Wearable device-measured moderate to vigorous physical activity and risk of degenerative aortic valve stenosis.

BACKGROUND AND AIMS: Physical activity has proven effective in preventing atherosclerotic cardiovascular disease, but its role in preventing degenerative valvular heart disease (VHD) remains uncertain. This study aimed to explore the dose-response association between moderate to vigorous physical activity (MVPA) volume and the risk of degenerative VHD among middle-aged adults. METHODS: A full week of accelerometer-derived MVPA data from 87 248 UK Biobank participants (median age 63.3, female: 56.9%) between 2013 and 2015 were used for primary analysis. Questionnaire-derived MVPA data from 361 681 UK Biobank participants (median age 57.7, female: 52.7%) between 2006 and 2010 were used for secondary analysis. The primary outcome was the diagnosis of incident degenerative VHD, including aortic valve stenosis (AS), aortic valve regurgitation (AR), and mitral valve regurgitation (MR). The secondary outcome was VHD-related intervention or mortality. RESULTS: In the accelerometer-derived MVPA cohort, 555 incident AS, 201 incident AR, and 655 incident MR occurred during a median follow-up of 8.11 years. Increased MVPA volume showed a steady decline in AS risk and subsequent AS-related intervention or mortality risk, levelling off beyond approximately 300 min/week. In contrast, its association with AR or MR incidence was less apparent. The adjusted rates of AS incidence (95% confidence interval) across MVPA quartiles (Q1-Q4) were 11.60 (10.20, 13.20), 7.82 (6.63, 9.23), 5.74 (4.67, 7.08), and 5.91 (4.73, 7.39) per 10 000 person-years. The corresponding adjusted rates of AS-related intervention or mortality were 4.37 (3.52, 5.43), 2.81 (2.13, 3.71), 1.93 (1.36, 2.75), and 2.14 (1.50, 3.06) per 10 000 person-years, respectively. Aortic valve stenosis risk reduction was also observed with questionnaire-based MVPA data [adjusted absolute difference Q4 vs. Q1: AS incidence, -1.41 (-.67, -2.14) per 10 000 person-years; AS-related intervention or mortality, -.38 (-.04, -.88) per 10 000 person-years]. The beneficial association remained consistent in high-risk populations for AS, including patients with hypertension, obesity, dyslipidaemia, and chronic kidney disease. CONCLUSIONS: Higher MVPA volume was associated with a lower risk of developing AS and subsequent AS-related intervention or mortality. Future research needs to validate these findings in diverse populations with longer durations and repeated periods of activity monitoring.

Long non-coding RNA Linc00657 up-regulates Skp2 to promote the progression of cervical cancer through lipid reprogramming and regulation of immune microenvironment.

More and more evidence shows that long non-coding RNA (lncRNA) plays an important role in the biological behavior of many kinds of malignant tumors, but the specific function of lncRNA Linc00657 in cervical cancer is still unknown. The purpose of this study is to explore the effect of Linc00657 on the malignant progression of cervical cancer and its potential mechanism. In two kinds of cervical cancer cell lines and normal cervical epithelial cells, qRT-PCR showed increased expression of Linc00657 in cervical cancer cells. Through MTT, clone formation test, flow cytometry, wound healing test and Transwell test, it has been found that overexpression of Linc00657 could promote the proliferation,migration and invasion of cervical cancer cells，and inhibit apoptosis. Through the StarBase database, it was found that there may be a mutual regulatory relationship between Linc00657 and Skp2, and Skp2 may be the downstream target of Linc00657. QRT-PCR detection confirmed that the expression of Skp2 was increased in cervical cancer cells with overexpression of Linc00657. TIMER2 database found that Skp2 was associated with lipid metabolic enzymes and immune cell infiltration. It was found that Linc00657 knockdown inhibited tumor growth and metastasis and inhibited the expression of Skp2 in vivo. In short, our research shows that Linc00657 has carcinogenic properties in cervical cancer, and LINC00657 promotes the occurrence of cervical cancer by up-regulating the expression of Skp2. We predict that Linc00657/mir30s/Skp2 axis plays a role in the malignant progression of cervical cancer. In addition, Skp2 may participate in cancer immune response and promote lymph node metastasis of cervical cancer through lipid reprogramming. These findings also provide promising targets for the diagnosis and treatment of cervical cancer.

