Ageing induces tissue-specific transcriptomic changes in Caenorhabditis elegans.

Ageing is a complex process with common and distinct features across tissues. Unveiling the underlying processes driving ageing in individual tissues is indispensable to decipher the mechanisms of organismal longevity. Caenorhabditis elegans is a well-established model organism that has spearheaded ageing research with the discovery of numerous genetic pathways controlling its lifespan. However, it remains challenging to dissect the ageing of worm tissues due to the limited description of tissue pathology and access to tissue-specific molecular changes during ageing. In this study, we isolated cells from five major tissues in young and old worms and profiled the age-induced transcriptomic changes within these tissues. We observed a striking diversity of ageing across tissues and identified different sets of longevity regulators therein. In addition, we found novel tissue-specific factors, including irx-1 and myrf-2, which control the integrity of the intestinal barrier and sarcomere structure during ageing respectively. This study demonstrates the complexity of ageing across worm tissues and highlights the power of tissue-specific transcriptomic profiling during ageing, which can serve as a resource to the field.

Loss of PBX1 function in Leydig cells causes testicular dysgenesis and male sterility.

Leydig cells are essential components of testicular interstitial tissue and serve as a primary source of androgen in males. A functional deficiency in Leydig cells often causes severe reproductive disorders; however, the transcriptional programs underlying the fate decisions and steroidogenesis of these cells have not been fully defined. In this study, we report that the homeodomain transcription factor PBX1 is a master regulator of Leydig cell differentiation and testosterone production in mice. PBX1 was highly expressed in Leydig cells and peritubular myoid cells in the adult testis. Conditional deletion of Pbx1 in Leydig cells caused spermatogenic defects and complete sterility. Histological examinations revealed that Pbx1 deletion impaired testicular structure and led to disorganization of the seminiferous tubules. Single-cell RNA-seq analysis revealed that loss of Pbx1 function affected the fate decisions of progenitor Leydig cells and altered the transcription of genes associated with testosterone synthesis in the adult testis. Pbx1 directly regulates the transcription of genes that play important roles in steroidogenesis (Prlr, Nr2f2 and Nedd4). Further analysis demonstrated that deletion of Pbx1 leads to a significant decrease in testosterone levels, accompanied by increases in pregnenolone, androstenedione and luteinizing hormone. Collectively, our data revealed that PBX1 is indispensable for maintaining Leydig cell function. These findings provide insights into testicular dysgenesis and the regulation of hormone secretion in Leydig cells.

A distinct role of STING in regulating glucose homeostasis through insulin sensitivity and insulin secretion.

Insulin resistance and ß-cell dysfunction are two main molecular bases yet to be further elucidated for type 2 diabetes (T2D). Accumulating evidence indicates that stimulator of interferon genes (STING) plays an important role in regulating insulin sensitivity. However, its function in ß-cells remains unknown. Herein, using global STING knockout (STING-/-) and ß-cell-specific STING knockout (STING-ßKO) mouse models, we revealed a distinct role of STING in the regulation of glucose homeostasis through peripheral tissues and ß-cells. Specially, although STING-/- beneficially alleviated insulin resistance and glucose intolerance induced by high-fat diet, it surprisingly impaired islet glucose-stimulated insulin secretion (GSIS). Importantly, STING is decreased in islets of db/db mice and patients with T2D, suggesting a possible role of STING in ß-cell dysfunction. Indeed, STING-ßKO caused glucose intolerance due to impaired GSIS, indicating that STING is required for normal ß-cell function. Islet transcriptome analysis showed that STING deficiency decreased expression of ß-cell function-related genes, including Glut2, Kcnj11, and Abcc8, contributing to impaired GSIS. Mechanistically, the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and cleavage under targets and tagmentation (CUT&Tag) analyses suggested that Pax6 was the transcription factor that might be associated with defective GSIS in STING-ßKO mice. Indeed, Pax6 messenger RNA and protein levels were down-regulated and its nuclear localization was lost in STING-ßKO ß-cells. Together, these data revealed a function of STING in the regulation of insulin secretion and established pathophysiological significance of fine-tuned STING within ß-cells and insulin target tissues for maintaining glucose homeostasis.

IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of ß cells.

Recessive mutations in IER3IP1 (immediate early response 3 interacting protein 1) cause a syndrome of microcephaly, epilepsy, and permanent neonatal diabetes (MEDS). IER3IP1 encodes an endoplasmic reticulum (ER) membrane protein, which is crucial for brain development; however, the role of IER3IP1 in ß cells remains unknown. We have generated two mouse models with either constitutive or inducible IER3IP1 deletion in ß cells, named IER3IP1-ßKO and IER3IP1-ißKO, respectively. We found that IER3IP1-ßKO causes severe early-onset, insulin-deficient diabetes. Functional studies revealed a markedly dilated ß-cell ER along with increased proinsulin misfolding and elevated expression of the ER chaperones, including PDI, ERO1, BiP, and P58IPK. Islet transcriptome analysis confirmed by qRT-PCR revealed decreased expression of genes associated with ß-cell maturation, cell cycle, and antiapoptotic genes, accompanied by increased expression of antiproliferation genes. Indeed, multiple independent approaches further demonstrated that IER3IP1-ßKO impaired ß-cell maturation and proliferation, along with increased condensation of ß-cell nuclear chromatin. Inducible ß-cell IER3IP1 deletion in adult (8-wk-old) mice induced a similar diabetic phenotype, suggesting that IER3IP1 is also critical for function and survival even after ß-cell early development. Importantly, IER3IP1 was decreased in ß cells of patients with type 2 diabetes (T2D), suggesting an association of IER3IP1 deficiency with ß-cell dysfunction in the more-common form of diabetes. These data not only uncover a critical role of IER3IP1 in ß cells but also provide insight into molecular basis of diabetes caused by IER3IP1 mutations.

Single-cell transcriptome analyses reveal critical regulators of spermatogonial stem cell fate transitions.

BACKGROUND: Spermatogonial stem cells (SSCs) are the foundation cells for continual spermatogenesis and germline regeneration in mammals. SSC activities reside in the undifferentiated spermatogonial population, and currently, the molecular identities of SSCs and their committed progenitors remain unclear. RESULTS: We performed single-cell transcriptome analysis on isolated undifferentiated spermatogonia from mice to decipher the molecular signatures of SSC fate transitions. Through comprehensive analysis, we delineated the developmental trajectory and identified candidate transcription factors (TFs) involved in the fate transitions of SSCs and their progenitors in distinct states. Specifically, we characterized the Asingle spermatogonial subtype marked by the expression of Eomes. Eomes+ cells contained enriched transplantable SSCs, and more than 90% of the cells remained in the quiescent state. Conditional deletion of Eomes in the germline did not impact steady-state spermatogenesis but enhanced SSC regeneration. Forced expression of Eomes in spermatogenic cells disrupted spermatogenesis mainly by affecting the cell cycle progression of undifferentiated spermatogonia. After injury, Eomes+ cells re-enter the cell cycle and divide to expand the SSC pool. Eomes+ cells consisted of 7 different subsets of cells at single-cell resolution, and genes enriched in glycolysis/gluconeogenesis and the PI3/Akt signaling pathway participated in the SSC regeneration process. CONCLUSIONS: In this study, we explored the molecular characteristics and critical regulators of subpopulations of undifferentiated spermatogonia. The findings of the present study described a quiescent SSC subpopulation, Eomes+ spermatogonia, and provided a dynamic transcriptional map of SSC fate determination.

THBS1 promotes angiogenesis and accelerates ESCC malignant progression by the HIF-1/VEGF signaling pathway.

