bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of gut bacteria producing long chain homologs of vitamin K2 on colorectal carcinogenesis
Authors: Smajdor Joanna , Jedlińska Katarzyna , Porada Radosław , Górska-Ratusznik Anna , Policht Aleksandra , Śróttek Małgorzata , Więcek Grażyna , Baś Bogusław , Strus Magdalena
Published: November 2023

Colorectal cancer (CRC) is one of the foremost causes of cancer-related deaths. Lately, a close connection between the course of CRC and the intestinal microbiota has been revealed. Vitamin K2 (VK2) is a bacterially derived compound that plays a crucial role in the human body. Its significant anti-cancer properties may result, inter alia, from a quinone ring possessing a specific chemical structure found in many chemotherapeutics. VK2 can be supplied to our body exogenously, i.e., through dietary supplements or fermented food (e.g., yellow cheese, fermented soybeans -Natto), and endogenously, i.e., through the production of bacteria that constantly colonize the human microbiome of the large intestine.

This paper focuses on endogenous K2 synthesized by the most active members of the human gut microbiome. This analysis tested 86 intestinally derived bacterial strains, among which the largest VK2 producers (Lactobacillus, Bifidobacterium, Bacillus) were selected. Moreover, based on the chosen VK2-MK4 homolog, the potential of VK2 penetration into Caco-2 cells in an aqueous environment without the coexistence of fats, pancreatic enzymes, or bile salts has been displayed. The influence of three VK2 homologs: VK2-MK4, VK2-MK7 and VK2-MK9 on apoptosis and necrosis of Caco-2 cells was tested proving the lack of their harmful effects on the tested cells. Moreover, the unique role of long-chain homologs (VK2-MK9 and VK2-MK7) in inhibiting the secretion of pro-inflammatory cytokines such as IL-8 (for Caco-2 tissue) and IL-6 and TNFα (for RAW 264.7) has been documented.
Typologies of dependency, household characteristics, and disparity in formal and informal care use: analysis of community-dwelling long-term care insurance claimants in an urban municipality of China
Authors: Fang Shuai , Liang Hong , Liang Yan
Published: November 2023

Background

A comprehensive understanding of subgroups of community-dwelling older adults and their long-term care (LTC) utilization can help to promote equality in the long-term services and support system. Dependency and household characteristics were found to affect the LTC utilization of homebound older adults. However, few studies considered the typologies of dependency of older populations according to co-occurring limitations, and little is known about differences in LTC use among elderly of typologies of dependency under distinct household conditions.

Methods

We aimed to identify typologies of dependency of older adults living at home and explore the disparities in formal care and informal care use among typologies of dependency by income and living situation. In this cross-sectional study, we used the public long-term care insurance (LTCI) database of Yiwu, Zhejiang Province, China, and included 1675 individuals aged ≥ 60 years living at home. Cluster analysis was conducted to determine typologies of dependency among older adults. A two-step multilevel analysis was used to examine disparities in formal and informal care use related to household income and living status among typologies of dependency.

Results

Seven dependency clusters were identified. Pro-wealthy inequalities in both formal and informal care use were found in the least dependent cluster and the limited-locomotion cluster. Pro-poor inequalities in formal care use were found in the fully dependent cluster without impaired vision and the cluster with intact continence and vision. Living with family members was positively associated with receiving formal care for the fully dependent cluster. Older adults in most clusters were more likely to use informal care when living with family members, except for the least dependent cluster and the limited-locomotion cluster.

Conclusions

Our findings suggest that household inequalities in LTC use varied among typologies of dependency of older adults, which may provide insights for researchers and policymakers to develop tailored LTC and targeted LTCI programs for older adults living at home and their family caregivers, considering both typologies of dependency and household characteristics.
The association of statin therapy and cancer: a meta-analysis
Authors: Chen Zijian , Wu Panyun , Wang Jiangang , Chen Pengfei , Fang Zhenfei , Luo Fei
Published: November 2023

Background

Statins are routinely prescribed to lower cholesterol and have been demonstrated to have significant benefits in atherosclerotic cardiovascular disease. However, whether statin therapy has effects on cancer risk remains controversial. In this study, we investigated the influence of statin therapy on cancer incidence and mortality by conducting a comprehensive meta-analysis of randomized controlled trials.