Potassium levels and the risk of all-cause and cardiovascular mortality among patients with cardiovascular diseases: a meta-analysis of cohort studies.

BACKGROUND: Abnormal blood potassium levels are associated with an increased risk of cardiometabolic diseases and mortality in the general population; however, evidence regarding the association between dyskalemia and mortality among patients with cardiovascular disease (CVD) remains inconclusive. This study aimed to evaluate the association of potassium levels with all-cause and cardiovascular mortality among patients with CVD. METHODS: PubMed, Embase, Web of Science, and Cochrane Library databases were searched up to August 2023 to identify relevant cohort studies among patients with CVD, such as myocardial infarction, stroke, and heart failure. Abnormal potassium levels were considered as hypokalemia or hyperkalemia. The primary outcomes were all-cause mortality based on follow-up length (including in-hospital, short-term and long-term mortality) and cardiovascular mortality. The methodological quality of included studies was assessed by using the Newcastle-Ottawa Scale. The pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models. Restricted cubic splines were applied to explore the dose-response relationship. RESULTS: Thirty-one cohort studies involving 227,645 participants with an average age of 68.3 years were included in the meta-analysis, all of which achieved moderate to high quality. Hyperkalemia was significantly associated with an approximately 3.0-fold increased risk of all-cause in-hospital mortality (RR:2.78,95CI%:1.92,4.03), 1.8-fold of all-cause short-term mortality (RR:1.80, 95CI%:1.44,2.27), 1.3-fold of all-cause long-term mortality (RR:1.33, 95CI%:1.19,1.48) and 1.2-fold of cardiovascular mortality (RR:1.19, 95CI%:1.04,1.36). Similar positive associations were also observed between hypokalemia and risk of all-cause mortality and cardiovascular mortality. The RRs of all-cause in-hospital, short-term, long-term mortality and cardiovascular mortality with hyperkalemia were attenuated to 2.21 (95CI%:1.60,3.06), 1.46(95CI%:1.25,1.71), 1.23 (95CI%:1.09,1.39) and 1.13 (95CI%:1.00,1.27) when treating hypokalemia together with normokalemia as the reference group. A U-shaped association was observed between potassium levels and mortality, with the lowest risk at around 4.2 mmol/L. CONCLUSIONS: Both hypokalemia and hyperkalemia were positively associated with the risk of mortality in patients with CVD. Our results support the importance of potassium homeostasis for improving the CVD management. REGISTRATION: PROSPERO, CRD42022324337.

Effect of Day 3 cell number on the live birth rate of vitrified-warmed Day 5 single blastocyst transfer in young women.

BACKGROUND: Previous studies have reported inconsistent results regarding blastocyst selection with a high day 3 (D3) cell number and the eventual pregnancy outcomes. Thus, in this study, the relationship between the D3 cell number and clinical outcomes of day 5 single blastocyst transfer (SBT) in vitrified-warmed transfer cycles was investigated. METHODS: Our retrospective study included 1144 day 5 SBT in vitrified-warmed cycles between February 2016 and February 2021. All cycles were the first vitrified-warmed cycles, and the female patients were less than 35 years of age. Based on the D3 cell number, the cycles were divided into four groups, as follows: group A (3-7 cells, n = 130); group B (8-9 cells, n = 621); group C (10-12 cells, n = 328); and group D (13-16 cells, n = 65). The differences in the live birth rate (LBR), clinical pregnancy rate, and miscarriage rate were examined among the four groups. RESULTS: The LBR and clinical pregnancy rate increased with the D3 cell number (P < 0.01). No significant difference was found in the miscarriage rate among the groups (P = 0.055). After adjusting for confounding factors, the LBR was significantly higher in groups C (odds ratio [OR] = 1.477, 95% confidence interval [CI]: 1.124-1.941, P = 0.005) and D (OR = 2.000, 95% CI: 1.166-3.429, P = 0.012) than in group B. CONCLUSIONS: A high D3 cell number (> 9 cells) was associated with a high LBR in the vitrified-warmed day 5 SBT cycles of patients < 35 years of age. The cell number of D3 embryos can be an important reference indicator for blastocyst selection. Among blastocysts with the same morphological score, those with > 9 cells on D3 can be preferentially selected for transplantation.