Previously, we demonstrated that the expression of THBS1 is increased in esophageal squamous cell carcinoma (ESCC) tissues and is correlated with lymph node metastasis and poor prognosis, indicating that THBS1 might be a candidate oncogene in ESCC. In this study, we future studied the specific role of THBS1 in ESCC and its molecular mechanism. Silencing THBS1 expression resulted in inhibition of cell migration and cell invasion of ESCC cells, the decrease of colony formation and proliferation. Tube formation of human umbilical vein endothelial cells (HUVECs) in vitro was decreased when cultured with conditioned medium from THBS1-silenced cells. The expression of CD31, a marker for blood vessel endothelial cells, was decreased in tumor tissues derived from THBS1-silenced tumors in vivo. Silencing THBS1 leaded the decreased of hypoxia-inducible factor-1α (HIF-1α), HIF-1ß, and VEGFA protein. The expression of p-ERK and p-AKT were declined in HUVECs following incubation with conditioned medium from THBS1-silenced ESCC cells compared conditioned medium from control cells. Furthermore, the treatment with bevacizumab boosted the decrease of the p-ERK and p-AKT levels in HUVECs incubated with the conditioned medium from THBS1-silenced ESCC cells. THBS1 silencing combined with bevacizumab blocked VEGF, inhibited to the tube formation, colony formation and migration of HUVECs, which were superior to that of bevacizumab alone. We presumed that THBS1 can enhance HIF-1/VEGF signaling and subsequently induce angiogenesis by activating the AKT and ERK pathways in HUVECs, resulting in bevacizumab resistance. THBS1 would be a potential target in tumor antiangiogenesis therapies.

Mobile phone problem use and depressive symptoms: the mediating role of social support and attitude to aging among Chinese older adults.

BACKGROUND: Little is known about mobile phone problem use (MPPU) among older adults. This study investigated critical factors affecting MPPU and filled the gap between MPPU and depressive symptoms in older people. METHODS: A cross-sectional study was conducted in community (n = 376) with questionnaires of Multidimensional Scale of Perceived Social Support (MSPSS), Geriatric Depression Scale (GDS-15), Attitudes to Aging Questionnaire (AAQ) and Mobile Phone Problem Use Scale (MPPUS). RESULTS: 80.9% of older people used smartphones and spend less than three hours on mobile phone per day. The average MPPU score of Chinese elderly is greater than the cut off to 41. Female (ß = -0.11, P = 0.037), living with spouse (ß = -0.17, P = 0.03), and late marriage age (ß = -0.16, P = 0.007) are less likely to develop MPPU. The relationship between MPPU and depressive symptoms was partially mediated by social support and attitude to aging. CONCLUSION: Elderly people generally have higher MPPU scores. MPPU was associated with depressive symptoms, through social support and attitude to aging.

Pancreatic lipase-related protein 2 is selectively expressed by peritubular myoid cells in the murine testis and sustains long-term spermatogenesis.

Spermatogenesis is a complicated process of germ cell differentiation that occurs within the seminiferous tubule in the testis. Peritubular myoid cells (PTMCs) produce major components of the basement membrane that separates and ensures the structural integrity of seminiferous tubules. These cells secrete niche factors to promote spermatogonial stem cell (SSC) maintenance and mediate androgen signals to direct spermatid development. However, the regulatory mechanisms underlying the identity and function of PTMCs have not been fully elucidated. In the present study, we showed that the expression of pancreatic lipase-related protein 2 (Pnliprp2) was restricted in PTMCs in the testis and that its genetic ablation caused age-dependent defects in spermatogenesis. The fertility of Pnliprp2 knockout animals (Pnliprp2-/-) was normal at a young age but declined sharply beginning at 9 months. Pnliprp2 deletion impaired the homeostasis of undifferentiated spermatogonia and severely disrupted the development and function of spermatids. Integrated analyses of single-cell RNA-seq and metabolomics data revealed that glyceride metabolism was changed in PTMCs from Pnliprp2-/- mice. Further analysis found that 60 metabolites were altered in the sperm of the Pnliprp2-/- animals; notably, lipid metabolism was significantly dysregulated. Collectively, these results revealed that Pnliprp2 was exclusively expressed in PTMCs in the testis and played a novel role in supporting continual spermatogenesis in mice. The outcomes of these findings highlight the function of lipid metabolism in reproduction and provide new insights into the regulation of PTMCs in mammals.

Association between physical frailty, circadian syndrome and cardiovascular disease among middle-aged and older adults: a longitudinal study.

