bluuebunny/crossref_metadata_2025 huggingface dataset:
ESAS SÖZLEŞME İLE YÖNETİM KURULUNA ÜYE SEÇİMİNİN AĞIRLAŞTIRILMASI VE AĞIRLAŞTIRILMIŞ NİSABA AYKIRI GENEL KURUL KARARININ GEÇERSİZLİĞİ
Authors: Saat Dursun
Published: November 2024

Anonim ortaklığın yönetim kurulu genel kurul tarafından seçilmektedir. Genel kurul, yönetim kurulunun seçileceği toplantıda esas sözleşmede aksine bir düzenleme bulunmadığı müddetçe 6102 sayılı Türk Ticaret Kanunu’nun (TTK) 418. maddesinde belirtilen toplantı ve karar nisaplarına uymak zorundadır. Çalışmamızda öncelikle, yönetim kuruluna üye seçimim hususunda 418.maddede düzenlenen yeter sayıların şirket esas sözleşmesi ile ağırlaştırılıp ağırlaştırılmayacağı konusunda üzerinde durulacak ve bu kapsamda TTK m.340’da düzenlenen emredici hükümler ilkesi ışığında yorumlar yapılmaya çalışacaktır. Özellikle birinci genel kurul toplantısında aranan ağırlaştırıcı nisabın ikinci genel kurul toplantısı bakımından da geçerli olup olmadığı da ifade edilecektir. Akabinde genel kurulunun esas sözleşme ile ağırlaştırılmış nisaba aykırı kararlarının geçersizliği tespit edilmeye çalışacaktır. Genel kurul kararının yoklukla mı malul yoksa iptal edilebilir nitelikte bir karar mı olduğu konusunda değerlendirmelerde bulunurken bir yandan öğreti görüşleri diğer yandan ise yüksek yargının yerleşik haline gelmiş olan içtihatları dikkate alınacaktır.
GÖREV SÜRESİ SONA EREN YÖNETİM KURULU ÜYELERİNİN HUKUKİ STATÜLERİNİN TÜRK VE İSVİÇRE YARGI KARARLARI IŞIĞINDA KARŞILAŞTIRMALI ANALİZİ VE TESPİT EDİLEN SORUNLARA İLİŞKİN ÖNERİLER
Authors: Toraman Çolgar Emek
Published: November 2024

Bu makalede, görev süresi biten ve yeniden seçilmeyen yönetim kurulu üyelerinin hukuki durumları tespit edilmiş ve bu tespitin yaratacağı çeşitli sorunlara Türk ve İsviçre yargı kararları ışığında çözüm önerileri paylaşılmıştır. TTK ile OR hükümlerindeki parallelik nedeniyle karşılaştırma için İsviçre hukuku seçilmiştir. Ancak anılan hükümlerdeki benzerliklere rağmen, Türk ve İsviçre mahkemeleri ile öğretisinin konuyu çok farklı bakış açısıyla ele almaları dikkat çekicidir ve bu nedenle karşılaştırmalı analizi yapılmaya değerdir. Konu, Türk öğreti ve yargısını uzun yıllardır meşgul eden, üzerinde çokça tartışılan ve hakkında kıymetli eserler verilen bir konudur. Öte yandan bu çalışma ile mevcut bilimsel birikimden yararlanılarak, özellikle süresi bitmesine rağmen şirketi fiilen yöneten kişilerin görev, yetki ve hukuki sorumlulukları tartışılmış, benimsenen bakış açısının şirketin temsili ile diğer menfaat sahiplerinin menfaatleri için yaratacağı sorunlara çözüm bulunmaya çaba gösterilmiştir.
Exploring the rumen microbial function in Angus bulls with divergent residual feed intake
Authors: Sidney Taylor , Treon Emily , Taiwo Godstime , Felton Eugene , Fan Peixin , Ogunade Ibukun M.
Published: November 2024

This study leverages Shotgun metagenomics to assess the rumen microbial community and functionality in Angus bulls with differing residual feed intake-expected progeny difference (RFI-EPD) values, aiming to elucidate the microbial contributions to feed efficiency. Negative RFI-EPD bulls (NegRFI: n=10; RFI-EPD= -0.3883 kg/d) and positive RFI-EPD bulls (PosRFI: n=10; RFI-EPD=0.2935 kg/d) were selected from a group of 59 Angus bulls (average body weight (BW) = 428 ± 18.8 kg; 350 ± 13.4 d of age) fed a high-forage total mixed ration after a 60-d testing period. At the end of the 60-d period, rumen fluid samples were collected for bacterial DNA extraction and subsequent shotgun metagenomic sequencing. Results of the metagenome analysis revealed greater gene richness in NegRFI bulls, compared to PosRFI. Analysis of similarity revealed a small but noticeable difference (P =0.052; R-value = 0.097) in the rumen microbial community of NegRFI and PosRFI bulls. Linear Discriminant Analysis effect size (Lefse) was utilized to identify the differentially abundant taxa. The Lefse results showed that class Fibrobacteria (LDA = 5.1) and genus Fibrobacter (LDA = 4.8) were greater in NegRFI bulls, compared to PosRFI bulls. Relative abundance of the carbohydrate-active enzymes was also compared using Lefse. The results showed greater relative abundance of glycoside hydrolases and carbohydrate-binding modules such as GH5, CBM86, CBM35, GH43, and CBM6 (LDA > 3.0) in NegRFI bulls whereas GH13 and GT2 were greater in PosRFI bulls. The distinct metabolic and microbial profiles observed in NegRFI, compared to PosRFI bulls, characterized by greater gene richness and specific taxa such as Fibrobacter, and variations in carbohydrate-active enzymes, underscore the potential genetic and functional differences in their rumen microbiome. These findings contribute to a deeper understanding of the interplay between rumen microbiota and feed efficiency in Angus bulls, opening avenues for targeted interventions and advancements in livestock management practices.
Insights into the pathogenesis of gestational and hepatic diseases: the impact of ferroptosis
Authors: You Yilan , Qian Zhiwen , Jiang Ying , Chen Lingyan , Wu Danping , Liu Lu , Zhang Feng , Ning Xin , Zhang Yan , Xiao Jianping
Published: November 2024