Structural and metabolic cumulus cell alteration affects oocyte quality in underweight women.

This study aimed to investigate the structural and metabolic changes in cumulus cells of underweight women and their effects on oocyte maturation and fertilization. The cytoplasmic ultrastructure was analyzed by electron microscopy, mitochondrial membrane potential by immunofluorescence, and mitochondrial DNA copy number by relative quantitative polymerase chain reaction. The expression of various proteins including the oxidative stress-derived product 4-hydroxynonenal (4-HNE) and autophagy and apoptosis markers such as Vps34, Atg-5, Beclin 1, Lc3-I, II, Bax, and Bcl-2 was assessed and compared between groups. Oocyte maturation and fertilization rates were lower in underweight women (P < 0.05), who presented with cumulus cells showing abnormal mitochondrial morphology and increased cell autophagy. Compared with the mitochondrial DNA copies of the control group, those of the underweight group increased but not significantly. The mitochondrial membrane potential was similar between the groups (P = 0.8). Vps34, Atg-5, Lc3-II, Bax, and Bcl-2 expression and 4-HNE levels were higher in the underweight group compared with the control group (P < 0.01); however, the Bax/Bcl-2 ratio was lower in the underweight group compared with the control group (P = 0.031). Additionally, Beclin 1 protein levels were higher in the underweight group compared with the control group but without statistical significance. In conclusion, malnutrition and other conditions in underweight women may adversely affect ovulation, and the development, and fertilization of oocytes resulting from changes to the intracellular structure of cumulus cells and metabolic processes. These changes may lead to reduced fertility or unsatisfactory reproduction outcomes in women.

Ultrasensitive dynamic light scattering immunodetection of alpha-fetoprotein using heptamer-amplified nanoparticle crosslinking aggregation.

A novel construction strategy is introduced for an ultrasensitive dynamic light scattering (DLS) immunosensor targeting alpha fetoprotein (AFP). This approach relies on a self-assembled heptamer fusion protein (A1-C4bpα), incorporating the dual functions of multivalent recognition and crosslinking aggregation amplification due to the presence of seven AFP-specific A1 nanobodies on the A1-C4bpα heptamer. Leveraging antibody-functionalized magnetic nanoparticles for target AFP capture and DLS signal output, the proposed heptamer-assisted DLS immunosensor offers high sensitivity, strong specificity, and ease of operation. Under the optimized conditions, the designed DLS immunosensor demonstrates excellent linear detection of AFP in the concentration range 0.06 ng mL-1 to 512 ng mL-1, with a detection limit of 15 pg mL-1. The selectivity, accuracy, precision, practicability, and reliability of this newly developed method were further validated through an assay of AFP levels in spiked and actual human serum samples. This work introduces a novel approach for constructing ultrasensitive DLS immunosensors, easily extendable to the sensitive determination of other targets via simply replacing the nanobody sequence, holding great promise in various applications, particularly in disease diagnosis.

Deterministic Fabrication of a Coupled Cavity-Emitter System in Hexagonal Boron Nitride.

Light-matter interactions in optical cavities underpin many applications of integrated quantum photonics. Among various solid-state platforms, hexagonal boron nitride (hBN) is gaining considerable interest as a compelling van der Waals host of quantum emitters. However, progress to date has been limited by an inability to engineer simultaneously an hBN emitter and a narrow-band photonic resonator at a predetermined wavelength. Here, we overcome this problem and demonstrate deterministic fabrication of hBN nanobeam photonic crystal cavities with high quality factors over a broad spectral range (∼400 to 850 nm). We then fabricate a monolithic, coupled cavity-emitter system designed for a blue quantum emitter that has an emission wavelength of 436 nm and is induced deterministically by electron beam irradiation of the cavity hotspot. Our work constitutes a promising path to scalable on-chip quantum photonics and paves the way to quantum networks based on van der Waals materials.

