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1.
Cancer Res ; 2024 Sep 09.
Article in English | MEDLINE | ID: mdl-39250301

ABSTRACT

Tumor stroma plays a critical role in fostering tumor progression and metastasis. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma. Identifying the key molecular determinants for the pro-tumor properties of CAFs could enable the development of more effective treatment strategies. Herein, through analyses of single-cell sequencing data, we identified a population of CAFs expressing high levels of sulfatase 1 (SULF1), which was associated with poor prognosis in colorectal cancer (CRC) patients. CRC models using mice with conditional SULF1 knockout in fibroblasts revealed the tumor-supportive function of SULF1+ CAFs. Mechanistically, SULF1+ CAFs enhanced the release of vascular endothelial growth factor A (VEGFA) from heparan sulfate proteoglycan (HSPG). The increased bioavailability of VEGFA initiated the deposition of extracellular matrix (ECM) and enhanced angiogenesis. In addition, intestinal microbiota-produced butyrate suppressed SULF1 expression in CAFs through its HDAC inhibitory activity. The insufficient butyrate production in CRC patients increased the abundance of SULF1+ CAFs, thereby promoting tumor progression. Importantly, tumor growth inhibition by HDAC inhibition was dependent on SULF1 expression in CAFs, and CRC patients with more SULF1+ CAFs were more responsive to treatment with the HDAC inhibitor chidamide. Collectively, these findings unveil the critical role of SULF1+ CAFs in CRC and provide a strategy to stratify CRC patients for HDAC inhibitor treatment.

2.
Comput Struct Biotechnol J ; 23: 3211-3221, 2024 Dec.
Article in English | MEDLINE | ID: mdl-39257527

ABSTRACT

Regulated cell death is a pivotal regulatory mechanism governing the development and homeostasis of multicellular organisms. A comprehensive understanding of RCD's regulatory mechanisms is crucial for developing novel therapeutic strategies against diseases associated with cell death, such as cancer and neurodegenerative diseases. However, existing data repositories support limited types of cell death data and lack comprehensive annotation and analytical functionalities. Thus, establishing an extensive cell death database is an urgent imperative. To address this gap, we developed the Regulated Cell Death Database (RCDdb, chenyclab.com/RCDdb), the first comprehensively manually annotated database designed to support annotations and analytical capabilities across all RCD types. We compiled 3090 marker gene annotations associated with 15 RCD types from 2180 relevant articles. The RCDdb includes annotation data on these marker genes concerning diseases, drugs, pathways, proteins, and gene expressions. Furthermore, it provides 49 diverse visualization methods to present this information. More importantly, the RCDdb features three online analysis tools for identifying and analyzing RCD-related features within user-submitted data. Furthermore, the RCDdb offers a user-friendly interface for querying, browsing, analysis, and visualization of detailed information associated with each RCD category. This resource promises to significantly aid researchers in better understanding the mechanisms of cell death, thereby accelerating progress in research and therapeutic strategies aimed at combating RCD-related diseases.

3.
Animals (Basel) ; 14(16)2024 Aug 14.
Article in English | MEDLINE | ID: mdl-39199877

ABSTRACT

Changes in physiological and biochemical parameters are crucial for the reproductive performance and health of perinatal ewes. This study investigated the temporal variations in feed intake, nutrient digestibility, serum parameters, and ruminal fermentation on days 21, 14, and 7 before lambing (Q21, Q14, and Q7) and days 3, 7, and 14 after lambing (H3, H7, and H14). The results showed that dry matter intake (DMI) and glucose (Glu) gradually decreased (p < 0.05) before lambing and increased (p < 0.05) after lambing. The digestibility of dry matter (DMD), crude protein (CPD), and acid detergent fiber (ADFD) increased (p < 0.05) before lambing, then decreased (p < 0.05) on day H3, and then increased (p < 0.05) on day H14. The rumen pH, NH3-N, and triglycerides (TG) gradually increased (p < 0.05) before lambing and were higher (p < 0.05) on day Q7 than after lambing. The concentrations of acetate, butyrate, and total volatile fatty acids (T-VFA) were lower (p < 0.05) on day Q7 than those on days Q21 and Q14, then increased (p < 0.05) after lambing. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) concentrations gradually decreased (p < 0.05) in perinatal ewes. BHBA and NEFA concentrations were lower (p < 0.05) on day Q21 than those from days Q14 to H14. The rumen microbiota compositions were different (p < 0.05) in perinatal ewes, and g_Anaerovibrio, g_Lachnobacterium, and g_Schwartzia were positively correlated (p < 0.05) with DMI, Glu, acetate, propionate, and T-VFA, and negatively correlated (p < 0.05) with LDL-C. g_Bacillus was negatively correlated (p < 0.05) with DMI, Glu, acetate, propionate, butyrate, and T-VFA, but positively correlated (p < 0.05) with rumen pH and LDL-C. In summary, the DMI, nutrient digestibility, rumen fermentation, and serum parameters changed during the perinatal period of ewes, and the changes in DMI, serum glucose, acetate, propionate, and T-VFA were related to the rumen bacteria.