BACKGROUND: Physical frailty (PF) and circadian syndrome (CircS) are proposed as novel risks for cardiovascular disease (CVD), but little attention is paid to their combined impact on CVD. This study aimed to investigate the association of PF, CircS and CVD in middle-aged and older adults. METHODS: The sample comprised 8512 participants aged at least 45 years from the China Health and Retirement Longitudinal Study (CHARLS) 2011. PF was examined by the physical frailty phenotype scale. CircS was assessed by the components of the International Diabetes Federation (IDF) MetS plus short sleep duration and depression. The cut-off for CircS was set as ≥ 4. CVD was defined as the presence of physician-diagnosed heart disease and/or stroke. A total of 6176 participants without CVD recruited from CHARLS 2011 and were followed up in 2018. RESULTS: The prevalence of CVD in total populations, neither CircS or PF, PF alone, CircS alone and both CircS and PF were 13.0%, 7.4%, 15.5%, 17.4%, and 30.2%, respectively. CircS was more likely to be PF [OR (95%CI): 2.070 (1.732 ∼ 2.472)] than those without CircS. Both CircS alone [OR (95% CI): 1.954 (1.663 ∼ 2.296)], and coexisting CircS and PF [3.508 (2.739 ∼ 4.494)] were associated with CVD. Longitudinal analysis showed that individuals with both CircS and PF (HR: 1.716, 95%CI: 1.314 ∼ 2.240) and CircS alone [1.520 (1.331 ∼ 1.737)] were more likely to have new onset CVD than neither CircS or PF peers. CONCLUSION: PF and CircS together are associated with higher CVD risk, which provided new evidence for a strong relation that warrants attention to assessing PF and CircS and in community to promote healthy aging.

Unraveling the mediation role of frailty and depression in the relationship between social support and self-management among Chinese elderly COPD patients: a cross-sectional study.

BACKGROUND: Self-management (SM) is the key factor in controlling the progression of chronic obstructive pulmonary disease (COPD). Previous studies have reported that majority of COPD patients later presented with frailty and mental health diseases, which affect self-management. This study attempted to explore the mediation role of depression and frailty between social support and self-management in elderly COPD population. METHODS: Six hundred twenty-seven stable elderly COPD patients admitted to 5 public hospitals in Ningxia, China were selected as study subjects by convenience sampling method. Self-management, frailty, depression and social support were assessed using the COPD Self-management Scale (COPD-SMS), Frail Scale (FS), 15-item Geriatric Depression Scale (GDS-15), and Social Support Rating Scale (SSRS) respectively. The Pearson correlation analysis was used to assess the correlation between variables. Additionally, SPSS25.0 PROCESS plugin Model 6 was used to explore the mediating effects of frailty and depression in the relationship between social support and self-management. RESULTS: The mean participant age was 72.87 ± 7.03 years, 60.4% of participants were male. The mean total score of the COPD-SMS was 156.99 ± 25.15. Scores for the SSRS, FS, and GDS-15 were significantly correlated with COPD-SMS (p < 0.05). The analysis of the mediation effect demonstrated that social support has a direct predictive effect on self- management (ß = 1.687, 95%CI: 1.359 to 2.318). Additionally, social support can also predict self- management indirectly through the mediation of depression (ß = 0.290, 95%CI: 0.161 to 0.436) and frailty-depression (ß = 0.040, 95%CI: 0.010 to 0.081). However, the mediation effect of frailty alone was not found to be statistically significant (ß =-0.010, 95%CI: -0.061 to 0.036). The direct effect accounted for 84.06% of the total effect, while the indirect effect accounted for 15.94% of the total effect. CONCLUSION: Self-management among elderly COPD patients was relatively moderate to low. Furthermore, frailty and depression were found to have a partially mediation role in the relationship between social support and self-management. Therefore, healthcare professionals need to comprehensively consider the frailty and depression status of patients, and implement targeted intervention measures as part of their care, which can improve the self-management of elderly COPD patients.

Ecological risk assessment of heavy metals in desulfurized seawater discharged from a coal-fired power plant in Qingdao.

