere soil of chlorotic plants; it was one phylum less and one order, 11 families, 59 genera, and 313 species more than in that of normal plant. Bacterial community and distribution patterns in the rhizosphere soil of chlorotic plants were distinct from those of normal plants and the relative abundance and microbiome diversity were more stable in the rhizosphere soils of normal than in chlorotic plants. Three (Nitrospira defluvii, Gemmatirosa kalamazoonesis, and Sulfuricella denitrificans) of the top five species (N. defluvii, G. kalamazoonesis, S. denitrificans, Candidatus Nitrosoarchaeum koreensis, and Candidatus Koribacter versatilis). were the identical and aerobic in both rhizosphere soils, but their relative abundance decreased by 48, 37, and 22%, respectively, and two of them (G. aurantiaca and Ca. S. usitatus) were substituted by an ammonia-oxidizing soil archaeon, Ca. N. koreensis and a nitrite and nitrate reduction related species, Ca. K. versatilis in that of chlorotic plants, which indicated the adverse soil aeration in the rhizosphere soil of chlorotic plants. A water-impermeable tables was found to reduce the soil aeration, inhibit root growth, and cause some absorption root death from infection by Fusarium solani. CONCLUSIONS: It was waterlogging or/and poor drainage of the soil may inhibit Fe uptake not the amounts of AFe in the rhizosphere soil of chlorotic plants that caused FDC in this study.

Exome-Based Case-Control Analysis Highlights the Pathogenic Role of Ciliary Genes in Transposition of the Great Arteries.

RATIONALE: Transposition of the great arteries (TGA) is one of the most severe types of congenital heart diseases. Understanding the clinical characteristics and pathogenesis of TGA is, therefore, urgently needed for patient management of this severe disease. However, the clinical characteristics and genetic cause underlying TGA remain largely unexplored. OBJECTIVE: We sought to systematically examine the clinical characteristics and genetic cause for isolated nonsyndromic TGA. METHODS AND RESULTS: We recruited 249 patients with TGA (66 family trios) and performed whole-exome sequencing. The incidence of patent ductus arteriosus in dextro-TGA (52.7%) and dextrocardia/mesocardia in congenitally corrected TGA (32.8%) were significantly higher than that in other subtypes. A high prevalence of bicuspid pulmonic valve (9.6%) was observed in patients with TGA. Similar results were observed in a replication group of TGA (n=132). Through a series of bioinformatics filtering steps, we obtained 82 candidate genes harboring potentially damaging de novo, loss of function, compound heterozygous, or X-linked recessive variants. Established congenital heart disease-causing genes, such as FOXH1, were found among the list of candidate genes. A total of 19 ciliary genes harboring rare potentially damaging variants were also found; for example, DYNC2LI1 with a de novo putatively damaging variant. The enrichment of ciliary genes supports the roles of cilia in the pathogenesis of TGA. In total, 33% of the TGA probands had >1 candidate gene hit by putatively deleterious variants, suggesting that a portion of the TGA cases were probably affected by oligogenic or polygenic inheritance. CONCLUSIONS: The findings of clinical characteristic analyses have important implications for TGA patient stratification. The results of genetic analyses highlight the pathogenic role of ciliary genes and a complex genetic architecture underlying TGA.

Mechanisms connecting insomnia to hopelessness among Chinese older adults: Serial mediating roles of fatigue and social support.

