-
The Journal of Biological Chemistry May 2024Infiltration of monocyte-derived cells to sites of infection and injury is greater in males than in females, due in part, to increased chemotaxis, the process of...
Infiltration of monocyte-derived cells to sites of infection and injury is greater in males than in females, due in part, to increased chemotaxis, the process of directed cell movement toward a chemical signal. The mechanisms governing sexual dimorphism in chemotaxis are not known. We hypothesized a role for the store-operated calcium entry (SOCE) pathway in regulating chemotaxis by modulating leading and trailing edge membrane dynamics. We measured the chemotactic response of bone marrow derived macrophages (BMDMs) migrating towards complement component 5a (C5a). Chemotactic ability was dependent on sex and inflammatory phenotype (M0, M1, M2), and correlated with SOCE. Notably, females exhibited a significantly lower magnitude of SOCE than males. When we knocked out the SOCE gene, stromal interaction molecule 1 (STIM1), it eliminated SOCE and equalized chemotaxis across both sexes. Analysis of membrane dynamics at the leading and trailing edges showed that STIM1 influences chemotaxis by facilitating retraction of the trailing edge. Using BTP2 to pharmacologically inhibit SOCE mirrored the effects of STIM1 knockout, demonstrating a central role of STIM/Orai-mediated calcium signaling. Importantly, by monitoring the recruitment of adoptively transferred monocytes in an in vivo model of peritonitis, we show that increased infiltration of male monocytes during infection is dependent on STIM1. These data support a model in which STIM1-dependent SOCE is necessary and sufficient for mediating the sex difference in monocyte recruitment and macrophage chemotactic ability by regulating trailing edge dynamics.
PubMed: 38815866
DOI: 10.1016/j.jbc.2024.107422 -
PloS One 2024The aim of this study was to investigate the mediating effects of health literacy on the relationship between frailty and health-related quality of life (HRQOL) among...
PURPOSE
The aim of this study was to investigate the mediating effects of health literacy on the relationship between frailty and health-related quality of life (HRQOL) among community-dwelling older adults.
METHODS
This study used the Korean Frailty and Aging Cohort Database (KFACD) for secondary data analysis. We selected data from 1,631 people without missing main variable values for analysis. Frailty was determined based on the modified Fried's phenotype [MFP], and HRQOL was measured using the Korean version of the 5-level EuroQol questionnaire (EQ-5D-5L). Health literacy was assessed using the questions on the Behavioral Risk Factor Surveillance System (BRFSS) used by the U.S. Center for Disease Control and Prevention. To examine the mediating role of health literacy in the relationship between frailty and HRQOL, Baron & Kenny's three-step mediating effect verification method was utilized.
RESULTS
The participants had a mean frailty score of 1.37±1.02, health literacy score of 8.56±2.59, and HRQOL score of 0.84±0.10. Frailty was negatively correlated with health literacy (r = -0.27, p < .001) and HRQOL (r = -0.32, p < .001), while health literacy was positively correlated with HRQOL (r = 0.34, p < .001). We observed that health literacy played a partial mediating role in the relationship between frailty and HRQOL.
CONCLUSION
To increase older adults' HRQOL, measures that directly prevent and manage frailty as well as interventions that target the enhancement of health literacy are needed.
Topics: Humans; Quality of Life; Aged; Male; Female; Health Literacy; Independent Living; Frailty; Aged, 80 and over; Republic of Korea; Frail Elderly; Surveys and Questionnaires
PubMed: 38814978
DOI: 10.1371/journal.pone.0303164 -
PloS One 2024Alterations in the brain's connectivity or the interactions among brain regions have been studied with the aid of resting state (rs)fMRI data attained from large numbers...
Alterations in the brain's connectivity or the interactions among brain regions have been studied with the aid of resting state (rs)fMRI data attained from large numbers of healthy subjects of various demographics. This has been instrumental in providing insight into how a phenotype as fundamental as age affects the brain. Although machine learning (ML) techniques have already been deployed in such studies, novel questions are investigated in this work. We study whether young brains develop properties that progressively resemble those of aged brains, and if the aging dynamics of older brains provide information about the aging trajectory in young subjects. The degree of a prospective monotonic relationship will be quantified, and hypotheses of brain aging trajectories will be tested via ML. Furthermore, the degree of functional connectivity across the age spectrum of three datasets will be compared at a population level and across sexes. The findings scrutinize similarities and differences among the male and female subjects at greater detail than previously performed.
Topics: Humans; Male; Female; Brain; Adult; Magnetic Resonance Imaging; Aging; Aged; Middle Aged; Young Adult; Healthy Volunteers; Machine Learning; Connectome; Brain Mapping; Adolescent; Aged, 80 and over
PubMed: 38814972
DOI: 10.1371/journal.pone.0300720 -
The Turkish Journal of Pediatrics May 2024Hyaline fibromatosis syndrome is a rare autosomal recessive disorder caused by ANTXR2 pathogenic variants. The disorder is characterized by the deposition of amorphous...