Ferroptosis, a distinct form of non-apoptotic cell death characterized by iron dependency and lipid peroxidation, is increasingly linked to various pathological conditions in pregnancy and liver diseases. It plays a critical role throughout pregnancy, influencing processes such as embryogenesis, implantation, and the maintenance of gestation. A growing body of evidence indicates that disruptions in these processes can precipitate pregnancy-related disorders, including pre-eclampsia (PE), gestational diabetes mellitus (GDM), and intrahepatic cholestasis of pregnancy (ICP). Notably, while ICP is primarily associated with elevated maternal serum bile acid levels, its precise etiology remains elusive. Oxidative stress induced by bile acid accumulation is believed to be a significant factor in ICP pathogenesis. Similarly, the liver’s susceptibility to oxidative damage underscores the importance of lipid metabolism dysregulation and impaired iron homeostasis in the progression of liver diseases such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), cholestatic liver injury, autoimmune hepatitis (AIH), acute liver injury, viral hepatitis, liver fibrosis, and hepatocellular carcinoma (HCC). This review discusses the shared signaling mechanisms of ferroptosis in gestational and hepatic diseases, and explores recent advances in understanding the mechanisms of ferroptosis and its potential role in the pathogenesis of gestational and hepatic disorders, with the aim of identifying viable therapeutic targets.
The mammalian Ire1 inhibitor, 4µ8C, exhibits broad anti-Aspergillus activity in vitro and in a treatment model of fungal keratitis
Authors: Kamath Manali M. , Adams Emily M. , Lightfoot Jorge D. , Wells Becca L. , Fuller Kevin K.
Published: November 2024

Objective

The fungal unfolded protein response consists of a two-component relay in which the ER-bound sensor, IreA, splices and activates the mRNA of the transcription factor, HacA. Previously, we demonstrated that hacA is essential for Aspergillus fumigatus virulence in a murine model of fungal keratitis (FK), suggesting the pathway could serve as a therapeutic target. Here we investigate the antifungal properties of known inhibitors of the mammalian Ire1 protein both in vitro and in a treatment model of FK.

Methods

The antifungal activity of Ire1 inhibitors was tested against conidia of several A. fumigatus isolates by a broth microdilution assay and against fungal biofilm by XTT reduction. The influence of 4μ8C on hacA mRNA splicing in A. fumigatus was assessed through gel electrophoresis and qRT-PCR of UPR regulatory genes. The toxicity and antifungal profile of 4μ8C in the cornea was assessed by applying drops to uninfected or A. fumigatus-infected corneas 3 times daily starting 4 hours post-inoculation. Corneas were evaluated daily through slit-lamp imaging and optical coherence tomography, or at endpoint through histology or fungal burden quantification via colony forming units.

Results

Among six Ire1 inhibitors screened, the endonuclease inhibitor 4μ8C displayed the strongest antifungal profile with an apparent fungicidal action. The compound both blocked conidial germination and hyphal metabolism of A. fumigatus Af293 in the same concentration range that blocked hacA splicing and UPR gene induction (60-120 µM). Topical treatment of sham-inoculated corneas with 0.5 and 2.5 mM 4μ8C did not impact corneal clarity, but did transiently inhibit epithelialization of corneal ulcers. Relative to vehicle-treated Af293-infected corneas, treatment with 0.5 and 2.5 mM drug resulted in a 50% and >90% reduction in fungal load, respectively, the latter of which corresponded to an absence of clinical signs of infection or corneal pathology.

Conclusion

The in vitro data suggest that 4μ8C displays antifungal activity against A. fumigatus through the specific inhibition of IreA. Topical application of the compound to the murine cornea can furthermore block the establishment of infection, suggesting this class of drugs can be developed as novel antifungals that improve visual outcomes in FK patients.
Relationship between Cardiometabolic index and endometriosis in a US nationally representative sample: results from NHANES 1999-2006
Authors: Hou Jiarui , Chen Wenting , Wang Rui , Huang Xuchun , Cao Xiaojing , Wang Xiaoyun
Published: November 2024

Background

Endometriosis is an estrogen-dependent gynecological endocrine condition and a systemic inflammatory disease associated to improper lipid metabolism and increased cardiovascular risk. The Cardiometabolic Index (CMI) is a novel indicator representing visceral adipose tissue distribution and metabolic dysfunction, integrating lipid metabolism indicators and the waist-to-height ratio. While anomalies in lipid metabolism are often associated with (BMI) Body Mass Index, literature consistently shows a negative link between endometriosis and female BMI, and some studies have found that endometriosis is one of the few reproductive diseases not persistently positively correlated with obesity. Given the limitations of BMI, a comprehensive index like CMI is crucial for exploring the incidence of endometriosis. Currently, research on the correlation between CMI and endometriosis is lacking, prompting this study to investigate this association.