4.
Quant Imaging Med Surg ; 14(8): 5737-5747, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-39144051

ABSTRACT

Background: Patients with lung cancer accompanied by sarcopenia may have a poor prognosis. Normally, low muscle mass associated with sarcopenia is assessed using the skeletal muscle index (SMI). It remains unclear whether the standardized skeletal muscle area (SMA) using 2-dimensional (2D) vertebral metrics (called the skeletal muscle vertebral related index, SMVI) could substitute for SMI when it is missing. The aim of this study was to investigate the feasibility of SMVI as an alternative to SMI, and their associations with overall survival (OS) in patients with non-small cell lung cancer (NSCLC). Methods: In this single-center study, a retrospective analysis was conducted on 433 NSCLC patients who underwent computed tomography (CT) scans. At the third lumbar vertebra (L3) level, measurements were taken for SMA, vertebral body area, transverse vertebral diameter (TVD), longitudinal vertebral diameter (LVD), and vertebral height (VH). The 4 SMVIs were skeletal muscle vertebral ratio (SMVR) (SMA/vertebral body area), skeletal muscle transverse vertebral diameter index (SMTVDI) (SMA/TVD2), skeletal muscle longitudinal vertebral diameter index (SMLVDI) (SMA/LVD2), and skeletal muscle vertebral height index (SMVHI) (SMA/VH2). The patients were categorized into low and high muscle mass groups based on SMI, and the differences in SMVIs between the 2 groups were compared to assess their correlation with SMI. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were utilized to assess the discriminatory ability. Kaplan-Meier curves were employed to compare the survival disparity between the 2 groups. Results: We included 191 male and 242 female patients in this study. Compared to the high muscle mass group, patients in the low muscle mass group exhibited significantly lower SMVR, SMTVDI, SMLVDI, and SMVHI (all P<0.05). All 4 SMVIs showed a positive correlation with SMI, with Spearman correlation coefficients of 0.83, 0.76, 0.75, and 0.67, respectively (all P<0.001). The AUC for diagnosing low muscle mass was higher than 0.8 for all 4 SMVI parameters. The Kaplan-Meier curve revealed that the low-risk group had a better survival probability than the high-risk group in the SMVR, SMTVDI, and SMLVDI. Conclusions: The SMVI functions as an alternative metric for evaluating skeletal muscle mass in the assessment of NSCLC based on SMI.

5.
J Neuroimmunol ; 395: 578441, 2024 Aug 20.
Article in English | MEDLINE | ID: mdl-39216158

ABSTRACT

INTRODUCTION: Dendritic cells (DCs) are crucial to form ectopic germinal centers (GCs) in the hyperplastic thymus (HT), which are typically found in anti-acetylcholine receptor autoantibody-positive myasthenia gravis (MG) patients. However, the characteristics of such DCs in the HT and their roles in thymic hyperplasia formation remain unclear. METHODS: We collected thymic tissue from MG patients and patients who underwent cardiac surgery. The tissues were cut into sections for immunohistochemistry and immunofluorescence or digested into a single cell suspension for flow cytometry. RESULTS: In addition to formation of ectopic GCs, we found that the proportion of the medulla in the thymic parenchyma was higher than that in the cortex (areacortex/areamedulla, 1.279 vs. 0.6576) in the HT of MG patients. The density of conventional dendritic cells (cDCs) in the HT was 131 ± 64.36 per mm2, whereas in normal thymic tissue, the density was 59.17 ± 22.54 per mm2. The more abundant cDCs expressed co-stimulatory molecules (CD80 and CD86) strongly. Moreover, the more abundant subset was mainly CD141+ DCs (cDC1s), accounting for an increase from 15% to 29%. However, these increased cDC1s appeared to be unrelated to Hassall's corpuscles and ectopic GCs. CONCLUSION: Thymic hyperplasia in MG patients is manifested as an increase in the proportion of the thymic medulla accompanied by increases in the density and functional activation as well as changes in the subset composition of cDCs.