Methods

Systematic searches by Cochrane, Embase, Medline, and PubMed were performed to locate data from eligible randomized controlled trials related to statin therapy and oncology. Our main endpoints were cancer incidence and mortality. Fixed-effects models were used in this study.

Results

This meta-analysis comprised thirty-five randomized controlled studies. Twenty-eight included studies reported cancer incidence, and eighteen reported cancer mortality. The pooled results indicated no reduction in cancer incidence with statins compared to placebo [OR = 0.99, 95% CI (0.95, 1.03)]. In addition, statins did not decrease cancer mortality [OR = 0.99, 95% CI (0.91, 1.07)]. This study also performed a number of subgroup analyses, which showed no effect of statins on cancer subtypes such as genitourinary and breast cancer. Neither the type of statin nor long-term treatment with statins had an effect on cancer incidence and mortality.

Conclusion

Through comprehensive analysis, we found that statin therapy does not reduce cancer incidence or mortality while protecting the cardiovascular system.

Trial registration

Prospero CRD42022377871.
Opposite effects of low-carbohydrate high-fat diet on metabolism in humans and mice
Authors: Cai Lingli , Xia Xinyi , Gu Yunjie , Hu Lili , Li Cheng , Ma Xiaojing , Yin Jun
Published: November 2023

Background

Low-carbohydrate diet (LCD) is effective for weight loss and glycaemic control in humans. Here, the study aimed to explore the effects of LCD/high-fat diet (HFD) in both humans and mice.

Methods

Twenty-two overweight or obese participants received LCD for 3 weeks. Based on carbohydrate intake > 10% or ≤ 10% of calories, the participants were divided into moderate LCD (MLCD) and very LCD (VLCD) groups. The participants completed a 10-question food preference survey. Meanwhile, C57BL/6J mice were assigned to five groups: chow diet (CD, 10% fat), HFD with 60%, 70%, and 75% fat from cocoa butter (HFD-C), and HFD with 60% fat from lard (HFD-L) and fed for 24 weeks. Eight mice were acclimatised for the food-choice test.

Results

LCD decreased the total energy intake in humans. The VLCD group showed greater weight loss and better glycaemic control than the MLCD group. A food preference survey showed that 65% of participants tended to choose high-carbohydrate foods. In mice, HFD resulted in energy overconsumption, obesity, and metabolic disorders. When CD and HFD-L were administered simultaneously, mice rarely consumed CD. In the HFD-C groups, the energy intake and body weight increased with increasing dietary fat content. Compared with the HFD-C group, the HFD-L group consumed more energy and had poorer metabolism.

Conclusions

Lower carbohydrate intake contributed to lower energy intake and improved metabolism in humans. In mice, diets with a higher proportion of fat become more attractive and obesogenic by fixing the fat sources. Since the mice preferred lard to cocoa butter, lard induced excess energy intake and poorer metabolism. Different food preferences may be the underlying mechanism behind the opposite effects of the LCD/HFD in humans and mice.

Trial registration

The clinical trial was registered with the Chinese Clinical Trial Registry (www.chictr.org.cn). The registration number is ChiCTR1800016786. All participants provided written informed consent prior to enrolment.
Aggregated Hendra virus C-protein activates the NLRP3 inflammasome to induce inflammation
Authors: Barry Kristian , Harpur Christopher , Lam Maggie , Tate Michelle D. , Mansell Ashley
Published: November 2023

Background

Hendra virus is an emerging virus with a geographically broad host reservoir. In humans, Hendra virus causes excessive inflammatory disease of the lung and nervous system. Our current understanding as to how Hendra virus or what factors induce inflammation is limited and as such, there are currently no therapeutic options available for patients who contract Hendra virus. Recent studies have identified viral aggregating proteins as drivers of inflammation in influenza A virus and SARS-CoV-2 virus. In this study, we sought to identify potential aggregating Hendra virus proteins as proof-of-concept that inflammasome activation may induce inflammation and contribute to disease pathology.

Results

Here, we have identified that a peptide analogue of Hendra virus C protein (termed HeVc) forms aggregates and activates the NLRP3 inflammasome through phagocytic uptake into cells in vitro. Treatment of cells with the specific NLRP3 inhibitor MCC950 ameliorated IL-1β secretion responses in vitro. Critically, in vivo intranasal inoculation of mice with aggregated HeVc peptide induced pulmonary inflammation, suggesting HeVc may drive immunopathology during infection. Importantly, mice treated with MCC950 demonstrated reduced IL-1β secretion into the bronchoalveolar space, highlighting the role of NLRP3 in host HeV infections and a potential therapeutic strategy to reduce disease pathology.

