-
The ISME Journal Jul 2024Effector proteins secreted by bacteria that infect mammalian and plant cells often subdue eukaryotic host cell defenses by simultaneously affecting multiple targets....
Effector proteins secreted by bacteria that infect mammalian and plant cells often subdue eukaryotic host cell defenses by simultaneously affecting multiple targets. However, instances when a bacterial effector injected in the competing bacteria sabotage more than a single target have not been reported. Here, we demonstrate that the effector protein, LtaE, translocated by the type IV secretion system (T4SS) from the soil bacterium Lysobacter enzymogenes into the competing bacterium, Pseudomonas protegens, affects several targets, thus disabling the antibacterial defenses of the competitor. One LtaE target is the transcription factor, LuxR1, that regulates biosynthesis of the antimicrobial compound, orfamide A. Another target is the sigma factor, PvdS, required for biosynthesis of another antimicrobial compound, pyoverdine. Deletion of the genes involved in orfamide A and pyoverdine biosynthesis disabled the antibacterial activity of P. protegens, whereas expression of LtaE in P. protegens resulted in the near-complete loss of the antibacterial activity against L. enzymogenes. Mechanistically, LtaE inhibits the assembly of the RNA polymerase complexes with each of these proteins. The ability of LtaE to bind to LuxR1 and PvdS homologs from several Pseudomonas species suggests that it can sabotage defenses of various competitors present in the soil or on plant matter. Our study thus reveals that the multi-target effectors have evolved to subdue cell defenses not only in eukaryotic hosts but also in bacterial competitors.
PubMed: 38959853
DOI: 10.1093/ismejo/wrae121 -
European Journal of Paediatric... Jun 2024CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy. Ganaxolone, a neuroactive steroid, reduces the frequency of major motor seizures in...
CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy. Ganaxolone, a neuroactive steroid, reduces the frequency of major motor seizures in children with CDD. This analysis explored the effect of ganaxolone on non-seizure outcomes. Children (2-19 years) with genetically confirmed CDD and ≥ 16 major motor seizures per month were enrolled in a double-blind randomized placebo-controlled trial. Ganaxolone or placebo was administered three times daily for 17 weeks. Behaviour was measured with the Anxiety, Depression and Mood Scale (ADAMS), daytime sleepiness with the Child Health Sleep Questionnaire, and quality of life with the Quality of Life Inventory-Disability (QI-Disability) scale. Scores were compared using ANOVA, adjusted for age, sex, number of anti-seizure mediations, baseline 28-day major motor seizure frequency, baseline developmental skills, and behaviour, sleep or quality of life scores. 101 children with CDD (39 clinical sites, 8 countries) were randomized. Median (IQR) age was 6 (3-10) years, 79.2 % were female, and 50 received ganaxolone. After 17 weeks of treatment, Manic/Hyperactive scores (mean difference 1.27, 95%CI -2.38,-0.16) and Compulsive Behaviour scores (mean difference 0.58, 95%CI -1.14,-0.01) were lower (improved) in the ganaxolone group compared with the placebo group. Daytime sleepiness scores were similar between groups. The total change in QOL score for children in the ganaxolone group was 2.6 points (95%CI -1.74,7.02) higher (improved) than in the placebo group but without statistical significance. Along with better seizure control, children who received ganaxolone had improved behavioural scores in select domains compared to placebo.
PubMed: 38959712
DOI: 10.1016/j.ejpn.2024.06.005 -
European Journal of Obstetrics,... Apr 2024Use clinical pain measurement tools to investigate and compare the prevalence of pelvic loin disoders in women with and without endometriosis.
OBJECTIVE
Use clinical pain measurement tools to investigate and compare the prevalence of pelvic loin disoders in women with and without endometriosis.
STUDY DESIGN
Chronic pelvic pain (CPP) associated with endometriosis has diverse origins, including musculoskeletal factors. Musculoskeletal dysfunction in the pelvic region is theorized to result from sustained muscular contraction, triggered by altered visceral stimuli and adoption of antalgic postures, causing secondary damage to muscles, ligaments, and joints. CPP significantly impacts quality of life, relationships, sexuality, and mental health. However, limited data exists on musculoskeletal impacts of endometriosis and CPP. It was made a case-control study at Maternidade Escola Assis Chateaubriand from August 2017 to January 2021. Evaluated 71 women: 41 in endometriosis group (EG) and 30 in control group (CG). Data collection included sociodemographic questionnaires, musculoskeletal physiotherapeutic evaluations, pain mapping, pressure pain thresholds, kinesiophobia, and disability measurements. Statistical analysis was performed using Spearman's Rho test to determine correlations.