6.
JACS Au ; 4(8): 2915-2924, 2024 Aug 26.
Article in English | MEDLINE | ID: mdl-39211615

ABSTRACT

PROTAC (Proteolysis TArgeting Chimeras) is a promising therapeutic approach for targeted protein degradation that recruits an E3 ubiquitin ligase to a specific protein of interest (POI), leading to its degradation by the proteasome. Recently, we developed a novel split-and-mix PROTAC system based on liposome self-assembly (LipoSM-PROTAC) which could achieve target protein degradation at comparable concentrations comparable to small molecules. In this study, we expanded protein targets based on the LipoSM-PROTAC platform and further examined its therapeutic effects in vivo. Notably, this platform could efficiently degrade the protein level of MEK1/2 in A375 cells or Alk in NCI-H2228 cells and display obvious tumor inhibition (60-70% inhibition rate) with negligible toxicity. This study further proved the LipoSM-PROTAC's application potentials.

7.
Vaccines (Basel) ; 12(8)2024 Jul 25.
Article in English | MEDLINE | ID: mdl-39203968

ABSTRACT

BACKGROUND: Measles and rubella are vaccine-preventable diseases targeted for elimination in most World Health Organization regions, and China is considered to have momentum towards measles elimination. Therefore, this study aimed to assess the population immunity levels against measles and rubella in Zhejiang Province in China in order to provide valuable insights for informing future public health measures and contributing to the ongoing global campaign against these diseases. MATERIALS AND METHODS: A cross-sectional serological survey was conducted in 2022. A total of 2740 blood samples were collected from healthy individuals spanning the age range of 0-59 years, representing diverse demographic strata across 11 prefectures in Zhejiang Province in China. The sera were tested for measles and rubella IgG antibodies to determine positivity rates and geometric mean concentrations (GMCs). RESULTS: The overall positivity rate for the measles IgG antibody was 85.3%, with a GMC of 588.30 mIU/mL. The positivity rate for the rubella IgG antibody was 70.9%, and the GMC was 35.30 IU/mL. Measles IgG antibody positivity rates across the 0-11 months, 12-23 months, 24-35 months, 3-5 years, 6-9 years, 10-14 years, 15-19 years, 20-29 years, and 30-59 years age groups were 63.1%, 92.5%, 97.0%, 94.0%, 85.8%, 77.3%, 86.9%, 84.9%, and 88.7%, respectively (trend χ2 = 118.34, p < 0.001). Correspondingly, rubella antibody positivity rates for these same age brackets were 55.9%, 87.9%, 94.7%, 88.2%, 69.9%, 54.2%, 72.6%, 67.5%, and 74.3% (trend χ2 = 199.18, p < 0.001). Both univariate and multivariate analyses consistently demonstrated that age, immunization history, and differing economic levels were significant factors contributing to variations in antibody levels. CONCLUSIONS: The seroprevalence of measles and rubella was lower than that required for herd immunity. Periodic vaccination campaigns should be launched to increase immunity.