Conclusion

Taken together, these results identify Hendra virus C protein as a possible contributor to immunopathology during Hendra virus infections. Importantly, these studies highlight a potential role for NLRP3 in driving disease-associated inflammation, critically identifying a possible therapeutic strategy to alleviate disease-associated inflammation of infected patients through targeting of the NLRP3 inflammasome.
Comparison between oblique lumbar interbody fusion and posterior lumbar interbody fusion for the treatment of lumbar degenerative diseases: a systematic review and meta-analysis
Authors: An Bochen , Ren Bowen , Han Zhenchuan , Mao Keya , Liu Jianheng
Published: November 2023

Background

Although oblique lumbar interbody fusion (OLIF) has produced good results for lumbar degenerative diseases (LDDs), its efficacy vis-a-vis posterior lumbar interbody fusion (PLIF) remains controversial. This meta-analysis aimed to compare the clinical efficacy of OLIF and PLIF for the treatment of LDDs.

Methods

A comprehensive assessment of the literature was conducted, and the quality of retrieved studies was assessed using the Newcastle–Ottawa Scale. Clinical parameters included the visual analog scale (VAS), and Oswestry Disability Index (ODI) for pain, disability, and functional levels. Statistical analysis related to operative time, intraoperative bleeding, length of hospital stay, lumbar lordosis angle, postoperative disc height, and complication rates was performed. The PROSPERO number for the present systematic review is CRD42023406695.

Results

In total, 574 patients (287 for OLIF, 287 for PLIF) from eight studies were included. The combined mean postoperative difference in ODI and lumbar VAS scores was − 1.22 and − 0.43, respectively. In postoperative disc, height between OLIF and PLIF was 2.05. The combined advantage ratio of the total surgical complication rate and the mean difference in lumbar lordosis angle between OLIF and PLIF were 0.46 and 1.72, respectively. The combined mean difference in intraoperative blood loss and postoperative hospital stay between OLIF and PLIF was − 128.67 and − 2.32, respectively.

Conclusion

Both the OLIF and PLIF interventions showed good clinical efficacy for LDDs. However, OLIF demonstrated a superior advantage in terms of intraoperative bleeding, hospital stay, degree of postoperative disc height recovery, and postoperative complication rate.
Concomitant minimally invasive surgery for tricuspid valve papillary fibroelastoma and right lung cancer in an elderly patient: a case report and review of the literature
Authors: Wang Yalin , Saheb Neckwaree Aboo Bakar Shah Ameer , Husanova Firyuza , Li Weidong , Xu Hongfei
Published: November 2023

Background

It is very common for patients with newly diagnosed lung masses to have heart disease. However, papillary fibroelastomas (PFEs) of the tricuspid valve (TV) combined with lung cancer are rarely reported. It is thus unclear whether a two-stage surgery or concomitant surgery is optimal.

Case presentation

We report the case of a 73-year-old Chinese male who was diagnosed with PFEs on the TV by transthoracic echocardiography (TTE) examination while being evaluated to undergo video-assisted thoracic surgery (VATS) for a right lower lung nodule. We resected both the PFEs and the lung nodule via right minithoracotomy. The surgery was uneventful, and histopathology reports confirmed PFEs of the TV and moderately to poorly differentiated squamous cell carcinoma. The patient recovered uneventfully, and there was no sign of tumor recurrence during 15 months of follow-up.

Conclusions

We suggest that after careful evaluation, concomitant minimally invasive radical resection of primary lung cancer after cardiac PFE removal is an acceptable and safe treatment strategy and should be performed as soon as possible.
Transcatheter mitral valve implantation with Tendyne System Ten Years since the First In-Human Implant A systematic review
Authors: Ahmed Ahmed , Aziz Tarek A. Abdel , AlAsaad Mohannad M. R. , Majthoob Motaz , Toema Ahmed
Published: November 2023

Background

Transcatheter mitral valve replacement (TMVR) using the Tendyne™ valve is regarded as one of the most studied TMVR systems. The first human experience with the procedure was reported in 2013. The present study aims to systemically revise the published literature to document the global experience with TMVR using the Tendyne™ valve.