Livestock turnover and dynamic livestock carrying capacity are crucial factors for alpine grassland management: The Qinghai-Tibetan plateau as a case study.

Alpine grasslands are distributed widely on high-elevated ranges and plateaus from the wet tropics to polar regions, accounting for approximately 3% of the world's land area. The Qinghai-Tibetan Plateau (QTP) is the highest and largest plateau in the world, and approximately 60% of the plateau consists of alpine grassland, which is used mainly for grazing animals. Livestock structure was determined in Guinan (GN), Yushu (YS) and Maqu counties (MQ) on the QTP by interviewing 235 local pastoralists. Based on data collected from GN, the livestock carrying capacity was calculated using herbage dry matter biomass intake (LCCm) by the livestock, and the metabolizable energy yield (LCCe) and digestible crude protein (LCCp) available in pasture. The pasture area per household differed among the regions of the QTP, which was the main reason for the difference in livestock stocking rate. The householders raised the appropriate proportion of breeding females and young yaks and sheep in GN and MQ, but not in YS, to maintain a constant turnover. Most pasture in YS was used at the community level, especially in summer. The calculated carrying capacities based on metabolizable energy yield (LCCe) of the pasture and dry matter biomass (LCCm) were similar in most months except for August, when the value of LCCe was higher than LCCm. Based on the digestible protein of the pasture, the calculated livestock carrying capacity overestimated the actual carrying capacity during the herbage growing season from May to September. Appropriate practices should be taken in different regions of QTP, such as providing supplementary feed, especially protein, during the forage non-growing season. Livestock carrying capacity should be adjusted dynamically, and calculated by a number of parameters. The stocking rate should be controlled to optimize livestock production and curb or minimize grassland degradation to generate a sustainable system. This study examined the grasslands and LCC on the QTP, but the results could be applied to grasslands worldwide.

T-cell immunoglobulin- and mucin-domain-containing molecule-4 maintains adipose tissue homeostasis by orchestrating M2 macrophage polarization via nuclear factor kappa B pathway.

Obesity is generally associated with low-grade inflammation. Adipose tissue macrophages (ATMs) orchestrate metabolic inflammation. The classical (M1-like) or alternative (M2-like) activation of ATMs is functionally coupled with the metabolic status of fat tissues. It has been found that T-cell immunoglobulin- and mucin-domain-containing molecule-4 (Tim-4) inhibits inflammation by regulating macrophages. However, the exact role of Tim-4 in macrophage polarization and obesity remains unknown. Here, we identified Tim-4 as a critical switch governing macrophage M1/M2 polarization and energy homeostasis. Tim-4 deletion led to spontaneous obesity in elder mice and promoted obesity severity of db/db mice. Obesity microenvironment enhanced the expression of Tim-4 in white adipose tissue and ATMs. In vitro, we detected an increase in M1-like cells and decrease in M2-like cells in both peritoneal macrophages and bone marrow-derived macrophages from Tim-4 knockout mice. Mechanistically, we demonstrated that Tim-4 promoted M2-like macrophages polarization via suppressing nuclear factor kappa B (NF-κB) signaling pathway. In addition, we found that Tim-4 promoted TLR4 internalization, which might contribute to regulation of NF-κB signaling. Collectively, these results indicated that Tim-4 maintained adipose tissue homeostasis by regulating macrophage polarization via NF-κB pathway, which would provide a new target for obesity intervention.

HLA-DR genetic polymorphisms and hepatitis B virus mutations affect the risk of hepatocellular carcinoma in Han Chinese population.