RESULTS
Mean age of participants was 31 years. EG exhibited lower pain threshold variations in lumbopelvic trigger points than CG (P < .05). Significant muscle flexibility differences between groups were observed; EG had reduced flexibility (P < .05). Most common pain areas were hypogastrium in EG (48.78 %) and left lumbar in CG (30 %). EG had higher kinesiophobia values (P = .009). There was a weak association between kinesiophobia-pressure threshold association observed in CG's lumbar pelvic region.
CONCLUSION
Women with Endometriosis and CPP exhibit higher prevalence of musculoskeletal disorder, lower pain thresholds, decreased lumbopelvic muscle range of motion, higher kinesiophobia scores, and increased disability indices with low back pain compared to healthy women.
PubMed: 38959628
DOI: 10.1016/j.ejogrb.2024.04.030 -
Molecular Genetics and Metabolism Jun 2024Our report describes clinical, genetic, and biochemical features of participants with a molecularly confirmed congenital disorder of glycosylation (CDG) enrolled in the...
OBJECTIVE
Our report describes clinical, genetic, and biochemical features of participants with a molecularly confirmed congenital disorder of glycosylation (CDG) enrolled in the Frontiers in Congenital Disorders of Glycosylation (FCDGC) Natural History cohort at year 5 of the study.
METHODS
We enrolled individuals with a known or suspected CDG into the FCDGC Natural History Study, a multicenter prospective and retrospective natural history study of all genetic causes of CDG. We conducted a cross-sectional analysis of baseline study visit data from participants with confirmed CDG who were consented into the FCDGC Natural History Study (5U54NS115198) from October 2019 to November 2023.
RESULTS
Three hundred thirty-three subjects consented to the FCDGC Natural History Study. Of these, 280 unique individuals had genetic data available that was consistent with a diagnosis of CDG. These 280 individuals were enrolled into the study between October 8, 2019 and November 29, 2023. One hundred forty-one (50.4%) were female, and 139 (49.6%) were male. Mean and median age at enrollment was 10.1 and 6.5 years, respectively, with a range of 0.22 to 71.4 years. The cohort encompassed individuals with disorders of N-linked protein glycosylation (57%), glycosylphosphatidylinositol anchor disorder (GPI anchor) (15%), disorders of Golgi homeostasis, trafficking and transport (12%), dolichol metabolism disorders (5%), disorders of multiple pathways (6%), and other (5%). The most frequent presenting symptom(s) leading to diagnosis were developmental delay/disability (77%), followed by hypotonia (56%) and feeding difficulties (42%). Mean and median time between first related symptom and diagnosis was 2.7 and 0.8 years, respectively. One hundred percent of individuals in our cohort had developmental differences/disabilities at the time of their baseline visit, followed by 97% with neurologic involvement, 91% with gastrointestinal (GI)/liver involvement, and 88% with musculoskeletal involvement. Severity of disease in individuals was scored on the Nijmegen Progression CDG Rating Scale (NPCRS) with 27% of scores categorized as mild, 44% moderate, and 29% severe. Of the individuals with N-linked protein glycosylation defects, 83% of those with data showed a type 1 pattern on carbohydrate deficient transferrin (CDT) analysis including 82/84 individuals with PMM2-CDG, 6% a type 2 pattern, 1% both type 1 and type 2 pattern and 10% a normal or nonspecific pattern. One hundred percent of individuals with Golgi homeostasis and trafficking defects with data showed a type 2 pattern on CDT analysis, while Golgi transport defect showed a type II pattern 73% of the time, a type 1 pattern for 7%, and 20% had a normal or nonspecific pattern. Most of the variants documented were classified as pathogenic or likely pathogenic using ACMG criteria. For the majority of the variants, the predicted molecular consequence was missense followed by nonsense and splice site, and the majority of the diagnoses are inherited in an autosomal recessive pattern but with disorders of all major nuclear inheritance included.
DISCUSSION
The FCDGC Natural History Study serves as an important resource to build future research studies, improve clinical care, and prepare for clinical trial readiness. Herein is the first overview of CDG participants of the FCDGC Natural History Study.
PubMed: 38959600
DOI: 10.1016/j.ymgme.2024.108509 -
Multiple Sclerosis and Related Disorders Jun 2024Previous evidence suggests sex differences in the clinical course of relapsing remitting multiple sclerosis (RRMS), but comprehensive early-stage prospective studies are...