Methods

The present review was conducted in line with the PRISMA statement on systematic reviews. Database included in the search process were Scopus, Web of Science and Pubmed. Search was processed using multiple keywords combinations and was adjusted to English literature only.

Results

We included 26 articles in the final analysis reporting data from 319 patients. Patients recruited by the included studies comprised 192 males (60.2%) and 127 females (39.8%). In the studied patients, mitral annular calcification (MAC) was reported in 107 patients (33.5%). Preoperatively, MR grades 1,2 and 3–4 were reported in 3,5 and 307 patients respectively. Postoperatively, MR grades 1, 2 and 4 were reported in only 12, 3 and 1 patients respectively. Technical success was achieved in 309 patients (96.9%). Follow up durations widely varied among different studies from just days before discharge to 6 years. At the end of follow up, 79 patients died (24.8%) including 52 patients (16.3%) due to cardiovascular causes.

Conclusions

Management of mitral valve disease using the Tendyne system appears to be a promising minimally invasive option for many high-risk patients with accepted procedural feasibility and safety profile.
Late-onset symptomatic hyperprolactinemia in 6-pyruvoyl-tetrahydropterin synthase deficiency
Authors: Hsu Rai-Hseng , Lee Ni-Chung , Chen Hui-An , Hwu Wuh-Liang , Chang Tung-Ming , Chien Yin-Hsiu
Published: November 2023

Background

Tetrahydrobiopterin (BH4) deficiency caused by 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is a rare disorder that is one of the major causes of hyperphenylalaninemia in Taiwan.

Methods

In this study, we reviewed the clinical courses of 12 adolescent and adult patients (7 females and 5 males) with PTPS deficiency.

Results

The patients were treated shortly after diagnosis through newborn screening with a combination of BH4, levodopa/carbidopa, and 5-OH-tryptophan. Their plasma phenylalanine and tyrosine levels were well controlled, and their prolactin levels were also decreased after treatment. However, their prolactin levels gradually rose as they grew into puberty, and at a current age of 27.5 [interquartile range (IQR 7.9)] years, five of the 12 patients had either highly elevated prolactin levels (> 100 ng/mL in one male patient, normal reference values, male < 11 ng/mL, female < 17 ng/mL) or symptoms, including irregular menstruation, amenorrhea, and breast swelling (in four female patients). The dosage of levodopa in these five patients (14.3 (IQR 3.0) mg/kg/day) was slightly higher than that in the other patients (p = 0.05). Magnetic resonance imaging studies did not reveal an increase in the size of the anterior pituitary gland, although a Rathke cleft cyst was found in one patient. Two patients received cabergoline treatment, which promptly lowered prolactin levels and relieved symptoms.

Conclusions

Hyperprolactinemia is common in female patients with PTPS deficiency, especially after puberty. A long-acting dopamine agonist, such as cabergoline, may be a necessary adjunctive treatment for most patients with BH4 deficiency.
Regulation of the Hippo/YAP axis by CXCR7 in the tumorigenesis of gastric cancer
Authors: Wang Tianshi , Wang Dehai , Sun Yanan , Zhuang Ting , Li Xin , Yang Huijie , Zang Yifeng , Liu Ziping , Yang Penghe , Zhang Chenmiao , Cui Jiayao , Fu Mingxi , Zhang Shuqing , Su Peng , Li Zhongbo , Zhu Jian , Ding Yinlu
Published: November 2023

Background

The Hippo pathway is crucial in organ size control and tumorigenesis. Dysregulation of the Hippo/YAP axis is commonly observed in gastric cancer, while effective therapeutic targets for the Hippo/YAP axis are lacking. Identification of reliable drug targets and the underlying mechanisms that could inhibit the activity of the Hippo/YAP axis and gastric cancer progression is urgently needed.

Methods

We used several gastric cancer cell lines and xenograft models and performed immunoblotting, qPCR, and in vivo studies to investigate the function of CXCR7 in gastric cancer progression.