BACKGROUND: Human leucocyte antigen (HLA)-DR plays a crucial role in the immune response against hepatitis B virus (HBV). We aimed to investigate the associations of HLA-DR single nucleotide polymorphisms (SNPs) with the generation of hepatocellular carcinoma (HCC)-related HBV mutations. The effects of HLA-DR SNPs and their interactions with HBV mutations on HCC risks were also determined. METHODS: Five HLA-DR SNPs (rs3135363, rs9268644, rs35445101, rs24755213, and rs984778) were genotyped in 792 healthy controls, 586 chronic hepatitis B (CHB) patients, 536 liver cirrhosis (LC) patients, and 1500 HCC patients using quantitative PCR. Sanger sequencing was used to identify the HBV mutations. Logistic regression model was performed to evaluate the association of HLA-DR SNPs with HCC risk and the frequencies of HCC-related HBV mutations. RESULTS: The variant genotypes at rs3135363, rs9268644, rs35445101, rs24755213, and rs984778 were associated with decreased HCC risks. In genotype C HBV-infected subjects, variant genotypes of these SNPs were associated with decreased frequencies of HCC-related HBV mutations such as C1653T, T1674C/G, G1719T, T1753A/C, A1762T/G1764A, A1846T, G1896A, G1899A, and preS deletion. AG genotype at rs3135363, CA genotype at rs9268644, and AG genotype at rs24755213 reduced the generation of T1753A/C and G1896A in genotype B HBV-infected subjects, respectively. In addition, the interactions of rs3135363, rs9268644, rs24755213 with C1653T, T1753A/C, A1846T, and G1896A decreased the risks of HCC. CONCLUSIONS: HLA-DR genetic polymorphisms might predispose the host to immunoselection of HCC-related HBV mutations and affect the HCC risks possibly through interacting with HBV mutations.

Potassium status and the risk of type 2 diabetes, cardiovascular diseases, and mortality: a meta-analysis of prospective observational studies.

Epidemiological evidence on the association between potassium and cardiometabolic outcomes remains controversial. This study aimed to examine associations of dietary intake and blood and urinary levels of potassium with risk of type 2 diabetes, cardiovascular disease (CVD), and mortality. Relevant prospective studies were retrieved through a comprehensive search of four electronic databases up to July 1, 2023. Random-effects models were used to pool the study-specific relative risks (RRs) and 95% confidence intervals (CIs). Fifty-six studies were included in this meta-analysis. A higher intake of potassium was significantly associated with a 16% lower risk of CVD (RR: 0.84, 95% CI: 0.78-0.90). Similar inverse associations were also observed between potassium intake and mortality. Each 1.0 g/d increment in potassium intake was associated with a decreased risk of CVD (RR: 0.85, 95% CI: 0.80-0.91) and all-cause mortality (RR: 0.93, 95% CI: 0.88-0.99). For blood and urinary potassium levels, higher level of blood potassium increased the risk of all-cause mortality by 23% (RR: 1.23, 95% CI: 1.11-1.36). The association of blood potassium levels with mortality was nonlinear (Pnon-linearit<0.001). However, urinary potassium levels were inversely associated with the risk of all-cause mortality (RR: 0.84, 95% CI: 0.76-0.93). Our findings support the benefits of moderate potassium consumption for primary prevention of chronic diseases and premature death.

Toll-interacting protein participates in immunity and development of the lepidopteran insect Antheraea pernyi.

Toll-interacting protein (Tollip) participates in multiple biological processes. However, the biological functions of Tollip proteins in insects remain to be further explored. Here, the genomic sequence of tollip gene from Antheraea pernyi (named Ap-Tollip) was identified with a length of 15,060 bp, including eight exons and seven introns. The predicted Ap-Tollip protein contained conserved C2 and CUE domains and was highly homologous to those tollips from invertebrates. Ap-Tollip was highly expressed in fat body compared with other determined tissues. As far as the developmental stages were concerned, the highest expression level was found at the 14th day in eggs or the 3rd day of the 1st instar. Ap-Tollip was also obviously regulated by lipopolysaccharide, polycytidylic acid or 20E in different tissues. In addition, the interaction between Ap-Tollip and ubiquitin was confirmed by western blotting and pull-down assay. RNAi of Ap-Tollip significantly affected the expression levels of apoptosis and autophagy-related genes. These results indicated that Ap-Tollip was involved in immunity and development of A. pernyi.