BACKGROUND: Hopelessness and insomnia remain growing mental health issues worldwide, their relationship has been neglected by international development policies, especially in the countries with rapidly aging population like China. However, there is little conclusive evidence on the mechanisms through which insomnia severity influences hopelessness. Based on previous research regarding the significant associations among fatigue, social support, insomnia and hopelessness, this study aims to investigate the relationship between insomnia and hopelessness as well as how insomnia affects hopelessness through fatigue and social support. METHODS: A population-based data including 946 community-dwelling older adults extracted from "Elderly Care Household Survey in 2019" in Beijing were used. The age of the participants ranged from 66 to 97 years old, and 53.3% of the respondents were female. Intercorrelations among insomnia, fatigue, social support and hopelessness were examined. Serial multiple mediation models were analyzed by the bootstrapping method to assess whether fatigue and social support serially mediate the relationship between insomnia and hopelessness. RESULTS: Higher level of insomnia severity (coefficient = 0.0421, p < 0.001), higher level of fatigue (coefficient = 0.0171, p < 0.001), and lower level of social support (coefficient = -0.0320, p < 0.001) were significantly associated with higher level of hopelessness. Fatigue and social support in serial, mediated the relationship between insomnia and hopelessness (total effect: coefficient = 0.0623, 95% CI [0.0466, 0.0780]; total direct effect: coefficient = 0.0421, 95% CI [0.0262, 0.0581]; total indirect effect: coefficient = 0.0202, 95% CI [0.0147, 0.0272]). CONCLUSIONS: Improving sleep quality and eliminating fatigue could effectively alleviate the sense of hopelessness among Chinese older adults. In addition, establishing stronger social support brought by social network from family and friends could confer resilience against the negative effects of despair brought by insomnia. Our findings highlighted the mechanism connecting insomnia to hopelessness, which would inspire the future practice.

Productive engagement, sleep-wake disturbances, and loneliness: SEM analysis of depressive symptoms of community-dwelling Chinese elders.

OBJECTIVES: This study set out to examine the bidirectional relationship between loneliness and productive engagement, delineate the association between different dimensions of productive engagement and depression, and explore the potential mediating effect of sleep-wake disturbances in the relationship between loneliness and/or productive engagement and depression. METHOD: Data from a total of 4427 older adults in China were included in the analysis. Factor analysis was conducted to explore a set of discrete dimensions of productive engagement (recreational activities, group artistic and learning activities, sportive activities, paid work, volunteering, and family caregiving). Structural equation modeling was used to assess the potential relationships between loneliness, multidimensional productive engagement, sleep-wake disturbances, and depression. RESULTS: All dimensions of productive engagement were found to be negatively associated with loneliness, except for paid work which was associated with elevated level of self-reported loneliness. Sleep-wake disturbances mediated the relationship between leisure activities and depression but this was not significantly related to other forms of productive engagement. The direct effect of productive engagement on depression varied, in that leisure activities and family caregiving were negatively associated with depressive symptoms, while doing paid work was positively associated with depressive symptoms. Volunteering was not significantly related to depressive symptoms. DISCUSSION: This study makes an important contribution to the research on the relationship between loneliness, productive engagement, sleep-wake disturbances, and depression, by distinguishing the different effects of different dimensions of productive engagement. The findings provide a robust stimulus for intervention programs and other forms of social work practice seeking to mitigate depressive symptoms in older adults.

Determination of water in organic solvents and raw food products by fluorescence quenching of a crystalline vinyl-functionalized COF.

Covalent organic frameworks (COFs) with good chemical stability, flexible chemical functionalization, tunable pore sizes, and high specific surface areas have been increasingly employed in the field of fluorescence sensing. In this work, a crystalline vinyl-functionalized COF TzDa-V was facilely prepared through a room-temperature synthetic method via condensation reaction between 4,4',4″-(1,3,5-triazine-2,4,6-triyl)trianiline (Tz) and 2,5-diallyloxyterephthalaldehyde (Da-V). The intermolecular charge transfer (ICT) effect endowed the TzDa-V with fluorescence characteristic, and it was sensitive to trace water and can be quenched due to the disruption of ICT process by water. On this base, the prepared COF TzDa-V with excellent chemical/thermal stability was applied to sensing of trace water in common organic solvents such as DMF, acetone, THF, and ethyl acetate with rapid response (less than 10 s), satisfactory sensing range (0.5-18% water in DMF, 0.5-15% water in acetone, 0.5-16% water in THF, 0.5-5% in ethyl acetate, v/v), and high sensitivity. The limits of detection for water in DMF, acetone, THF, and ethyl acetate were 0.0497%, 0.0590%, 0.0502%, and 0.0766% (v/v), respectively. The proposed probe was successfully used for the detection of trace water in food products such as salt and sugar. The COF TzDa-V would be a good candidate for application in water sensing.