Objective

To investigate the association between the CMI and the risk of having endometriosis in a sample representing the entire U.S. population.

Study design

A cross-sectional analysis was conducted using data from four cycles of the National Health and Nutrition Examination Survey (NHANES) spanning the years 1999 to 2006. The study included individuals aged 20 to 54 with a documented history of endometriosis and complete CMI data. Logistic regression analysis, subgroup and interaction analyses, smooth curve fitting, and restricted cubic splines (RCS) were utilized to examine the association between CMI and endometriosis.

Results

The study found that individuals with higher CMI had an increased probability of developing endometriosis. This relationship remained significant after adjusting for potential confounders such as age, ethnicity, Poverty Income Ratio (PIR), drinking, smoking, education level, and marital status. The fully adjusted model revealed a positive correlation between CMI and endometriosis (OR = 1.21; 95% CI, 1.04–1.40, p < 0.05). Subgroup and interaction analyses showed no significant effect modification by age, BMI, PIR, hypertension, drinking, smoking, or menarche age (all p-values for interaction > 0.05).

Conclusion

Our study shows a link between CMI and the chance of getting endometriosis.Due to the common occurrence of endometriosis and the lack of clarity surrounding their cause, more study is needed to confirm our results and find out if CMI could be used as a warning sign for endometriosis.
Transcriptomic profiling with vascular tension analyses reveals molecular targets and phenotypes in preeclamptic placental vasculature
Authors: Zhang Eryun , Zhou Tao , Zheng Qiutong , Zheng Xiaomin , Zhang Yingying , Liu Bailin , Tang Jiaqi , Xu Zhice
Published: November 2024

Introduction

The placental vascular system plays an important role in the development of pregnancy hypertension in preeclampsia. The gene profiles of whole placental tissue (containing blood vessels and many other structural components) and pure vascular tissue should be very different. All previous reports using RNA-seq analysis in the placenta have tested its whole tissue or the villous part, and thus the gene profiles in the pure placental blood vessels are unknown.

Methods

This study was the first to address this point with RNA-seq in human placenta at the transcript level. Isolated placental micro-vessels from normal and preeclamptic pregnancies were used for RNA-seq analysis, real-time quantitative polymerase chain reaction (RT-qPCR) verification, and vascular function tests. Furthermore, a vascular function-centric core network was constructed to show the gene-gene interactions and gene-function associations in the placental vessel system.

Results

Differential expression analysis identified a total of 486 significantly changed transcripts. Bioinformatics analysis further confirmed that multiple genes were highly related to blood vessel and placental phenotypes. Several hub genes, including ELMO1, YWHAE, and IL6ST, were significantly reduced in the placental vessels in preeclampsia. Vascular tension experiments showed that angiotensin II-mediated vasoconstriction and exogenous NO donor sodium nitroprusside-induced vasodilation were decreased, while phenylephrine-mediated vascular responses were unchanged in placental micro-vessels in preeclampsia.

Discussion

The results provide important insights into the pathological process in the placental vasculature in preeclampsia and offer great potential for further investigation of these molecular targets in the human placental vascular system.
Visfatin and VEGF levels are not increased in adolescent girls with polycystic ovary syndrome
Authors: Skrzyńska Karolina , Zachurzok Agnieszka , Pietrusik Agnieszka , Jakubowska-Kowal Karolina , Gawlik-Starzyk Aneta
Published: November 2024

Introduction

PCOS is one of the most commonly occurring endocrinopathies among women and increasingly affects adolescent populations. The connection between PCOS and various endocrinological, psychological, and CVD is increasingly recognized. Some studies have shown elevated levels of visfatin and VEGF among patients with PCOS, which are markers of vascular endothelial dysfunction. In our study, we evaluated the concentration of these parameters, focusing solely on a group of adolescents with PCOS, to assess whether these early markers of CVD are present at an early stage of diagnosis.

Material and methods

In total, 80 adolescent girls participated in the study. 47 adolescents diagnosed with PCOS were included in the study group (mean age 15.68 ± 1.18 years, BMI 26.66 ± 6.41 kg/m2), while the remaining 33 regularly menstruating individuals (mean age 15.79 ± 1.22 years, BMI 25.44 ± 7.24 kg/m2) were assigned to the control group. Each participant underwent imaging, biochemical, and hormonal tests. Additionally, markers of endothelial dysfunction: VEGF and visfatin, were measured in all adolescents.

Results

Both VEGF and visfatin levels did not differ significantly between PCOS and control group (p=0.30 and p=0.15, respectively). In the group of adolescent girls with PCOS, visfatin was significantly correlated with HDL, FSH, cortisol, and testosterone levels >55 ng/dl. VEGF was significantly correlated with fasting glucose, glucose levels after OGTT, estradiol, and waist circumference >80 cm.

Conclusion

It can be indirectly inferred that both visfatin and VEGF should not be used as early markers for cardiometabolic complications among adolescent patients with PCOS. On the other hand, low visfatin levels, through their negative correlation with HDL, may have a protective effect on cardiovascular complications, while low VEGF levels, through their positive correlation with glucose levels, may have a protective influence on carbohydrate metabolism disorders.
Integrated multiomics characterization reveals cuproptosis-related hub genes for predicting the prognosis and clinical efficacy of ovarian cancer
Authors: Xiaorong Yang , Lu Xu , Fangyue Xu , Chao Xu , Jun Gao , Qiang Wen
Published: November 2024

Background

As a prevalent malignancy in women, ovarian cancer (OC) presents a challenge in clinical practice because of its poor prognosis and poor therapeutic efficacy. The mechanism by which cuproptosis activity is accompanied by immune infiltration in OC remains unknown. Here, we investigated cuproptosis-related OC subtypes and relevant immune landscapes to develop a risk score (RS) model for survival prediction.