Stress response and tolerance mechanisms of NaHCO3 exposure based on biochemical assays and multi-omics approach in the liver of crucian carp (Carassius auratus).

The development and utilization of saline-alkaline water, an important backup resource, has received widespread attention. However, the underuse of saline-alkaline water, threatened by the single species of saline-alkaline aquaculture, seriously affects the development of the fishery economy. In this work, a 30-day NaHCO3 stress experimental study combined with analyses of untargeted metabolomics, transcriptome, and biochemical approaches was conducted on crucian carp to provide a better understanding of the saline-alkaline stress response mechanism in freshwater fish. This work revealed the relationships among the biochemical parameters, endogenous differentially expressed metabolites (DEMs), and differentially expressed genes (DEGs) in the crucian carp livers. The biochemical analysis showed that NaHCO3 exposure changed the levels of several physiological parameters associated with the liver, including antioxidant enzymes (SOD, CAT, GSH-Px), MDA, AKP, and CPS. According to the metabolomics study, 90 DEMs are involved in various metabolic pathways such as ketone synthesis and degradation metabolism, glycerophospholipid metabolism, arachidonic acid metabolism, and linoleic acid metabolism. In addition, transcriptomics data analysis showed that a total of 301 DEGs were screened between the control group and the high NaHCO3 concentration group, of which 129 up-regulated genes and 172 down-regulated genes. Overall, NaHCO3 exposure could cause lipid metabolism disorders and induce energy metabolism imbalance in the crucian carp liver. Simultaneously, crucian carp might regulate its saline-alkaline resistance mechanism by enhancing the synthesis of glycerophospholipid metabolism, ketone bodies, and degradation metabolism, at the same time increasing the vitality of antioxidant enzymes (SOD, CAT, GSH-Px) and nonspecific immune enzyme (AKP). Herein, all results will provide new insights into the molecular mechanisms underlying the stress responses and tolerance to saline-alkaline exposure in crucian carp.

Fast Recognition and Counting Method of Dragon Fruit Flowers and Fruits Based on Video Stream.

Dragon fruit (Hylocereus undatus) is a tropical and subtropical fruit that undergoes multiple ripening cycles throughout the year. Accurate monitoring of the flower and fruit quantities at various stages is crucial for growers to estimate yields, plan orders, and implement effective management strategies. However, traditional manual counting methods are labor-intensive and inefficient. Deep learning techniques have proven effective for object recognition tasks but limited research has been conducted on dragon fruit due to its unique stem morphology and the coexistence of flowers and fruits. Additionally, the challenge lies in developing a lightweight recognition and tracking model that can be seamlessly integrated into mobile platforms, enabling on-site quantity counting. In this study, a video stream inspection method was proposed to classify and count dragon fruit flowers, immature fruits (green fruits), and mature fruits (red fruits) in a dragon fruit plantation. The approach involves three key steps: (1) utilizing the YOLOv5 network for the identification of different dragon fruit categories, (2) employing the improved ByteTrack object tracking algorithm to assign unique IDs to each target and track their movement, and (3) defining a region of interest area for precise classification and counting of dragon fruit across categories. Experimental results demonstrate recognition accuracies of 94.1%, 94.8%, and 96.1% for dragon fruit flowers, green fruits, and red fruits, respectively, with an overall average recognition accuracy of 95.0%. Furthermore, the counting accuracy for each category is measured at 97.68%, 93.97%, and 91.89%, respectively. The proposed method achieves a counting speed of 56 frames per second on a 1080ti GPU. The findings establish the efficacy and practicality of this method for accurate counting of dragon fruit or other fruit varieties.

Reconfigurable Laser-Stimulated Lock-In Thermography for Surface Micro-Crack Detection.