8.
Eur J Pharm Sci ; 202: 106888, 2024 Aug 25.
Article in English | MEDLINE | ID: mdl-39191357

ABSTRACT

Fentanyl combined with bupivacaine in subarachnoid anesthesia exerts a strong synergistic analgesic effect, extending the duration of analgesia. However, the mechanism of enhanced analgesic effect of fentanyl remains elusive. The present study investigated the potential mechanism of the analgesic effect of fentanyl when combined with bupivacaine. The subarachnoid injection (SI) rat model was employed, and SI of fentanyl or/and bupivacaine was used to investigate their analgesic effect. Dorsal root ganglion (DRG)' RNA sequencing (RNA-Seq) and bioinformatics analysis were performed to evaluate the downstream mechanisms of MicroRNAs (miRNAs). Further validation tests included RT-PCR, Western blot, and immunofluorescence. A single SI of fentanyl or bupivacaine decreased the positive responses to stimulation when used alone or in combination. RNA-seq results revealed that miR-381-3p played a role in the fentanyl-driven promotion of analgesia. Bioinformatics analysis and dual-luciferase reporter identified TRPM7 as a direct downstream target gene of miR-381-3p. In vitro, overexpression of miR-381-3p could further block fentanyl-induced expression of TRPM7, p-ERK1/2, CGRP, and SP. In addition, antagomir-381-3p reversed the inhibitory effect of fentanyl on the expression of TRPM7, p-ERK1/2, CGRP, and SP, in vivo; however, TRPM7 siRNA rescued the effect of antagomir-381-3p. In conclusion, fentanyl inhibits p-ERK by targeting TRPM7 via miR-381-3p, lowering the production of CGRP and SP, and ultimately inducing analgesic effects.

9.
Front Microbiol ; 15: 1407270, 2024.
Article in English | MEDLINE | ID: mdl-39171271

ABSTRACT

Coix seed is a good product for both medicinal and food use, which is highly susceptible to aflatoxin B1 (AFB1) contamination during field transport, storage, and processing. The aim of this study is to find microbial strains that can solve the problem of contamination of coix seed. In this study, the AFB1-degrading microorganism SX1-1 was isolated and identified as a Bacillus megaterium based on morphology, microscopy, and 16S rDNA sequencing. The optimum culture conditions for SX1-1 to degrade AFB1 were determined to be 12 h. The optimum degradation conditions were 72 h, 57°C, and an initial pH of 8.0. The highest degradation of AFB1 was observed in the fermentation supernatant of the SX1-1 strain, with a degradation rate of 97.45%. In addition, whole-genome sequencing analysis of this strain revealed the presence of a number of enzymes that could potentially degrade AFB1. Importantly, SX1-1 was able to degrade AFB1-contaminated coix seed in situ by 50.06% after co-culture. In conclusion, this strain had a high AFB1 degradation ability, and has great potential and great application as a biocontrol agent for AFB1 degradation of coix seed.

10.
Neurol Sci ; 2024 Aug 28.
Article in English | MEDLINE | ID: mdl-39196497

ABSTRACT

INTRODUCTION: Here, we describe the clinical characteristics and therapeutic effects of myasthenia gravis (MG) coexisting with thyroid eye disease (TED). METHODS: We collated clinical data from MG patients in our hospital between 2012 and 2022 and analyzed the clinical characteristics of MG patients with hyperthyroidism, MG patients with TED and ocular myasthenia gravis (OMG) patients with TED. RESULTS: We recruited 62 MG patients with hyperthyroidism, including 13 MG patients with TED and 10 OMG patients with TED. There were 70 MG patients without hyperthyroidism; 29 of these were OMG. Compared with patients without hyperthyroidism, patients with hyperthyroidism had an earlier age at onset and milder clinical symptoms (P < 0.05). The incidence of thymus hyperplasia in patients with hyperthyroidism and TED was significantly lower than that in patients without TED (38.5% vs. 69.4%, P < 0.05); these patients also had a significantly lower antibody titer for the acetylcholine receptor [0.72 (0.27, 14.93) nmol/L vs. 2.38 (0.28, 49.51) nmol/L, P < 0.05]. Diplopia was significantly more frequent in OMG patients with TED than in patients with OMG (84.6% vs. 44.8%, P < 0.05), and the rate of diplopia in OMG patients with TED was significantly higher after treatment with bromostigmine and glucocorticoid (69.2% vs. 3.4%, P < 0.05). CONCLUSIONS: MG patients with TED had a significantly lower incidence of thymus hyperplasia and a lower antibody titer for the acetylcholine receptor. Patients with OMG and TED are more likely to develop diplopia; it is very difficult to treat diplopia in these patients.