Methods

Cuproptosis-related genes (CRGs) were identified to construct molecular subtypes via an unsupervised clustering algorithm based on the expression profiles of survival-related CRGs in the GEO database. Single-cell datasets were used to estimate immune infiltration among subtypes. The RS oriented from molecular subtypes was developed via LASSO Cox regression in the TCGA OC dataset and independently validated in the GEO and TCGA datasets. Hub markers from RS were identified in tissues and cell lines. The function of the key gene from RS was identified in vitro.

Results

We investigated cuproptosis activity and immune infiltration to establish three clinical subtypes of OC based the differentially expressed genes (DEGs) from CRGs to create an RS model validated for clinical efficacy and prognosis. Six hub genes from the RS served as ongenic markers in OC tissues and cell lines. The function of GAS1 in the RS model revealed that it exerts oncogenic effects.

Conclusions

Our study provides a novel RS model including 6 hub genes associated with cuproptosis and immune infiltration to predict OC prognosis as well as clinical efficacy.
Growth, immunomodulatory, histopathological, and antibacterial effects of phytobiotic-incorporated diets on Oreochromis niloticus in unchanged water
Authors: Fadel Amr , Metwally Mohamed M. M. , Hassan Habib Ul , Abdelmageed Adel A. , Arai Takaomi , Ahmed Mohammad Z. , Abdel-Aziz Mohamed F. A.
Published: November 2024

Phytobiotics are promising diet alternatives, yet their effectiveness in high-risk aquaculture conditions remains underexplored. Therefore, a 90-day feeding trial was conducted based on dietary supplementation of Nile tilapia, Oreochromis niloticus, with herbal extracts, namely, lemon balm [Melissa officinalis (MOE)], marjoram [Origanum majorana (OME)], and chamomile [Matricaria chamomilla (MCE)] with 0% water change. The treated groups were compared to groups untreated with herbs or control groups [positive control (PC; 0% water change) and negative control (NC; 20% water exchange per day]. Fish were cultured at stocking density (20 fish m-3: 1.8kg of biomass/m3). We conducted a physicochemical analysis of the water and the clinical responses, growth, and immune responses of the fish were evaluated. Furthermore, the herbal-supplemented fish were then challenged with a pathogenic Edwardseilla tarda strain and mortality was monitored. In the 1st and 2nd months, the water parameters were within the permissible limits. After that, a fatally low dissolved oxygen concentration and the highest levels of ammonia, nitrite, nitrate, and pH were recorded during the 3rd month. Blood and immune assays were conducted in the treated groups and control groups. The herbal-treated groups appeared healthy, but during the 3rd month, lethargy and decreased appetite were evident. Generally, the herbal-treated fish showed improved growth performance parameters, survival rates, and resistance against pathogenic bacteria E. tarda, particularly in the OME and MOE-treated groups compared to the positive control group. Finally, phytobiotic supplements were shown to improve fish stress tolerance and immune activation for a certain period under stressful conditions or unchanged water, based on the stocking density, dosages of herbs used, and the extent of deterioration of the water quality.
Human errors analysis for remotely controlled ships during collision avoidance
Authors: Zhou Ying , Liu Zhengjiang , Wang Xinjian , Xie Hui , Tao Juncheng , Wang Jin , Yang Zaili
Published: November 2024

To address human errors in collision avoidance tasks of remotely controlled ships, this study aims to develop a comprehensive framework for human error analysis within the context of autonomous ships. Firstly, the Hierarchical Task Analysis method is utilized to identify crew collision avoidance tasks associated with the traditional ship, and these tasks are then dissected into different operational stages using the Information Decision Action in a Crew cognitive model. Secondly, a combination of the fault hypothesis method and expert opinions are used to identify potential human error that may occur during collision avoidance operations of remotely controlled ships. Thirdly, an integrated approach is proposed to build a quantitative risk assessment model, which combines Failure Mode and Effects Analysis, Evidential Reasoning, and Belief rules-based Bayesian Network. Then, axiomatic analysis is used to verify the robustness and applicability of the risk assessment model. Finally, based on the results of quantitative risk assessment, specific measures are proposed for enhancing the safety of collision avoidance process of remotely controlled ships. The findings show that uncoordinated interactions of human-computer systems during the decision-making stage are a pivotal factor in the collision avoidance process. Therefore, future design efforts for remote-control centre should prioritize improving the clarity of human-computer interaction interfaces.
Coexisting metabolic dysfunction-associated steatotic liver disease exacerbates in-hospital outcomes in patients with heat stroke
Authors: Zhang Ping , Tang Guo , Gao Hongguang , Zhang Tianshan , Yang Sha , Cheng Tao , Yao Rong
Published: November 2024

Purpose

This study aimed to investigate the impact of coexisting metabolic dysfunction-associated steatotic liver disease (MASLD) on in-hospital mortality and organ injury markers in patients with heat stroke (HS).