Despite the prevalence of discharge of large volumes of heavy-metal-bearing seawater from coal-fired power plants into adjacent seas, studies on the associated ecological risks remain limited. This study continuously monitored concentrations of seven heavy metals (i.e. As, Cd, Cr, Cu, Hg, Pb, and Zn) in surface seawater near the outfall of a coal-fired power plant in Qingdao, China over three years. The results showed average concentrations of As, Cd, Cr, Cu, Hg, Pb, and Zn of 2.63, 0.33, 2.97, 4.63, 0.008, 0.85, and 25.00 µg/L, respectively. Given the lack of data on metal toxicity to local species, this study investigated species composition and biomass near discharge outfalls and constructed species sensitivity distribution (SSD) curves with biological flora characteristics. Hazardous concentrations for 5% of species (HC5) for As, Cd, Cr, Cu, Hg, Pb, and Zn derived from SSDs constructed from chronic toxicity data for native species were 3.23, 2.22, 0.06, 2.83, 0.66, 4.70, and 11.07 µg/L, respectively. This study further assessed ecological risk of heavy metals by applying the Hazard Quotient (HQ) and Joint Probability Curve (JPC) based on long-term heavy metal exposure data and chronic toxicity data for local species. The results revealed acceptable levels of ecological risk for As, Cd, Hg, and Pb, but unacceptable levels for Cr, Cu, and Zn. The order of studied heavy metals in terms of ecological risk was Cr > Cu ≈ Zn > As > Cd ≈ Pb > Hg. The results of this study can guide the assessment of ecological risk at heavy metal contaminated sites characterized by relatively low heavy metal concentrations and high discharge volumes, such as receiving waters of coal-fired power plant effluents.

Association of foods consumption and physical activity with prefrailty and frailty among Chinese older adults in urban communities: A cross-sectional study.

BACKGROUND AND OBJECTIVES: Frailty has become a public health challenge in China. To investigate the association of foods consumption and physical activity with prefrailty and frailty among older Chinese adults in urban communities. METHODS AND STUDY DESIGN: In a cross-sectional study from February to July 2023, 1183 older adults aged between 65y-88y were enrolled from urban communities in Chongqing and Shandong province, China. Frailty Index (FI) was applied to measure prefrailty and frailty. Partial proportional odds model was used to assess the association between foods consumption, physical activity and prefrailty/frailty. RESULTS: Higher Dietary Diversity Score (DDS), (OR=0.61, 95% CI=0.46-0.80; OR=0.47, 95% CI=0.28-0.79), Consuming animal-based foods ≥2 times/day (OR=0.62, 95% CI=0.47-0.82; OR=0.54, 95% CI=0.33-0.88), soy products ≥2 times/week (OR=0.69, 95% CI=0.53-0.89; OR=0.51, 95% CI=0.31-0.84), fresh vegetables ≥2 times/day (OR=0.42, 95% CI=0.31-0.57; OR=0.41, 95% CI=0.23-0.72), and nuts ≥2 times/week (OR=0.71, 95% CI=0.55-0.91; OR=0.52, 95% CI=0.32-0.85) was associated with a lower risk of prefrailty and frailty. In addition, higher frequency and longer duration of walking (OR=0.61, 95% CI=0.42-0.88; OR=0.63, 95% CI=0.48-0.81), exercise (OR=0.48, 95% CI=0.35-0.64; OR=0.44, 95% CI=0.32-0.61) per week were significantly associated with lower risk of prefrailty. Furthermore, higher frequency and longer duration of walking (OR=0.42, 95% CI=0.25-0.72; OR=0.46, 95% CI=0.29-0.74), and housework (OR=0.39, 95% CI=0.24-0.65; OR=0.57, 95% CI=0.34-0.96) per week, were significantly associated with lower frailty. CONCLUSIONS: Higher DDS and higher frequency of animal-based foods, soy products, fresh vegetables, and nuts consumption is significantly associated with lower risk of prefrailty and frailty. Additionally, walking and exercising are significantly associated with lower risk of prefrailty, while walking and doing housework is significantly associated with lower frailty.