Surface crack detection and sizing is essential for the manufacturing and maintenance of engines, run parts, and other metal elements of aircrafts. Among various non-destructive detection methods, the fully non-contact and non-intrusive technique based on laser-stimulated lock-in thermography (LLT) has recently attracted a lot of attention from the aerospace industry. We propose and demonstrate a system of reconfigurable LLT for three-dimensional surface crack detection in metal alloys. For large area inspection, the multi-spot LLT can speed up the inspection time by a factor of the number of spots. The minimum resolved size of micro-holes is ~50 µm in diameter limited by the magnification of the camera lens. We also study the crack length ranging from 0.8 to 3.4 mm by varying the modulation frequency of LLT. An empirical parameter related to the thermal diffusion length is found to show the linear dependence with the crack length. With the proper calibration, this parameter can be used to predict the sizing of the surface fatigue cracks. Reconfigurable LLT allows us to quickly locate the crack position and accurately measure its dimensions. This method is also applicable to the non-destructive detection of surface or sub-surface defect in other materials used in various industries.

Enantioselective Synthesis of Medium-Sized-Ring Lactones via Iridium-Catalyzed Z-Retentive Asymmetric Allylic Substitution Reaction.

Medium-sized rings are important structural units, but their synthesis, especially in a highly enantioselective manner, has been a great challenge. Herein we report an enantioselective synthesis of medium-sized-ring lactones by an iridium-catalyzed Z-retentive asymmetric allylic substitution reaction. The reaction features mild conditions and a broad substrate scope. Various eight- to 11-membered-ring lactones can be afforded in moderate to excellent yields (up to 88%) and excellent enantioselectivity (up to 99% ee). The utilization of both Z-allyl precursors and an Ir catalyst is critical for the medium-sized-ring formation.

Evaluation of prognostic staging systems of multiple myeloma in the era of novel agents.

This study aimed to evaluate the existing staging systems for multiple myeloma (MM) in the real world. From January 2010 to June 2019, we retrospectively analyzed 859 newly diagnosed MM patients from two institutions. Clinical data including laboratory findings, imaging examinations and staging system were obtained by reviewing medical records. Survival distributions were estimated using the Kaplan-Meier curve analysis, and Cox proportional hazards model were used to identified risk factors. The overall survival (OS) of eligible patients was 61.0 months. The Revised International Staging System (R-ISS) had a larger receiver operating characteristic curve area (0.603) than both the International Staging System (0.573) and the Durie Salmon staging system (0.567). In the group receiving immunomodulatory agents-based regimens, the median OS was 92.0 months in R-ISS I, 63.0 months in R-ISS II and 18.0 months in R-ISS III (p < 0.0001). In the group receiving proteasome inhibitors-based regimens, the median OS was 102.0 months in R-ISS I, 63.0 months in R-ISS II and 22.0 months in R-ISS III (p < 0.0001). In different subgroups grouped according to age, hemoglobin (HGB), creatinine, and Ca, R-ISS also had a good stratification effect. Patients in R-ISS II, which accounted for 69.9% of all patients, were further analyzed. Univariate and multivariate Cox analyses revealed that age >65 years (p = 0.001), HGB < 100 g/L (p < 0.001), elevated LDH (p = 0.001), and Ca (p = 0.010) were independent predictors of worse prognosis within R-ISS II. To conclusion, R-ISS remains a valuable staging system in the real world of the novel drug era. However, patients classified as R-ISS II still have great heterogeneity.

Microglial glutaminase 1 deficiency mitigates neuroinflammation associated depression.