Approach

HS patients were retrospectively identified between July 1, 2022 and September 30, 2023 at West China Hospital, Sichuan University. Baseline characteristics, such as demographics, initial vital signs, and organ functional indicators were collected. Outcome events included organ injury and in-hospital mortality. The Least Absolute Shrinkage and Selection Operator (Lasso) method was employed to identify the optimal predictors for in-hospital mortality in HS patients. Subsequently, multivariable logistic regression analysis was performed to assess the relationship between the presence of MASLD and in-hospital mortality as well as organ function indicators.

Findings

A total of 112 patients were included in the study, in which 27 (24.1%) had coexisting MASLD. Compared to those without MASLD, patients with MASLD had higher levels of various organ injury markers such as aspartate aminotransferase, urea nitrogen, serum cystatin C, creatinine, uric acid, myoglobin, creatine kinase and its isoenzymes upon admission (P < 0.05). The multivariable Logistic regression analysis indicated that the presence of MASLD is an independent risk factor for in-hospital mortality in HS patients.

Conclusion

This study firstly indicated that coexisting MASLD may exacerbate organ injury in HS patients and serve as an independent risk factor for in-hospital mortality.
Liver transplantation and comprehensive rehabilitation in the reversal of hepatic myelopathy: a case report
Authors: Liu Mingyue , Wang Rongping , Zhou Wenwen , Tian Chunyan , Wang Qian , Zhang Qin , Jin Shasha , Wu Liang
Published: November 2024

Hepatic myelopathy (HM) is a rare complication of end-stage chronic liver disease, primarily presenting as symmetrical lower limb weakness that progresses to spastic paralysis without sensory or sphincter dysfunction. We report a case of decompensated cirrhosis associated with hepatitis B virus and HM. The patient showed significant recovery after liver transplantation (LT) and comprehensive rehabilitation training. We summarize the patient’s clinical characteristics post-diagnosis and the assessment outcomes following integrated treatment.
An approach to reduce inhaler errors using Donabedian's triad
Authors: Cruz Dorothy May Isip , Karthika Manjush , Alzaabi Ashraf
Published: November 2024

Inhaler errors inversely affect the outcome of respiratory diseases. Inhaler devices, such as the metered-dose inhalers (MDI) and dry powder inhalers (DPI), are commonly used in treating respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD), and incorrect use of these devices can result in suboptimal treatment outcomes, increased probabilities of hospitalizations or admissions, and poorer quality of life. Patient related factors to inhaler errors include age, cognitive and physical abilities, education, language barriers, and preferences. Device-related factors such as inhaler design and operational complexity can also lead to errors. Finally, factors related to healthcare professionals (HCP) such as competency, level of knowledge in disease and inhaler device and availability to educate patients, can play a role in inhaler error. Quality management is a potential solution to this problem. Quality improvement strategies towards addressing inhaler misuse can increase patient satisfaction and improve patient outcomes. Donabedian's triad, which includes structure, process, and outcome can be utilized in developing a framework for reducing inhaler errors. Institutional solutions are more towards the structural and process changes in the triad, such as HCP training, checklists on training efficacy, provision of action plans, and availability of staff to educate and train patients. Patient-centered solutions focus more on process and outcome domains, such as improvement in lung functions, patient education, re-assessment and re-education of inhaler techniques, and adherence to treatment regimen. By focusing on structural and process domains, the quality of care can be enhanced, resulting in improved outcomes.
Transcriptome analyses reveal molecular mechanisms of novel compound heterozygous ACO2 variants causing infantile cerebellar retinal degeneration
Authors: Yang Wenke , Wang Shuyue , Yang Ke , Li Yanjun , Guo Zhenglong , Huang Jianmei , Wang Jinming , Liao Shixiu
Published: November 2024

Background and purpose

Infantile cerebellar retinal degeneration (ICRD) (OMIM #614559) is a rare autosomal recessive inherited disease associated with mutations in the aconitase 2 (ACO2) gene. We report a Chinese girl with novel compound heterozygous variants in ACO2, who presented at 7 months of age with psychomotor retardation, truncal hypotonia, and ophthalmologic abnormalities. This study aims to investigate the potential molecular mechanisms underlying ACO2 deficiency-induced neuropathy.

Methods

Whole exome sequencing was performed on family members to screen for potential pathogenic mutations, followed by Sanger sequencing for validation. Mitochondrial aconitase activity and mitochondrial DNA (mtDNA) copy number were measured using an aconitase activity detection kit and quantitative PCR, respectively. Transcriptome expression profiles from patient cells, and cerebellar and retinal organoids retrieved from the GEO database were integrated. Functional enrichment analysis and protein-protein interaction networks were used to identify key molecules, and their expression levels were validated using Western blot analysis.

Results

Genetic testing revealed novel compound heterozygous variations in the proband's ACO2 gene (NM:001098), including c.854A>G (p.Asn285Ser) and c.1183C>T (p.Arg395Cys). Predictive analysis of the tertiary structure of the ACO2 protein suggests that both p.Asn285Ser and p.Arg395Cys affect the binding ability of ACO2 to ligands. The mitochondrial aconitase activity and mtDNA copy number in the proband's leukocytes were significantly reduced. Transcriptomic data analysis identified 80 key candidate genes involved in ACO2-related neuropathy. Among these, LRP8 and ANK3, whose gene expression levels were significantly positively correlated with ACO2, were further validated by Western blot analysis.