Long non-coding RNAs as epigenetic mediator and predictor of glioma progression, invasiveness, and prognosis.

Gliomas are aggressive brain tumors with high mortality rate. Over the past several years, non-coding RNAs, specifically the long non-coding RNAs (lncRNAs), have emerged as biomarkers of considerable interest. Emerging data reveals distinct patterns of expressions of several lncRNAs in the glioma tissues, relative to their expression in normal brains. This has led to the speculation for putative exploitation of lncRNAs as diagnostic biomarkers as well as biomarkers for targeted therapy. With a focus on lncRNAs that have shown promise as epigenetic biomarkers in the proliferation, migration, invasion, angiogenesis and metastasis in various glioma models, we discuss several such lncRNAs. The data from cell line / animal model-based studies as well as analysis from human patient samples is presented for the most up-to-date information on the topic. Overall, the information provided herein makes a compelling case for further evaluation of lncRNAs in clinical settings.

Trace Analysis Method Based on UPLC-MS/MS for the Determination of (C2-C18) Per-and Polyfluoroalkyl Substances and Its Application to Tap Water and Bottled Water.

As the usage of long-chain perfluoroalkyl and polyfluoroalkyl substances (PFASs) may be gradually restricted, short-chain and even ultra-short-chain PFASs have been widely produced and used, which has put forward new requirements for the simultaneous analysis of the above substances. Using solid phase extraction two-fraction elution and ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), an experimental method was established for the simultaneous analysis of ultrashort-chain, short-chain, and long-chain PFASs and the precursor perfluorohexanesulfonamide (FHxSA) in low-concentration water, such as tap water and bottled water. By optimizing the volume of methanol in the first-fraction elution, the concentration of ammonia in the second-fraction elution, and the concentration of ammonium acetate in the mobile phase, the high recovery and low detection limit (0.01-3 ng/L) were obtained. In addition, this method was used to measure nine tap water samples and six bottled water samples for validation, and the results showed that the concentration of PFASs in bottled water was lower than that in tap water. This study first reported the trifluoroacetic acid concentration in bottled water (6.61 ± 9.60 ng/L), which was lower than that in tap water (1712 ± 174 ng/L). The main substances in tap water and bottled water are both ultrashort-chain PFASs (C2-C3), accounting for more than 50%. There are few reports on the simultaneous analysis of ultrashort-chain, short-chain, and long-chain PFASs (C2-C18) and the precursor FHxSA in low-concentration water samples, and the new method can be further developed for different environmental media.

Maize-legume intercropping achieves yield advantages by improving leaf functions and dry matter partition.

Intercropping can obtain yield advantages, but the mechanism of yield advantages of maize-legume intercropping is still unclear. Then, we explored the effects of cropping systems and N input on yield advantages in a two-year experiment. Cropping systems included monoculture maize (Zea mays L.) (MM), monoculture soybean (Glycine max L. Merr.) (MS), monoculture peanut (Arachis hypogaea L.) (MP), maize-soybean substitutive relay intercropping (IMS), and maize-peanut substitutive strip intercropping (IMP). N input included without N (N0) and N addition (N1). Results showed that maize's leaf area index was 31.0% and 34.6% higher in IMS and IMP than in MM. The specific leaf weight and chlorophyll a (chl a) of maize were notably higher by 8.0% and 18.8% in IMS, 3.1%, and 18.6% in IMP compared with MM. Finally, N addition resulted in a higher thousand kernels weight of maize in IMS and IMP than that in MM. More dry matter accumulated and partitioned to the grain, maize's averaged partial land equivalent ratio and the net effect were 0.76 and 2.75 t ha-1 in IMS, 0.78 and 2.83 t ha-1 in IMP. The leaf area index and specific leaf weight of intercropped soybean were 16.8% and 26% higher than MS. Although soybean suffers from shade during coexistence, recovered growth strengthens leaf functional traits and increases dry matter accumulation. The averaged partial land equivalent ratio and the net effect of intercropped soybean were 0.76 and 0.47 t ha-1. The leaf area index and specific leaf weight of peanuts in IMP were 69.1% and 14.4% lower than in the MP. The chlorophyll a and chlorophyll b of peanut in MP were 17.0% and 24.4% higher than in IMP. A less dry matter was partitioned to the grain for intercropped peanut. The averaged pLER and NE of intercropped peanuts were 0.26 and -0.55 t ha-1. In conclusion, the strengthened leaf functional traits promote dry matter accumulation, maize-soybean relay intercropping obtained a win-win yield advantage, and maize-peanut strip intercropping achieved a trade-off yield advantage.