Results

In our current study, we demonstrate that the membrane receptor CXCR7 (C-X-C chemokine receptor 7) is an important modulator of the Hippo/YAP axis. The activation of CXCR7 could stimulate gastric cancer cell progression through the Hippo/YAP axis in vitro and in vivo, while pharmaceutical inhibition of CXCR7 via ACT-1004–1239 could block tumorigenesis in gastric cancer. Molecular studies revealed that the activation of CXCR7 could dephosphorylate YAP and facilitate YAP nuclear accumulation and transcriptional activation in gastric cancer. CXCR7 functions via G-protein Gαq/11 and Rho GTPase to activate YAP activity. Interestingly, ChIP assays showed that YAP could bind to the promoter region of CXCR7 and facilitate its gene transcription, which indicates that CXCR7 is both the upstream signalling and downstream target of the Hippo/YAP axis in gastric cancer.

Conclusion

In general, we identified a novel positive feedback loop between CXCR7 and the Hippo/YAP axis, and blockade of CXCR7 could be a plausible strategy for gastric cancer.
Evaluation of deep learning-based feature selection for single-cell RNA sequencing data analysis
Authors: Huang Hao , Liu Chunlei , Wagle Manoj M. , Yang Pengyi
Published: November 2023

Background

Feature selection is an essential task in single-cell RNA-seq (scRNA-seq) data analysis and can be critical for gene dimension reduction and downstream analyses, such as gene marker identification and cell type classification. Most popular methods for feature selection from scRNA-seq data are based on the concept of differential distribution wherein a statistical model is used to detect changes in gene expression among cell types. Recent development of deep learning-based feature selection methods provides an alternative approach compared to traditional differential distribution-based methods in that the importance of a gene is determined by neural networks.

Results

In this work, we explore the utility of various deep learning-based feature selection methods for scRNA-seq data analysis. We sample from Tabula Muris and Tabula Sapiens atlases to create scRNA-seq datasets with a range of data properties and evaluate the performance of traditional and deep learning-based feature selection methods for cell type classification, feature selection reproducibility and diversity, and computational time.

Conclusions

Our study provides a reference for future development and application of deep learning-based feature selection methods for single-cell omics data analyses.
Skeletal muscle regeneration failure in ischemic-damaged limbs is associated with pro-inflammatory macrophages and premature differentiation of satellite cells
Authors: Southerland Kevin W. , Xu Yueyuan , Peters Derek T. , Lin Xin , Wei Xiaolin , Xiang Yu , Fei Kaileen , Olivere Lindsey A. , Morowitz Jeremy M. , Otto James , Dai Qunsheng , Kontos Christopher D. , Diao Yarui
Published: November 2023

Background

Chronic limb-threatening ischemia (CLTI), a severe manifestation of peripheral arterial disease (PAD), is associated with a 1-year limb amputation rate of approximately 15–20% and substantial mortality. A key feature of CLTI is the compromised regenerative ability of skeletal muscle; however, the mechanisms responsible for this impairment are not yet fully understood. In this study, we aim to delineate pathological changes at both the cellular and transcriptomic levels, as well as in cell–cell signaling pathways, associated with compromised muscle regeneration in limb ischemia in both human tissue samples and murine models of CLTI.

Methods

We performed single-cell transcriptome analysis of ischemic and non-ischemic muscle from the same CLTI patients and from a murine model of CLTI. In both datasets, we analyzed gene expression changes in macrophage and muscle satellite cell (MuSC) populations as well as differential cell–cell signaling interactions and differentiation trajectories.

Results

Single-cell transcriptomic profiling and immunofluorescence analysis of CLTI patient skeletal muscle demonstrated that ischemic-damaged tissue displays a pro-inflammatory macrophage signature. Comparable results were observed in a murine CLTI model. Moreover, integrated analyses of both human and murine datasets revealed premature differentiation of MuSCs to be a key feature of failed muscle regeneration in the ischemic limb. Furthermore, in silico inferences of intercellular communication and in vitro assays highlight the importance of macrophage-MuSC signaling in ischemia induced muscle injuries.