Conclusions

This study expands the spectrum of pathogenic ACO2 variants, elucidates the potential molecular mechanisms underlying ACO2-related neuropathy, provides in-depth support for the pathogenicity of ACO2 genetic variations, and offers new insights into the pathogenesis of ICRD.
Harnessing slow event-related fMRI to investigate trial-level brain-behavior relationships during object identification
Authors: Gotts Stephen J. , Gilmore Adrian W. , Martin Alex
Published: November 2024

Understanding brain-behavior relationships is the core goal of cognitive neuroscience. However, these relationships—especially those related to complex cognitive and psychopathological behaviors—have recently been shown to suffer from very small effect sizes (0.1 or less), requiring potentially thousands of participants to yield robust findings. Here, we focus on a much more optimistic case utilizing task-based fMRI and a multi-echo acquisition with trial-level brain-behavior associations measured within participant. In a visual object identification task for which the behavioral measure is response time (RT), we show that while trial-level associations between BOLD and RT can similarly suffer from weak effect sizes, converting these associations to their corresponding group-level effects can yield robust peak effect sizes (Cohen’s d = 1.0 or larger). Multi-echo denoising (Multi-Echo ICA or ME-ICA) yields larger effects than optimally combined multi-echo with no denoising, which is in turn an improvement over standard single-echo acquisition. While estimating these brain-behavior relationships benefits from the inclusion of a large number of trials per participant, even a modest number of trials (20–30 or more) yields robust group-level effect sizes, with replicable effects obtainable with relatively standard sample sizes (N = 20–30 participants per sample).
Influence of an inspiratory muscle fatigue protocol on older adults on respiratory muscle strength and heart rate variability. A randomized controlled trial
Authors: Ladriñán-Maestro Arturo , Sánchez-Infante Jorge , Martín-Vera Daniel , Del-Blanco-Muñiz José Ángel , Merino-Andrés Javier , Sánchez-Sierra Alberto
Published: November 2024

Introduction

Inspiratory muscle fatigue has been shown to have effects on the autonomic nervous system and physical condition. This study aimed to evaluate the influence of an inspiratory muscle fatigue protocol on respiratory muscle strength and heart rate variability in older adults.

Materials and methods

A randomized controlled clinical trial with double-blinding was carried out involving 24 individuals over 60 years old who demonstrated physical independence in walking and movement. Participants were distributed randomly into three groups: Inspiratory muscle fatigue, activation and control. Measurements of heart rate variability, diaphragmatic ultrasound, and maximum inspiratory pressure were taken at two stages: prior to the intervention (T1) and directly after treatment (T2).

Results

The inspiratory muscle fatigue group exhibited decrease scores in respiratory and heart rate variability subsequent to undergoing the diaphragmatic fatigue intervention compared to both the activation and control groups (p < 0.05). Conversely, the activation group demonstrated higher values in heart rate variability and respiratory capacity variables following the inspiratory muscle activation training (p < 0.05).

Conclusions

Fatigue of the inspiratory musculature appears to negatively impact heart rate variability and inspiratory muscle strength in older adults.

Clinical trial registration

https://clinicaltrials.gov/study/NCT06269042, identifier: NCT06269042.
Microstructure, electrical resistivity, and tensile properties of neutron-irradiated Cu–Cr–Nb–Zr
Authors: Perrin Alice , Hamaguchi Dai , Geringer Josina W. , Zinkle Steve , Yang Ying , Skutnik Steve , Poplawsky Jon , Katoh Yutai
Published: November 2024

High strength, high conductivity copper alloys that can resist creep at high temperatures are one of the primary candidates for efficient heat exchangers in fusion reactors. Cu–Cr–Nb–Zr (CCNZ) alloys, which were designed to improve the strength and creep life of ITER Cu–Cr–Zr (CCZ) reference alloys, have been found to have comparable electrical conductivity and tensile properties to CCZ alloys. The measured creep rupture times for these improved alloys is about ten times higher than the ITER reference alloys at 90–125 MPa at 500 °C. However, the effects of neutron irradiation on these alloys, and the ensuing material properties, have not been studied; thus, their utility in a fusion reactor environment is not well understood. This study characterizes the room temperature mechanical and electrical properties of a neutron-irradiated CCNZ alloy and compares them to a neutron-irradiated ITER reference heat sink CCZ alloy. Tensile specimens were neutron irradiated in the High Flux Isotope Reactor (HFIR) to 5 dpa between 250 °C and 325 °C. Post-irradiation characterization included electrical resistivity measurements, hardness, and tensile tests. Microstructural evaluation used scanning electron microscopy, energy dispersive x-ray spectroscopy, and atom probe tomography to characterize the irradiation-produced changes in the microstructure and investigate the mechanistic processes leading to post-irradiation properties. Transmutation calculations were validated with composition measurements from atom probe data and used to calculate contributions to the increased electrical resistivity measured after irradiation. Comparisons with CCZ alloys in the same irradiation heat found that the post-irradiated CCNZ and CCZ alloys had comparable electrical resistivity. Although CCNZ alloys suffered more irradiation hardening than CCZ, the overall tensile behavior deviated very little from non-irradiated values in the temperature range studied.
Prognostic significance of collagen content in solitary fibrous tumors of the central nervous system
Authors: Li Xiaoling , Zhang Hua , Hu Chengcong , Hu Liwen , Guo Huibin , Chen Hongbao , Li Guoping , Huang Qian , Jiang Shuie , Zhang Sheng , Xing Zhen , Wang Xingfu
Published: November 2024

Purpose

We aimed to explore the prognostic significance of collagen content in solitary fibrous tumors (SFTs) of the central nervous system (CNS) and preliminarily investigate its relationship with magnetic resonance imaging (MRI) features of SFTs.