Nonlinear transmission performance comparison employing 60 × 416.7-Gb/s TPS-64QAM and UD-16QAM systems with limited bandwidth.

The impacts of limited bandwidth on the nonlinear transmission performance are investigated by employing a truncated probabilistic shaped 64-ary quadrature amplitude modulation (TPS-64QAM) and a uniformly distributed 16-ary quadrature amplitude modulation (UD-16QAM) over a bandwidth-limited 75-GHz spaced 25-Tb/s (60 × 416.7 Gb/s) 6300-km transmission system. In terms of nonlinear performance measured by optimal launch power, theoretical analyses show that a 0.4-dB improvement could be introduced by UD-16QAM with respect to TPS-64QAM over a 6300-km transmission without limited bandwidth. However, contrary results would be observed that TPS-64QAM would outperform UD-16QAM by about 0.8 dB in terms of optimal launch power when the impacts of limited bandwidth are considered. Besides, numerical simulations and experimental results could both validate that about 1.0-dB optimal launch power improvement could be obtained by TPS-64QAM under bandwidth-limited cases, which is roughly similar to the results of theoretical analyses. Additionally, WDM experimental results show that all 60 tested channels could agree with the BER requirements by employing TPS-64QAM, further validating the superiority of TPS-64QAM compared to UD-16QAM under bandwidth-limited cases.

The Association of Age at Diagnosis of Hypertension with Cognitive Decline: the China Health and Retirement Longitudinal Study (CHARLS).

AIM: This study investigated whether an individual's age at diagnosis of hypertension, which is associated with a decline in cognitive performance in the China Health and Retirement Longitudinal Study (CHARLS) participants. METHODS: Our analysis was based on the CHARLS with baseline data collected between 2011 and 2018. We randomly selected a control participant for each hypertensive participant using propensity score. The cohort comprised 2413 individuals with hypertension and 2411 controls. Participants were divided into three groups as follows: non-hypertension, hypertension diagnose ≥55 years, and hypertension diagnose <55 years. Cognitive performance was measured in both visits and evaluated by the scores of the memory, executive function, and orientation and global cognitive. RESULTS: After multivariable adjustment, individuals with hypertension diagnosed <55 years had a significantly faster cognitive decline in memory test (ß (95% CI, -1.117 [-1.405, -0.83]), orientation test (ß (95% CI, -1.273 [-1.348, -1.198]) and global cognitive (ß (95% CI, -1.611 [-1.744, -1.478]) compared with the corresponding controls. A longer hypertension duration was associated with worse memory test (ß (95% CI, -0.069 [-0.113 to -0.025]). Among treated individuals, blood pressure control at baseline was inversely associated with the decline in orientation test (ß (95% CI, -0.659 [-0.939, -0.380]), orientation test (ß (95% CI, -0.259[-0.365, -0.153])and global cognitive (ß (95% CI, -0.124 [-0.162, -0.086]). CONCLUSIONS: Our findings suggest that hypertension diagnosed in mid-life is associated with worse cognition compared to late life. Besides, longer duration of diagnosis is associated with worse memory test. In addition to hypertension, pressure control might be critical for the preservation of cognitive function.

Deubiquitinase cylindromatosis (CYLD) regulates antibacterial immunity and apoptosis in Chinese mitten crab (Eriocheir sinensis).