11.
BMC Public Health ; 24(1): 2046, 2024 Jul 30.
Article in English | MEDLINE | ID: mdl-39080560

ABSTRACT

BACKGROUND: Does preschool height predict adult stature in undernourished settings? The extent to which preschool length or height forecasts young adult stature is unclear in chronically undernourished populations. METHODS: In 2006-8, we assessed height in a cohort of 2074 young adults, aged 16-23 years, in rural Nepal who, as preschoolers (≤ 4 year), were measured at baseline and again 16 months later during a vitamin A supplementation trial in 1989-91. We assessed by linear regression the ability of preschool length (L, measured < 24 mo) or height (Ht, 24-59 mo), at each year of age to predict 16-23 year old height, adjusted for month of young adult age, interval duration (in months), caste, preschool weight-for-height z-score and, in young women, time since menarche, marriage status and pregnancy history. RESULTS: Young women were a mean of 0.81, 1.11, 0.82, 0.24, 0.44 cm taller (all p < 0.01) and young men, 0.84, 1.18, 0.74, 0.64 and 0.48 cm taller (all p < 0.001) per cm of attained L/Ht at each successive preschool year of age and, overall, were 2.04 and 2.40 cm taller for each unit increase in preschool L/Ht z-score (L/HAZ) (both p < 0.001). Coefficients were generally larger for 16-month follow-up measurements. The percent of young adult height attained by children with normal L/HAZ (>-1) increased from 38-40% mid-infancy to ∼ 69-74% by 6 years of age. By 3-6 years of age heights of stunted children (L/HAZ<-2) were consistently ∼ 4-7% lower in their young adult height versus normal statured children. There was no effect of preschool vitamin A receipt. CONCLUSIONS: Shorter young children become shorter adults but predictive effects can vary by sex, age assessed, and may be influenced by year or season of measurement.


Subject(s)
Body Height , Rural Population , Humans , Nepal , Female , Child, Preschool , Male , Adolescent , Young Adult , Rural Population/statistics & numerical data , Infant , Cohort Studies , Vitamin A
12.
Environ Sci Technol ; 58(29): 12865-12874, 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-38995089

ABSTRACT

Short-term exposure to PM2.5 or O3 can increase mortality risk; however, limited studies have evaluated their interaction. A multicity time series study was conducted to investigate the synergistic effect of PM2.5 and O3 on mortality in China, using mortality data and high-resolution pollutant predictions from 272 cities in 2013-2015. Generalized additive models were applied to estimate associations of PM2.5 and O3 with mortality. Modification and interaction effects were explored by stratified analyses and synergistic indexes. Deaths attributable to PM2.5 and O3 were evaluated with or without modification of the other pollutant. The risk of total nonaccidental mortality increased by 0.70% for each 10 µg/m3 increase in PM2.5 when O3 levels were high, compared to 0.12% at low O3 levels. The effect of O3 on total nonaccidental mortality at high PM2.5 levels (1.26%) was also significantly higher than that at low PM2.5 levels (0.59%). Similar patterns were observed for cardiovascular or respiratory diseases. The relative excess risk of interaction and synergy index of PM2.5 and O3 on nonaccidental mortality were 0.69% and 1.31 with statistical significance, respectively. Nonaccidental deaths attributable to short-term exposure of PM2.5 or O3 when considering modification of the other pollutant were 28% and 31% higher than those without considering modification, respectively. Our results found synergistic effects of short-term coexposure to PM2.5 and O3 on mortality and suggested underestimations of attributable risks without considering their synergistic effects.


Subject(s)
Air Pollutants , Cities , Ozone , Particulate Matter , China/epidemiology , Humans , Air Pollutants/toxicity , Environmental Exposure , Mortality
13.
Sci Total Environ ; 948: 174883, 2024 Oct 20.
Article in English | MEDLINE | ID: mdl-39034013

ABSTRACT

Marine prokaryotes and microeukaryotes are essential components of microbial food webs, and drive the biogeochemical cycling. However, the underlying ecological mechanisms driving prokaryotic and microeukaryotic community assembly in large-scale coastal ecosystems remain unclear. In this study, we studied biogeographic patterns of prokaryotic and microeukaryotic communities in the coastal and shelf ecosystem of the China Seas. Results showed that prokaryotic richness was the highest in the Yangtze River Plume, whereas microeukaryotic richness decreased from south to north. Prokaryotic-microeukaryotic co-occurrence networks display greater complexity in the Yangtze River Plume compared to other regions, potentially indicating higher environmental heterogeneity. Furthermore, the cross-domain networks revealed that prokaryotes were more interconnected with each other than with microeukaryotes or between microeukaryotes, and all hub nodes were bacterial taxa, suggesting that prokaryotes may be more important for sustaining the stability and multifunctionality of coastal ecosystem than microeukaryotes. Variation Partitioning Analysis revealed that approximately equal proportions of environmental, biotic and spatial factors contribute to variations in microbial community composition. Temperature was the primary environmental driver of both prokaryotic and microeukaryotic communities across the China Seas. Additionally, stochastic processes (dispersal limitation) and deterministic processes (homogeneous selection) were two major ecological factors in shaping microeukaryotic and prokaryotic assemblages, respectively, suggesting their different environmental plasticity and evolutionary mechanisms. Overall, these results demonstrate both prokaryotic and microeukaryotic communities displayed a latitude-driven distribution pattern and different assembly mechanisms, improving our understanding of microbial biogeography patterns under global change and anthropogenic activity driven habitat diversification in the coastal and shelf ecosystem.