Methods

Collagen content was identified using Masson’s trichrome staining, and quantitatively assessed. Radiomic methods were applied to extract quantitative MRI features of SFTs, which were then analyzed in relation to collagen content.

Results

The collagen content in CNS SFTs was categorized into high- and low-content groups, with a cutoff value of 6%. Survival analysis indicated a positive correlation between collagen content and overall survival (OS). In multivariate Cox regression analysis, incorporating factors such as mitosis, necrosis, Ki67, and collagen content and other indicators, collagen content emerged as an independent prognostic factor. Collagen content demonstrated a negative correlation with tumor histological phenotype, Ki67, WHO grade, mitosis, necrosis, and brain invasion. Additionally, the signal intensity of SFTs on T2-weighted imaging (T2WI) decreased with increasing collagen content. Radiomics analysis identified 1,702 features from each patient’s region of interest, with 12 features showing significant differences between the high and low collagen content groups. Among the quantitative parameters and radiomic models, the combined T1- and T2WI models exhibited the highest diagnostic performance.

Conclusion

These findings suggest that collagen content is an independent prognostic risk factor for OS. Furthermore, combined radiomic models based on T1-and T2WI sequences may offer a more comprehensive, objective, and accurate assessment of collagen content in CNS SFTs.
A pyroptosis-related lncRNA risk model for the prediction of prognosis and immunotherapy response in head and neck squamous cell carcinoma
Authors: Ren Jingyuan , Yan Bingrui , Wang Xurui , Wang Yifei , Li Qiuying , Sun Yanan
Published: November 2024

Background

Recent research has highlighted pyroptosis as a key factor in cancer progression. This study aims to explore the association between pyroptosis-related signatures and overall survival (OS) in head and neck squamous cell carcinoma (HNSC) and develop a pyroptosis-related long non-coding RNA (lncRNA) risk model to predict prognosis and response to immunotherapy in HNSC.

Methods

We extracted expression data for 18 pyroptosis-related genes and identified lncRNA probes specific to HNSC by using datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Consensus clustering was performed to categorize HNSC patients into distinct subtypes. A six-lncRNA risk score model was constructed through univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. We evaluated the predictive ability of the lncRNA model for patients’ survival and immunotherapy response. Gene expression was evaluated using immunohistochemistry (IHC) and Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR).

Results

Our analysis revealed two distinct pyroptosis-related subtypes in HNSC patients, Cluster A and Cluster B. Notably, patients in Cluster B exhibited significantly poorer overall survival compared to those in Cluster A. Through differential expression analysis, we identified six lncRNAs (AC002331.1, CTA-384D8.35, RP11-291B21.2, AC006262.5, RP1-27K12.2, and RP11-54H7.4) that were differentially expressed between these clusters. A 6-lncRNA risk score model was developed, which successfully stratified patients into high- and low-risk groups with distinct overall survival outcomes. Validation using RT-qPCR confirmed the differential expression of these six lncRNAs in HNSC tumor tissues compared to adjacent normal tissues, we found that the expression of CTA-384D8.35 was significantly increased in the tumor group (t=-6.203, P<0.001). Furthermore, the 6-lncRNA risk score model demonstrated a significant association with patient response to immunotherapy, with the low-risk group exhibiting a higher objective response rate to immune checkpoint blockade (ICB) therapy and longer survival compared to the high-risk group.

Conclusion

Our study underscores the role of pyroptosis signatures in HNSC prognosis and identifies two distinct pyroptosis subtypes with differing survival outcomes. The six-lncRNA risk score model offers a valuable tool for predicting patient prognosis and potential benefits from ICB therapy. These findings highlight the importance of pyroptosis and associated lncRNAs in the tumor microenvironment, paving the way for novel targeted therapies in HNSC.
Selective uterine artery embolization is a valid adjuvant treatment of choriocarcinoma: a case report and literature review
Authors: Chen Yuying , Sun Tingting , Yuan Linjing , Huang Yucong , Yusufu Aligu , Zhang Yang , Zhang Xiaoyan , He Shasha , Ren Yufeng , Yao Shuzhong , Yang Guofen
Published: November 2024

Background

Cervical choriocarcinoma is an extremely rare malignancy that is often misdiagnosed due to its nonspecific symptoms, such as vaginal bleeding.

Case report

A 39-year-old female presented to the emergency department of the First Affiliated Hospital of Sun Yat-sen University with vaginal bleeding and a serum β-human chorionic gonadotropin (β-HCG) level of 229,386 mIU/mL. Initially, she was misdiagnosed with cervical pregnancy and subsequently underwent selective uterine artery embolization and cervical mass excision. However, pathological examination revealed the diagnosis of cervical choriocarcinoma.