BACKGROUND
Hyaline fibromatosis syndrome is a rare autosomal recessive disorder caused by ANTXR2 pathogenic variants. The disorder is characterized by the deposition of amorphous hyaline material in connective tissues. The hallmarks of the disease are joint contractures, generalized skin stiffness, hyperpigmented papules over extensor surfaces of joints, fleshy perianal masses, severe diarrhea, and gingival hypertrophy. The severity of the disease varies and prognosis is poor. No specific treatment is yet available. Most patients with the severe form of the condition pass away before the second year of age. In this study, we describe the clinical and molecular findings of a cohort of seven hyaline fibromatosis syndrome patients who were diagnosed and followed up at a single tertiary reference center in Turkey.
METHODS
Genomic DNA was extracted by standard salting out method from peripheric blood samples of three patients. In one patient DNA extraction was performed on pathology slides since peripheric blood DNA was not available. All coding exons of the ANTXR2 were amplified and sequenced on ABI Prism 3500 Genetic Analyser.
RESULTS
Sanger sequencing was performed in 3 patients and homozygous c.945T>G p.(Cys315Trp), c.1073dup p.(Ala359CysfsTer13), and c.1074del p.(Ala359HisfsTer50) variants were identified in ANTXR2. All patients passed away before the age of five years.
CONCLUSIONS
HFS is a rare, progressive disorder with a broad phenotypic spectrum. HFS can be recognized easily with distinctive clinical features. Nevertheless, it has poor prognosis with increased mortality due to severe clinical decompensation.
Topics: Humans; Hyaline Fibromatosis Syndrome; Male; Female; Infant; Child, Preschool; Receptors, Peptide; Turkey; Child
PubMed: 38814306
DOI: 10.24953/turkjpediatr.2024.4511 -
The Turkish Journal of Pediatrics May 2024We aimed to delineate the genotype and phenotype of patients with KCNQ2 mutations from South China.
BACKGROUND
We aimed to delineate the genotype and phenotype of patients with KCNQ2 mutations from South China.
METHODS
Clinical manifestations and characteristics of KCNQ2 mutations of patients from South China were analyzed. Previous patients with mutations detected in this study were reviewed.
RESULTS
Eighteen epilepsy patients with KCNQ2 mutations, including seven self-limited neonatal epilepsy (SeLNE), two self-limited infantile epilepsy (SeLIE) and nine developmental and epileptic encephalopathy (DEE) were enrolled. The age of onset (p=0.006), mutation types (p=0.029), hypertonia (p=0.000), and seizure offset (p=0.029) were different in self-limited epilepsy (SeLE) and DEE. De novo mutations were mainly detected in DEE patients (p=0.026). The mutation position, EEG or the age of onset were not predictive for the seizure or ID/DD outcome in DEE, while the development of patients free of seizures was better than that of patients with seizures (p=0.008). Sodium channel blockers were the most effective anti-seizure medication, while the age of starting sodium channel blockers did not affect the seizure or development offset. We first discovered the seizure recurrence ratio in SeLNE/SeLIE was 23.1% in South China. Four novel mutations (c.790T>C, c.355_363delGAGAAGAG, c.296+2T>G, 20q13.33del) were discovered. Each of eight mutations (c.1918delC, c.1678C>T, c.683A>G, c.833T>C, c.868G>A, c.638G>A, c.997C>T, c.830C>T) only resulted in SeLE or DEE, while heterogeneity was also found. Six patients in this study have enriched the known phenotype caused by the mutations (c.365C>T, c.1A>G, c.683A>G, c.833T>C, c.830C>T, c.1678C>T).
CONCLUSION
This research has expanded known phenotype and genotype of KCNQ2-related epilepsy, and the different clinical features of SeLE and DEE from South China.
Topics: Humans; KCNQ2 Potassium Channel; China; Female; Male; Mutation; Infant; Phenotype; Child, Preschool; Genotype; Child; Infant, Newborn; Epilepsy; Genetic Testing
PubMed: 38814296
DOI: 10.24953/turkjpediatr.2024.4593 -
Journal of Primary Care & Community... 2024In addition to the morbidity and mortality associated with acute infection, COVID-19 has been associated with persistent symptoms (>30 days), often referred to as Long...
BACKGROUND
In addition to the morbidity and mortality associated with acute infection, COVID-19 has been associated with persistent symptoms (>30 days), often referred to as Long COVID (LC). LC symptoms often cluster into phenotypes, resembling conditions such as fibromyalgia, postural orthostatic tachycardiac syndrome (POTS), and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). LC clinics have been established to best address the needs of LC patients and continuity of care. We developed a cross-sectional survey to assess treatment response through our LC Clinic (LCC).