Glutaminase 1 (GLS1) has recently been reported to be expressed in microglia and plays a crucial role in neuroinflamation. Significantly increased level of GLS1 mRNA expression together with neuroinflammation pathway were observed in postmortem prefrontal cortex from depressed patients. To find out the function of microglial GLS1 in depression and neuroinflammation, we generated transgenic mice (GLS1 cKO), postnatally losing GLS1 in microglia, to detect changes in the lipopolysaccharide (LPS)-induced depression model. LPS-induced anxiety/depression-like behavior was attenuated in GLS1 cKO mice, paralleled by a significant reduction in pro-inflammatory cytokines and an abnormal microglia morphological phenotype in the prefrontal cortex. Reduced neuroinflammation by GLS1 deficient microglia was a result of less reactive astrocytes, as GLS1 deficiency enhanced miR-666-3p and miR-7115-3p levels in extracellular vesicles released from microglia, thus suppressing astrocyte activation via inhibiting Serpina3n expression. Together, our data reveal a novel mechanism of GLS1 in neuroinflammation and targeting GLS1 in microglia may be a novel strategy to alleviate neuroinflammation-related depression and other disease.

Diversification of the phytophagous lineages of true bugs (Insecta: Hemiptera: Heteroptera) shortly after that of the flowering plants.

More than 95% of phytophagous true bug (Hemiptera: Heteroptera) species belong to four superfamilies: Miroidea (Cimicomorpha), Pentatomoidea, Coreoidea, and Lygaeoidea (all Pentatomomorpha). These iconic groups of highly diverse, overwhelmingly phytophagous insects include several economically prominent agricultural and silvicultural pest species, though their evolutionary history has not yet been well resolved. In particular, superfamily- and family-level phylogenetic relationships of these four lineages have remained controversial, and the divergence times of some crucial nodes for phytophagous true bugs have hitherto been little known, which hampers a better understanding of the evolutionary processes and patterns of phytophagous insects. In the present study, we used 150 species and concatenated nuclear and mitochondrial protein-coding genes and rRNA genes to infer the phylogenetic relationships within the Terheteroptera (Cimicomorpha + Pentatomomorpha) and estimated their divergence times. Our results support the monophyly of Cimicomorpha, Pentatomomorpha, Miroidea, Pentatomoidea, Pyrrhocoroidea, Coreoidea, and Lygaeoidea. The phylogenetic relationships across phytophagous lineages are largely congruent at deep nodes across the analyses based on different datasets and tree-reconstructing methods with just a few exceptions. Estimated divergence times and ancestral state reconstructions for feeding habit indicate that phytophagous true bugs explosively radiated in the Early Cretaceous-shortly after the angiosperm radiation-with the subsequent diversification of the most speciose clades (Mirinae, Pentatomidae, Coreinae, and Rhyparochromidae) in the Late Cretaceous.

Resistin induces chemokine and matrix metalloproteinase production via CAP1 receptor and activation of p38-MAPK and NF-κB signalling pathways in human chondrocytes.

OBJECTIVES: Adipokine resistin is highly expressed in the serum and synovial uid (SF) of patients with knee osteoarthritis (KOA) but its pathogenic role in KOA remains unclear. We aimed to explore the mechanism of resistin/CAP1 in human KOA chondrocytes. METHODS: We enrolled 103 patients with radiographic KOA and 86 healthy participants as controls. Resistin levels in serum and SF were determined by enzyme-linked immunosorbent assay (ELISA). CAP1 expression was measured in cartilage tissues using immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot. Effects of resistin on chondrocytes and CAP1 were evaluated via qRT-PCR and co-immunoprecipitation. The roles of CAP1, p38-MAPK, and NF-κB signalling pathways in KOA development were evaluated using adenovirus-mediated CAP1 short hairpin RNA, qRT-PCR, western blot, and ELISA. RESULTS: Resistin expression in serum and SF was elevated in severe radiographic KOA. CAP1 levels were higher in KOA cartilage and were positively correlated with resistin expression. Resistin promoted CCL3, CCL4, MMP13, and ADAMTS-4 expression through the CAP1 receptor. Resistin also directly bound to CAP1, as confirmed by co-immunoprecipitation. CAP1 knockdown in chondrocytes attenuated resistin-induced expression of CCL3, CCL4, MMP13, and ADAMTS-4 and activated p38-MAPK and NF-κB signalling pathways. CONCLUSIONS: Resistin binds CAP1 and upregulates the expression of proinflammatory cytokines and matrix-degrading enzymes via p38-MAPK and NF-κB signalling in human chondrocytes.