Subject(s)
Ecosystem , China , Oceans and Seas , Prokaryotic Cells , Microbiota , Biodiversity , Seawater , Bacteria/classification , Environmental Monitoring
14.
Curr Microbiol ; 81(8): 252, 2024 Jul 02.
Article in English | MEDLINE | ID: mdl-38953991

ABSTRACT

Spiroplasma, belonging to the class Mollicutes, is a small, helical, motile bacterium lacking a cell wall. Its host range includes insects, plants, and aquatic crustaceans. Recently, a few human cases of Spiroplasma infection have been reported. The diseases caused by Spiroplasma have brought about serious economic losses and hindered the healthy development of agriculture. The pathogenesis of Spiroplasma involves the ability to adhere, such as through the terminal structure of Spiroplasma, colonization, and invasive enzymes. However, the exact pathogenic mechanism of Spiroplasma remains a mystery. Therefore, we systematically summarize all the information about Spiroplasma in this review article. This provides a reference for future studies on virulence factors and treatment strategies of Spiroplasma.


Subject(s)
Spiroplasma , Virulence Factors , Spiroplasma/genetics , Animals , Humans , Virulence Factors/genetics , Virulence , Gram-Negative Bacterial Infections/microbiology , Plants/microbiology
15.
Bioorg Chem ; 151: 107676, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39068716

ABSTRACT

Dual-specificity tyrosine phosphorylation-regulated kinase A (DYRK1A) is a potential drug target for diabetes. The DYRK1A inhibitor can promote ß cells proliferation, increase insulin secretion and reduce blood sugar in diabetes. In this paper, a series ß-carboline-cinnamic acid skeletal derivatives were designed, synthesized and evaluated to inhibit the activity of DYRK1A and promote pancreatic islet ß cell proliferation. Pharmacological activity showed that all of the compounds could effectively promote pancreatic islet ß cell proliferation at a concentration of 1 µM, and the cell viability of compound A1, A4 and B4 reached to 381.5 %, 380.2 % and 378.5 %, respectively. Compound A1, A4 and B4 could also inhibit the expression of DYRK1A better than positive drug harmine. Further mechanistic studies showed that compound A1, A4 and B4 could inhibit DYRK1A protein expression via promoting its degradation and thus enhancing the expression of proliferative proteins PCNA and Ki67. Molecular docking showed that ß-carboline scaffold of these three compounds was fully inserted into the ATP binding site and formed hydrophobic interactions with the active pocket. Besides, these three compounds were predicted to possess better drug-likeness properties using SwissADME. In conclusion, compounds A1, A4 and B4 were potent pancreatic ß cell proliferative agents as DYRK1A inhibitors and might serve as promising candidates for the treatment of diabetes.


Subject(s)
Carbolines , Cell Proliferation , Cinnamates , Dose-Response Relationship, Drug , Drug Design , Dyrk Kinases , Molecular Docking Simulation , Protein Kinase Inhibitors , Protein Serine-Threonine Kinases , Protein-Tyrosine Kinases , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Carbolines/pharmacology , Carbolines/chemistry , Carbolines/chemical synthesis , Cell Proliferation/drug effects , Structure-Activity Relationship , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Molecular Structure , Cinnamates/pharmacology , Cinnamates/chemistry , Cinnamates/chemical synthesis , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Humans , Animals , Diabetes Mellitus/drug therapy , Diabetes Mellitus/metabolism , Cell Survival/drug effects
16.
Science ; 385(6704): eadm8762, 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38963845