METHODS
A 25-question survey (1-10 Likert scale) was expert- and content-validated by LCC clinicians, patients, and patient advocates. The survey assessed LC symptoms and the helpfulness of different interventions, including medications and supplements. A total of 852 LCC patients were asked to complete the survey, with 536 (62.9%) responding.
RESULTS
The mean time from associated COVID-19 infection to survey completion was 23.2 ± 6.4 months. The mean age of responders was 52.3 ± 14.1 (63% females). Self-reported symptoms were all significantly improved ( < .001) from the initial visit to the LCC (baseline) to the time of the follow-up survey. However, only 4.5% (24/536) of patients rated all symptoms low (1-2) at the time of the survey, indicating low levels of full recovery in our cohort. The patients rated numerous interventions as being helpful, including low-dose naltrexone (45/77; 58%), vagal nerve stimulation (18/34; 53%), and fisetin (28/44; 64%).
CONCLUSIONS
Patients report general improvements in symptoms following the initial LCC visit, but complete recovery rates remain low at 23.2 ± 6.4 months.
Topics: Humans; Cross-Sectional Studies; COVID-19; Middle Aged; Female; Male; Post-Acute COVID-19 Syndrome; Adult; Surveys and Questionnaires; Longitudinal Studies; Disease Progression; SARS-CoV-2; Aged
PubMed: 38813984
DOI: 10.1177/21501319241258671 -
Saudi Journal of Gastroenterology :... May 2024Colorectal cancer (CRC) ranks third in both the incidence and mortality rates among male and female cancers, and it is the leading digestive system cancer. Due to the...
BACKGROUND
Colorectal cancer (CRC) ranks third in both the incidence and mortality rates among male and female cancers, and it is the leading digestive system cancer. Due to the inter- and intratumor heterogeneity of cancer, the TNM system is insufficient for predicting prognosis, necessitating the use of molecular biomarkers for prognostic prediction. Toll-like receptors (TLRs) have been associated with CRC survival rates. This study focused on the investigation of the role and potential value of TLRs in CRC genotyping to aid in immunotherapy for CRC patients.
METHODS
Differential gene expression analysis was performed on CRC transcriptomic data from The Cancer Genome Atlas database. TLRs were referred from the literature, and their intersection with differentially expressed genes (DEGs) in CRC yielded TLR-DEGs. The expression patterns of TLR-DEGs were predicted using the STRING website, and copy number variations of TLR-DEGs were analyzed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on TLR-DEGs. ConsensusClusterPlus R package was used for clustering CRC patients, and ESTIMATE and GSEAbase were employed to analyze immune characteristics of different subtypes. Immune phenotyping scores and tumor immune dysfunction and exclusion scores were evaluated. DEGs of different subtypes were analyzed, followed by GO and KEGG enrichment analyses, the protein-protein interaction (PPI) network analysis, and further selection of hub genes. The sensitivity of drugs was assessed using the identified hub genes.
RESULTS
We identified 37 TLR-DEGs, and the PPI analysis revealed their coexpression, although they were distributed on different chromosomes. Enrichment analyses indicated that the 37 TLR-DEGs were linked to cancer cell immune response. Based on these TLR-DEGs, CRC patients were classified into three subtypes. Cluster2 exhibited lower survival rates and higher immune infiltration levels and predicted poorer response to immune checkpoint inhibitor therapy. The intersection of DEGs from cluster2 and cluster1 with DEGs from cluster2 and cluster3 yielded a set of 426 commonly shared DEGs. Enrichment analyses revealed that these shared DEGs might regulate immune cell viability. Eight common hub genes for different subtypes were further identified to predict drug-related correlations.
CONCLUSION
The developed TLR genotyping was used to predict the survival status and tumor microenvironment of CRC, providing a foundation for understanding the molecular mechanisms of TLR signaling and deepening its clinical significance.
PubMed: 38813725
DOI: 10.4103/sjg.sjg_424_23 -
Frontiers in Aging Neuroscience 2024There are sex differences in vulnerability and resilience to the stressors of aging and subsequent age-related cognitive decline. Cellular senescence occurs as a...