Conclusion

This case highlights the propensity for misdiagnosis of cervical choriocarcinoma. Selective uterine artery embolization proves to be an efficient measure to manage hemorrhage and potentially avoid unnecessary hysterectomy.
Tumor microenvironment and cancer metastasis: molecular mechanisms and therapeutic implications
Authors: Biray Avci Cigir , Goker Bagca Bakiye , Nikanfar Masoud , Takanlou Leila Sabour , Takanlou Maryam Sabour , Nourazarian Alireza
Published: November 2024

The tumor microenvironment (TME) plays a crucial role in cancer development and metastasis. This review summarizes the current research on how the TME promotes metastasis through molecular pathways, focusing on key components, such as cancer-associated fibroblasts, immune cells, endothelial cells, cytokines, and the extracellular matrix. Significant findings have highlighted that alterations in cellular communication within the TME enable tumor cells to evade immune surveillance, survive, and invade other tissues. This review highlights the roles of TGF-β and VEGF signaling in promoting angiogenesis and extracellular matrix remodeling, which facilitate metastasis. Additionally, we explored how metabolic reprogramming of tumor and stromal cells, influenced by nutrient availability in the TME, drives cancer progression. This study also evaluated the therapeutic strategies targeting these interactions to disrupt metastasis. By providing a multidisciplinary perspective, this study suggests that understanding the molecular basis of the TME can lead to more effective cancer therapies and identify potential avenues for future research. Future research on the TME should prioritize unraveling the molecular and cellular interactions within this complex environment, which could lead to novel therapeutic strategies and personalized cancer treatments. Moreover, advancements in technologies such as single-cell analysis, spatial transcriptomics, and epigenetic profiling offer promising avenues for identifying new therapeutic targets and improving the efficacy of immunotherapies, particularly in the context of metastasis.
OATP1A2 mediates Aβ1-42 transport and may be a novel target for the treatment of Alzheimer’s disease
Authors: Wen Jinhua , Zhao Menghua , Xiao Yuwei , Li Sihong , Hu Weiqiang
Published: November 2024

Alzheimer’s disease (AD) is a neurodegenerative disease with an unknown cause. Many studies have suggested that the imbalance between the clearance and accumulation of β-amyloid protein (Aβ) in the brain of AD patients is the main cause of AD development of AD. Meanwhile, drug transporters play a key role in the transport of drugs and endogenous substances in vivo as well as in the development of many diseases. Could they be related to the imbalance between Aβ clearance and accumulation? OATP1A2 is the most abundant subfamily of organic anion transporting polypeptides (OATPs) that transport amphipathic substrates. Its high bilateral expression in brain endothelial cells suggests it plays a crucial role in delivering drugs and neuroactive peptides to brain tissue. Could it also be involved in mediating the production and accumulation of Aβ in the central system? This could lead to an imbalance between Aβ clearance and accumulation, ultimately resulting in AD development. This hypothesis would be bold and novel in the field of science. In this study, we successfully established the OATP1A2-HEK293T transgenic cell model, and found that the uptake of Aβ1-42 by OATP1A2-HEK293T cells was significantly higher than that of NC-HEK293T control cells and human astrocytes by adding different concentrations of Aβ1-42 to the cells of each group, suggesting that OATP1A2 expressed in the human brain is involved in Aβ amyloid protein transport.
Trends of antiseizure medication utilization among pregnant people in four Canadian provinces from 1998 to 2023; a study from the Canadian mother-child cohort active surveillance initiative (CAMCCO)
Authors: Peymani Payam , Berard Anick , Winquist Brandace , Kaul Padma , Sheehy Odile , Lavu Alekhya , Leong Christine , Falk Jamie , Delaney Joseph A. , Kowalec Kaarina , Ng Marcus , Ruth Chelsea , Aboulatta Laila , Alessi-Severini Silvia , Dragan Roxana , Derksen Shelley , Barrett Olesya , Shams Golnaz , Eltonsy Sherif
Published: November 2024

Background

Epilepsy management during pregnancy is crucial for both the mother and fetus. The use of antiseizure medications (ASMs) during pregnancy requires careful consideration due to their potential effects on maternal and fetal health.

Methods

This study analyzed trends in ASMs use among pregnant people in four Canadian provinces over 20 years (Manitoba, Saskatchewan, Alberta, and Quebec). Descriptive statistics were utilized to examine the characteristics of the population, with the frequency and patterns of ASM use estimated throughout each trimester. Linear regression models were developed to analyze yearly patterns of ASM utilization for the overall study population, as well as for people with and without epilepsy.

Results

Among 1,317,141 pregnant individuals across four provinces, 0.7% had epilepsy. Of the total pregnancies, 1.7% (n = 22,783) were exposed to ASMs, comprising 4,392 from pregnant people with epilepsy (PPWE) and 18,391 from those without epilepsy (PPWOE). Results demonstrated varying trends in ASM usage between provinces, with an overall increase in usage among people without epilepsy in Manitoba, Saskatchewan, and Alberta. ASM use among PPWOE surged significantly in Manitoba (24.2–149.1 per 10,000 pregnant people), Saskatchewan (29.4–107.0 per 10,000), and Alberta (65.7–241.7 per 10,000) (p < 0.05). In Alberta, PPWE’s ASM exposure also rose, from 23.6 in 2008 to 43.0 per 10,000 pregnant people in 2021, while Quebec witnessed a decrease from 59.2 in 1998 to 45.5 per 10,000 pregnancies in 2015. Analysis of ASM use by trimester illustrated a substantial decline among PPWOE from 365 days pre-pregnancy to the third trimester in all provinces. ASM utilization by drug class showcased significant shifts, with second-generation ASMs experiencing a notable rise. Carbamazepine, once prominent, declined, making way for lamotrigine. Regional variations underscore diverse preferences, such as clonazepam’s sustained popularity in Manitoba and Quebec.

Conclusion

The study identified increasing trends in ASM use, particularly the increased use of second-generation ASMs, and differences in prescription patterns for pregnant individuals with and without epilepsy. These findings reveal changing ASM use patterns, including increased second-generation ASM use and regional disparities, providing valuable insights into real-world prescription practices.