ABSTRACT

Understanding how numerous quantitative trait loci (QTL) shape phenotypic variation is an important question in genetics. To address this, we established a permanent population of 18,421 (18K) rice lines with reduced population structure. We generated reference-level genome assemblies of the founders and genotyped all 18K-rice lines through whole-genome sequencing. Through high-resolution mapping, 96 high-quality candidate genes contributing to variation in 16 traits were identified, including OsMADS22 and OsFTL1 verified as causal genes for panicle number and heading date, respectively. We identified epistatic QTL pairs and constructed a genetic interaction network with 19 genes serving as hubs. Overall, 170 masking epistasis pairs were characterized, serving as an important factor contributing to genetic background effects across diverse varieties. The work provides a basis to guide grain yield and quality improvements in rice.


Subject(s)
Epistasis, Genetic , Genome, Plant , Oryza , Quantitative Trait Loci , Oryza/genetics , Whole Genome Sequencing , Chromosome Mapping , Genes, Plant , Genotype , Gene Regulatory Networks , Phenotype
17.
Article in English | MEDLINE | ID: mdl-39008384

ABSTRACT

In semi-supervised learning (SSL), many approaches follow the effective self-training paradigm with consistency regularization, utilizing threshold heuristics to alleviate label noise. However, such threshold heuristics lead to the underutilization of crucial discriminative information from the excluded data. In this paper, we present OTAMatch, a novel SSL framework that reformulates pseudo-labeling as an optimal transport (OT) assignment problem and simultaneously exploits data with high confidence to mitigate the confirmation bias. Firstly, OTAMatch models the pseudo-label allocation task as a convex minimization problem, facilitating end-to-end optimization with all pseudo-labels and employing the Sinkhorn-Knopp algorithm for efficient approximation. Meanwhile, we incorporate epsilon-greedy posterior regularization and curriculum bias correction strategies to constrain the distribution of OT assignments, improving the robustness with noisy pseudo-labels. Secondly, we propose PseudoNCE, which explicitly exploits pseudo-label consistency with threshold heuristics to maximize mutual information within self-training, significantly boosting the balance of convergence speed and performance. Consequently, our proposed approach achieves competitive performance on various SSL benchmarks. Specifically, OTAMatch substantially outperforms the previous state-of-the-art SSL algorithms in realistic and challenging scenarios, exemplified by a notable 9.45% error rate reduction over SoftMatch on ImageNet with 100K-label split, underlining its robustness and effectiveness.

18.
BMC Musculoskelet Disord ; 25(1): 549, 2024 Jul 16.
Article in English | MEDLINE | ID: mdl-39010020

ABSTRACT

OBJECTIVE: In chronic low back pain (CLBP), the relationship between spinal pathologies and paraspinal muscles fat infiltration remains unclear. This study aims to evaluate the relationship between MRI findings and paraspinal muscles morphology and fat infiltration in CLBP patients by quantitative MRI. METHODS: All the CLBP patients were enrolled from July 2021 to December 2022 in four medical institutions. The cross-sectional area (CSA) and proton density fat fraction (PDFF) of the multifidus (MF) and erector spinae (ES) muscles at the central level of the L4/5 and L5/S1 intervertebral discs were measured. MRI findings included degenerative lumbar spondylolisthesis (DLS), intervertebral disc degeneration (IVDD), facet arthrosis, disc bulge or herniation, and disease duration. The relationship between MRI findings and the paraspinal muscles PDFF and CSA in CLBP patients was analyzed. RESULTS: A total of 493 CLBP patients were included in the study (198 females, 295 males), with an average age of 45.68 ± 12.91 years. Our research indicates that the number of MRI findings are correlated with the paraspinal muscles PDFF at the L4/5 level, but is not significant. Moreover, the grading of IVDD is the primary factor influencing the paraspinal muscles PDFF at the L4-S1 level (BES at L4/5=1.845, P < 0.05); DLS was a significant factor affecting the PDFF of MF at the L4/5 level (B = 4.774, P < 0.05). After including age, gender, and Body Mass Index (BMI) as control variables in the multivariable regression analysis, age has a significant positive impact on the paraspinal muscles PDFF at the L4-S1 level, with the largest AUC for ES PDFF at the L4/5 level (AUC = 0.646, cut-off value = 47.5), while males have lower PDFF compared to females. BMI has a positive impact on the ES PDFF only at the L4/5 level (AUC = 0.559, cut-off value = 24.535). CONCLUSION: The degree of paraspinal muscles fat infiltration in CLBP patients is related to the cumulative or synergistic effects of multiple factors, especially at the L4/L5 level. Although age and BMI are important factors affecting the degree of paraspinal muscles PDFF in CLBP patients, their diagnostic efficacy is moderate.