There are sex differences in vulnerability and resilience to the stressors of aging and subsequent age-related cognitive decline. Cellular senescence occurs as a response to damaging or stress-inducing stimuli. The response includes a state of irreversible growth arrest, the development of a senescence-associated secretory phenotype, and the release of pro-inflammatory cytokines associated with aging and age-related diseases. Senolytics are compounds designed to eliminate senescent cells. Our recent work indicates that senolytic treatment preserves cognitive function in aging male F344 rats. The current study examined the effect of senolytic treatment on cognitive function in aging female rats. Female F344 rats (12 months) were treated with dasatinib (1.2 mg/kg) + quercetin (12 mg/kg) or ABT-263 (12 mg/kg) or vehicle for 7 months. Examination of the estrus cycle indicated that females had undergone estropause during treatment. Senolytic treatment may have increased sex differences in behavioral stress responsivity, particularly for the initial training on the cued version of the watermaze. However, pre-training on the cue task reduced stress responsivity for subsequent spatial training and all groups learned the spatial discrimination. In contrast to preserved memory observed in senolytic-treated males, all older females exhibited impaired episodic memory relative to young (6-month) females. We suggest that the senolytic treatment may not have been able to compensate for the loss of estradiol, which can act on aging mechanisms for anxiety and memory independent of cellular senescence.
PubMed: 38813533
DOI: 10.3389/fnagi.2024.1384554 -
Frontiers in Neuroscience 2024The relationship between routine cerebrospinal fluid (CSF) testing and the disease phenotype of amyotrophic lateral sclerosis (ALS) is unclear, and there are some...
BACKGROUND
The relationship between routine cerebrospinal fluid (CSF) testing and the disease phenotype of amyotrophic lateral sclerosis (ALS) is unclear, and there are some contradictions in current studies.
METHODS
This study aimed to analyze the relationship between CSF profiles and disease phenotype in ALS patients. We collected 870 ALS patients and 96 control subjects admitted to West China Hospital of Sichuan University. CSF microprotein, albumin, IgG, index of IgG (IgG), albumin quotient (Q), and serum IgG were examined.
RESULTS
In ALS patients, CSF IgG, and Q were significantly increased, while CSF IgG was decreased, compared with control subjects. Approximately one-third of ALS patients had higher CSF IgG levels. The multiple linear regression analysis identified that CSF IgG was weakly negatively associated with ALS functional rating scale revised (ALSFRS-R) scores ( = -0.062, = 0.041). This significance was found in male ALS but not in female ALS. The Cox survival analyses found that upregulated CSF IgG was significantly associated with the increased mortality risk in ALS [HR = 1.219 (1.010-1.470), = 0.039].
CONCLUSION
In the current study, the higher CFS IgG was associated with increased mortality risk of ALS. CSF IgG may be associated with the severity of ALS. These findings may be sex-specific.
PubMed: 38812975
DOI: 10.3389/fnins.2024.1375892 -
Frontiers in Endocrinology 2024Prader-Willi syndrome (PWS) is a rare disease, which shows a peculiar clinical phenotype, including obesity, which is different from essential obesity (EOB).... (Comparative Study)
Comparative Study
INTRODUCTION
Prader-Willi syndrome (PWS) is a rare disease, which shows a peculiar clinical phenotype, including obesity, which is different from essential obesity (EOB). Metabolomics might represent a valuable tool to reveal the biochemical mechanisms/pathways underlying clinical differences between PWS and EOB. The aim of the present (case-control, retrospective) study was to determine the metabolomic profile that characterizes PWS compared to EOB.
METHODS
A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeted metabolomic approach was used to measure a total of 188 endogenous metabolites in plasma samples of 32 patients with PWS (F/M = 23/9; age: 31.6 ± 9.2 years; body mass index [BMI]: 42.1 ± 7.0 kg/m), compared to a sex-, age- and BMI-matched group of patients with EOB (F/M = 23/9; age: 31.4 ± 6.9 years; BMI: 43.5 ± 3.5 kg/m).
RESULTS
Body composition in PWS was different when compared to EOB, with increased fat mass and decreased fat-free mass. Glycemia and HDL cholesterol were higher in patients with PWS than in those with EOB, while insulinemia was lower, as well as heart rate. Resting energy expenditure was lower in the group with PWS than in the one with EOB, a difference that was missed after fat-free mass correction. Carrying out a series of Tobit multivariable linear regressions, adjusted for sex, diastolic blood pressure, and C reactive protein, a total of 28 metabolites was found to be associated with PWS (vs. non-PWS, i.e., EOB), including 9 phosphatidylcholines (PCs) ae, 5 PCs aa, all PCs aa, 7 lysoPCs a, all lysoPCs, 4 acetylcarnitines, and 1 sphingomyelin, all of which were higher in PWS than EOB.
CONCLUSIONS
PWS exhibits a specific metabolomic profile when compared to EOB, suggesting a different regulation of some biochemical pathways, fundamentally related to lipid metabolism.
Topics: Humans; Prader-Willi Syndrome; Female; Male; Adult; Metabolomics; Case-Control Studies; Retrospective Studies; Obesity, Morbid; Metabolome; Young Adult; Body Mass Index; Body Composition; Chromatography, Liquid; Tandem Mass Spectrometry
PubMed: 38812813
DOI: 10.3389/fendo.2024.1386265