BACKGROUND
Previous evidence suggests sex differences in the clinical course of relapsing remitting multiple sclerosis (RRMS), but comprehensive early-stage prospective studies are lacking. We aim to quantify the impact of sex on clinical outcomes in early-stage RRMS.
METHODS
Utilizing prospective cohort data, we assessed the impact of biological sex on time-to-relapse, disability progression (Expanded Disability Status Scale [EDSS]), extremity function (Nine-Hole Peg Test, Timed-25-food walk test), cognition (Paced Auditory Serial Addition Test, Symbol Digit Modalities Test), quality-of-life (Hamburg Quality of Life Questionnaire in Multiple Sclerosis, Short-Form-36), fatigue (Fatigue Severity Scale, Fatigue Scale for Motor and Cognitive functions), and depression (Beck Depression Inventory-II) in clinically isolated syndrome (CIS) or RRMS patients. Inclusion was within 12 months of symptom onset. Linear, negative binomial, mixed, and Cox models estimated male vs. female effects at the four-year follow-up including baseline-to-follow-up course.
RESULTS
We included 149 patients (65.1 % female). Eighty-five completed four-year follow-up. No sex differences in time-to-relapse emerged (HR = 0.91;95 %CI = 0.53-1.58). Males had no increased risk of EDSS worsening (OR = 0.75;95 %CI = 0.21-2.35) compared to females. Similarly, minor/no sex differences emerged in other outcomes.
CONCLUSIONS
Four years after first manifestation, neither disease activity (disability progression and relapse rate) nor patient-reported outcomes showed sex-related disparities in this early-MS-cohort.
GOV IDENTIFIER
NCT01371071.
PubMed: 38959589
DOI: 10.1016/j.msard.2024.105749 -
International Immunopharmacology Jul 2024Intervertebral disc degeneration (IDD) is the leading cause of low back pain, which is one of the major factors leading to disability and severe economic burden.... (Review)
Review
Intervertebral disc degeneration (IDD) is the leading cause of low back pain, which is one of the major factors leading to disability and severe economic burden. Necroptosis is an important form of programmed cell death (PCD), a highly regulated caspase-independent type of cell death that is regulated by receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL)-mediated, play a key role in the pathophysiology of various inflammatory, infectious and degenerative diseases. Recent studies have shown that necroptosis plays an important role in the occurrence and development of IDD. In this review, we provide an overview of the initiation and execution of necroptosis and explore in depth its potential mechanisms of action in IDD. The analysis focuses on the connection between NP cell necroptosis and mitochondrial dysfunction-oxidative stress pathway, inflammation, endoplasmic reticulum stress, apoptosis, and autophagy. Finally, we evaluated the possibility of treating IDD by inhibiting necroptosis, and believed that targeting necroptosis may be a new strategy to alleviate the symptoms of IDD.
PubMed: 38959544
DOI: 10.1016/j.intimp.2024.112616 -
Journal of Gerontological Nursing Jul 2024Physical disabilities may exacerbate the natural decline in sleep quality that occurs with aging. In the current study, we assessed sleep quality and medicinal sleep aid... (Comparative Study)
Comparative Study
PURPOSE
Physical disabilities may exacerbate the natural decline in sleep quality that occurs with aging. In the current study, we assessed sleep quality and medicinal sleep aid use among 87 community-dwelling older adults with ( = 24) and without ( = 63) physical disabilities.
METHOD
Sleep quality, duration, and efficiency were assessed subjectively with the Pittsburgh Sleep Quality Index. Sleep duration and efficiency were objectively measured with actigraphy. Participants self-reported medicinal sleep aid use.
RESULTS
Significant group differences were observed in sleep duration measured objectively ( = 0.01) and subjectively ( = 0.04). No other group differences were observed for sleep factors ( > 0.05) or medicinal sleep aid use ( = 0.41).
CONCLUSION
Findings show that physical disability may be a factor in sleep duration; however, physical disability was not found to be associated with worsened sleep perception or greater reliance on medicinal sleep aids. Future research should consider longer objective actigraphy assessment windows and explore potential subgroup differences in sex and race/ethnicity. [(7), 12-18.].
Topics: Humans; Aged; Male; Female; Independent Living; Sleep Quality; Disabled Persons; Aged, 80 and over; Poverty; Actigraphy; Sleep; Middle Aged
PubMed: 38959511
DOI: 10.3928/00989134-20240618-03 -
Science Advances Jul 2024Down syndrome (DS) is the most common chromosomal disorder and a major cause of intellectual disability. The genetic etiology of DS is the extra copy of chromosome 21...