Subject(s)
Adipose Tissue , Chronic Pain , Low Back Pain , Lumbar Vertebrae , Magnetic Resonance Imaging , Paraspinal Muscles , Humans , Paraspinal Muscles/diagnostic imaging , Paraspinal Muscles/pathology , Male , Low Back Pain/diagnostic imaging , Low Back Pain/etiology , Female , Middle Aged , Prospective Studies , Adult , Lumbar Vertebrae/diagnostic imaging , Lumbar Vertebrae/pathology , Adipose Tissue/diagnostic imaging , Adipose Tissue/pathology , Chronic Pain/diagnostic imaging , Intervertebral Disc Degeneration/diagnostic imaging , Intervertebral Disc Degeneration/pathology
19.
J Am Chem Soc ; 146(28): 19397-19404, 2024 Jul 17.
Article in English | MEDLINE | ID: mdl-38959221

ABSTRACT

The magnetoelectric material has attracted multidisciplinary interest in the past decade for its potential to accommodate various functions. Especially, the external electric field can drive the quantum behaviors of such materials via the spin-electric coupling effect, with the advantages of high spatial resolution and low energy cost. In this work, the spin-electric coupling effect of Mn2+-doped ferroelectric organic-inorganic hybrid perovskite [(CH3)3NCH2Cl]CdCl3 with a large piezoelectric effect was investigated. The electric field manipulation efficiency for the allowed transitions was determined by the pulsed electron paramagnetic resonance. The orientation-included Hamiltonian of the spin-electric coupling effect was obtained via simulating the angle-dependent electric field modulated continuous-wave electron paramagnetic resonance. The results demonstrate that the applied electric field affects not only the principal values of the zero-field splitting tensor but also its principal axis directions. This work proposes and exemplifies a route to understand the spin-electric coupling effect originating from the crystal field imposed on a spin ion being modified by the applied electric field, which may guide the rational screening and designing of hybrid perovskite ferroelectrics that satisfy the efficiency requirement of electric field manipulation of spins in quantum information applications.

20.
Asia Pac J Clin Nutr ; 33(3): 405-412, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38965728

ABSTRACT

BACKGROUND AND OBJECTIVES: If the proportion of calcium intake over a whole day is related to the risk of cognitive impairment in adults is still largely unknown. This research aimed to examine the relation of dietary calcium intake at dinner versus breakfast with the risk of cognitive impairment by using data from the China Health and Nutrition Survey (CHNS). METHODS AND STUDY DESIGN: A total of 2,099 participants (including 668 cognitive impairment) in the CHNS (1997-2006) were included. The participants were categorized into 5 groups in accordance with the ratio of dietary calcium intake at dinner and breakfast (Δ = dinner/breakfast). After adjustment was conducted for a series of confounding factors, Cox hazard regression modelling was performed to discuss the relation of Δ with cognitive impairment. Dietary substitution models were used to explore the changes in cognitive impairment risk when a 5% dietary calcium intake at dinner was replaced with dietary calcium intake at breakfast. RESULTS: Participants in the highest distribution of Δ showed a greater susceptibility to cognitive impairment than those in the lowest quintile, with an adjusted hazard ratio of cognitive impairment of 1.38 (95% CI: 1.08-1.76). When maintaining total calcium intake, substituting 5% of dietary calcium intake at dinner with calcium intake at breakfast was related to an 8% decrease in the risk of cognitive impairment. CONCLUSIONS: Higher dietary calcium intake at dinner was associated with an increased risk of cognitive impairment, emphasizing the importance of appropriately distributing dietary calcium intake between breakfast and dinner.


Subject(s)
Breakfast , Calcium, Dietary , Cognitive Dysfunction , Humans , Calcium, Dietary/administration & dosage , Male , Female , China/epidemiology , Middle Aged , Cognitive Dysfunction/epidemiology , Cohort Studies , Adult , Meals , Nutrition Surveys , Aged , Risk Factors , East Asian People
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