Ubiquitination and deubiquitination of target proteins is an important mechanism for cells to rapidly respond to changes in the external environment. The deubiquitinase, cylindromatosis (CYLD), is a tumor suppressor protein. CYLD from Drosophila melanogaster participates in the antimicrobial immune response. In vertebrates, CYLD also regulates bacterial-induced apoptosis. However, whether CYLD can regulate the bacterial-induced innate immune response in crustaceans is unknown. In the present study, we reported the identification and cloning of CYLD in Chinese mitten crab, Eriocheir sinensis. Quantitative real-time reverse transcription polymerase chain reaction analysis showed that EsCYLD was widely expressed in all the examined tissues and was upregulated in the hemolymph after Vibrio parahaemolyticus challenge. Knockdown of EsCYLD in hemocytes promoted the cytoplasm-to-nucleus translocation of transcription factor Relish under V. parahaemolyticus stimulation and increased the expression of corresponding antimicrobial peptides. In vivo, silencing of EsCYLD promoted the removal of bacteria from the crabs and enhanced their survival. In addition, interfering with EsCYLD expression inhibited apoptosis of crab hemocytes caused by V. parahaemolyticus stimulation. In summary, our findings revealed that EsCYLD negatively regulates the nuclear translocation of Relish to affect the expression of corresponding antimicrobial peptides and regulates the apoptosis of crab hemocytes, thus indirectly participating in the innate immunity of E. sinensis.

Integrinß1/FAK/ERK signalling pathway is essential for Chinese mitten crab Eriocheir sinensis hemocyte survival.

Integrins are cellular adhesion molecules that mediate cell-cell, cell-extracellular matrix, and cell-pathogen interactions. Integrins can stimulate various signaling pathways by binding to different ligands, thereby exerting immunological functions. While integrins have been found to primarily play a role in bacterial agglutination, phagocytosis, and inhibition of apoptosis in invertebrates, the specific signaling pathway and mechanism of action remain unclear. In vertebrates, ß1 integrin and extracellular matrix interactions can associate with focal adhesion kinase (FAK) to initiate MAPK/ERK signaling and regulate cell survival; however, in invertebrates (e.g., Chinese mitten crab), the mechanisms of integrins are poorly understood. The purpose of this study was to investigate whether integrinß1/FAK activation of the MAPK/ERK pathway regulates hemocyte survival and the associated mechanism. Treatment with an integrinß1 inhibitor RGD (a conserved tripeptide Arg-Gly-Asp), decreased the levels of FAK and ERK expression and phosphorylation, followed by an intensification of apoptosis. Similar results were obtained following siRNA knockdown of integrinß1 expression. We further found that the attenuation of ERK phosphorylation enhanced the level of Caspase-3 expression. Together, these findings suggest that integrinß1 activates the FAK/ERK signaling cascade and is involved in the survival of Chinese mitten crab hemocytes.

Immune functions of the Dscam extracellular variable region in Chinese mitten crab.

In arthropods, there is only a single copy of Down Syndrome Cell Adhesion Molecule (Dscam) in the genome, but it can exist as numerous splice variants. There are three hypervariable exons in the extracellular domain and one hypervariable exon in the transmembrane domain. In Chinese mitten crab (Eriocheir sinensis), exons 4, 6 and 14 can produce 25, 34 and 18 alternative splice variants, respectively. In this study, through Illumina sequencing, we identified additional splice variants for exons 6 and 14, hence there may be > 50,000 Dscam protein variants. Sequencing of exons 4, 6 and 14 showed that alternative splicing was altered after bacterial stimulation. Therefore, we expressed and purified the extracellular variable region of Dscam (EsDscam-Ig1-Ig7). Exons 4.3, 6.46 and 14.18, three variable exons of the recombinant protein, were randomly selected. The functions of EsDscam-Ig1-Ig7 in immune defences of E. sinensis were subsequently explored. EsDscam-Ig1-Ig7 was discovered to bind to both Gram-positive Staphylococcus aureus and Gram-negative Vibrio parahaemolyticus, but it did not exhibit antibacterial activity. By promoting hemocyte phagocytosis and bacterial removal, EsDscam-Ig1-Ig7 can also shield the host from bacterial infection. The findings highlight the immunological activities of Dscam alternative splicing and reveal the potential for many more Dscam isoforms than were previously predicted in E. sinensis.