Down syndrome (DS) is the most common chromosomal disorder and a major cause of intellectual disability. The genetic etiology of DS is the extra copy of chromosome 21 (HSA21)-encoded genes; however, the contribution of specific HSA21 genes to DS pathogenesis remains largely unknown. Here, we identified ZBTB21, an HSA21-encoded zinc-finger protein, as a transcriptional repressor in the regulation of synaptic function. We found that normalization of the gene copy number in DS mice corrected deficits in cognitive performance, synaptic function, and gene expression. Moreover, we demonstrated that ZBTB21 binds to canonical cAMP-response element (CRE) DNA and that its binding to CRE could be competitive with CRE-binding factors such as CREB. ZBTB21 represses CRE-dependent gene expression and results in the negative regulation of synaptic plasticity, learning and memory. Together, our results identify ZBTB21 as a CRE-binding protein and repressor in cAMP-dependent gene regulation, contributing to cognitive defects in DS.
Topics: Down Syndrome; Animals; Mice; Cyclic AMP Response Element-Binding Protein; Synapses; Humans; Gene Expression Regulation; Transcription Factors; Transcription, Genetic; Neuronal Plasticity; Disease Models, Animal; Gene Dosage; Protein Binding
PubMed: 38959316
DOI: 10.1126/sciadv.adm7373 -
PloS One 2024Adults with a learning disability who receive social care are legally entitled to a personal budget. Personal budgets were introduced to promote choice and control in...
Adults with a learning disability who receive social care are legally entitled to a personal budget. Personal budgets were introduced to promote choice and control in support. Individual Service Funds were introduced as a flexible way that personal budgets can be managed by a provider while maintaining choice and control for the individual. Individual Service Funds have been shown to improve quality of life for individuals and efficiency in support. Despite this, only 20% of local authorities offer them to adults with a learning disability, demonstrating the need for resources to be developed to support their delivery. This protocol described a co-production study with key stakeholders to develop and refine Individual Service Fund resources. Our primary aim is to co-produce two actionable resources: to support development, delivery, consistency, and sustained provision of ISFs; and to support uptake and optimal use of ISFs by recipients. We also aim to user-test and evaluate these resources with three Local Authorities. The result of this study will be two resources that will support the uptake of Individual Service Funds for adults with a learning disability that will be freely available online.
Topics: Humans; Learning Disabilities; Budgets; Adult; Quality of Life
PubMed: 38959215
DOI: 10.1371/journal.pone.0306522 -
Medical Science Monitor : International... Jul 2024BACKGROUND Gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) is the most common histological subtype of extra-nodal DLBCL, but the risk factors, prognostic...
BACKGROUND Gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) is the most common histological subtype of extra-nodal DLBCL, but the risk factors, prognostic biomarkers, histopathological classifications, and treatment strategies have not had significant progress. Emerging evidence shows that cystatin SN (CST1) is involved in tumor progression in several cancer types, but its role in GI-DLBCL has not been revealed. MATERIAL AND METHODS We established a cohort consisting of 84 patients with GI-DLBCL who underwent surgical resection. The expression of CST1 in the cohort was investigated by immunohistochemistry, which divided the patients into subgroups with low or high expression of CST1. Moreover, the CST1 expression in GI-DLBCL tissues or adjacent GI tissues were compared with RT-qPCR. The correlation between CST1 expression and clinicopathological factors was analyzed with the chi-square test. The prognostic significance of CST1 was estimated by univariate and multivariate analysis, and statistical significance was analyzed with the log-rank test. RESULTS CST1 was aberrantly upregulated in GI-DLBCL tissues compared with in non-tumor GI tissues. High expression of CST1 indicated poor prognosis of GI-DLBCL (P=0.012), and CST1 can be regarded as an independent prognostic biomarker of GI-DLBCL (hazard ratio=3.07). In our study, serum lactate dehydrogenase (P=0.002), performance status (P=0.003), Lugano stage (P=0.002), and International Prognostic Index (P=0.001) were also prognostic factors of GI-DLBCL. CONCLUSIONS CST1 is an independent prognostic biomarker of GI-DLBCL, indicating unfavorable prognosis. Our results suggested that CST1 detection can be a promising method to stratify high-risk patients and guide individual treatment.
Topics: Humans; Male; Female; Lymphoma, Large B-Cell, Diffuse; Biomarkers, Tumor; Prognosis; Middle Aged; Gastrointestinal Neoplasms; Aged; Adult; Salivary Cystatins; Immunohistochemistry; Cohort Studies
PubMed: 38959178
DOI: 10.12659/MSM.943551