Conclusions

Collectively, our research provides the first single-cell transcriptome atlases of skeletal muscle from CLTI patients and a murine CLTI model, emphasizing the crucial role of macrophages and inflammation in regulating muscle regeneration in CLTI through interactions with MuSCs.
Unraveling genetic causality between type 2 diabetes and pulmonary tuberculosis on the basis of Mendelian randomization
Authors: Chen Shengnan , Zhang Weisong , Zheng Zhenquan , Shao Xiaolong , Yang Peng , Yang Xiaobin , Nan Kai
Published: November 2023

Background

The comorbidity rate between type 2 diabetes mellitus (T2DM) and pulmonary tuberculosis (PTB) is high and imposes enormous strains on healthcare systems. However, whether T2DM is causally associated with PTB is unknown owing to limited evidence from prospective studies. Consequently, the present study aimed to clarify the genetic causality between T2DM and PTB on the basis of Mendelian randomization (MR) analysis.

Methods

Genetic variants for T2DM and PTB were obtained from the IEU OpenGWAS project. The inverse variance weighted method was used as the main statistical analysis method and was supplemented with MR-Egger, weighted median, simple mode, and weighted mode methods. Heterogeneity was analyzed using Cochran’s Q statistic. Horizontal pleiotropy was assessed using the MR-PRESSO global test and MR-Egger regression. Robustness of the results was verified using the leave-one-out method.

Results

A total of 152 independent single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) to assess the genetic causality between T2DM and PTB. Patients with T2DM had a higher risk of PTB at the genetic level (odds ratio (OR) for MR-Egger was 1.550, OR for weighted median was 1.540, OR for inverse variance weighted was 1.191, OR for simple mode was 1.629, OR for weighted mode was 1.529). There was no horizontal pleiotropy or heterogeneity among IVs. The results were stable when removing the SNPs one by one.

Conclusions

This is the first comprehensive MR analysis that revealed the genetic causality between T2DM and PTB in the East Asian population. The study provides convincing evidence that individuals with T2DM have a higher risk of developing PTB at the genetic level. This offers a significant basis for joint management of concurrent T2DM and PTB in clinical practice.
The concurrent validity of the Lund University Checklist for Incipient Exhaustion and the Karolinska Exhaustion Disorder Scale: a replication study
Authors: Persson Roger , Österberg Kai , Björk Jonas
Published: November 2023

Objective

As part of our research on Swedish school principals, we examined the concurrent validity between the Karolinska Exhaustion Disorder Scale (KEDS) and the Lund University Checklist for Incipient Exhaustion (LUCIE) in a cross-sectional study sample (N = 2670). Specifically, we examined: (a) to what extent LUCIE and KEDS identified the same individuals and their level of agreement, and (b) to what extent the present observations among school-principals agreed with previous observations made in a highly educated and healthy study sample drawn from the general population.

Results

Depending on established cut-points on LUCIE, the Kappa agreement (K) between LUCIE and KEDS varied between fair (K = 0.34 [95% Confidence Interval = 0.30–0.38]) and moderate (K = 0.54 [95% Confidence Interval = 0.51–0.58]). While the instruments did not always identify the same individuals, the most reasonable comparison between KEDS and LUCIE was achieved when the cut-off on LUCIE was made between step two and step three. The results essentially replicated our previous results observed in a highly educated and healthy study sample drawn from the general population. The level of agreement suggests that KEDS and LUCIE scores are supplementary rather than interchangeable. Thus, individual result from KEDS and LUCIE are probably best understood in dialogue with the person screened.
DNA methylation sites in early adulthood characterised by pubertal timing and development: a twin study
Authors: Sehovic Emir , Zellers Stephanie M. , Youssef Markus K. , Heikkinen Aino , Kaprio Jaakko , Ollikainen Miina
Published: November 2023

Background

Puberty is a highly heritable and variable trait, with environmental factors having a role in its eventual timing and development. Early and late pubertal onset are both associated with various diseases developing later in life, and epigenetic characterisation of pubertal timing and development could lead to important insights. Blood DNA methylation, reacting to both genotype and environment, has been associated with puberty; however, such studies are relatively scarce. We investigated peripheral blood DNA methylation profiles (using Illumina 450 K and EPIC platforms) of 1539 young adult Finnish twins associated with pubertal development scale (PDS) at ages 12 and 14 as well as pubertal age (PA).

Results

Fixed effect meta-analysis of the two platforms on 347,521 CpGs in common identified 58 CpG sites associated (p < 1 × 10−5) with either PDS or PA. All four CpGs associated with PA and 45 CpGs associated with PDS were sex-specific. Thirteen CpGs had a high heritability (h2: 0.51–0.98), while one CpG site (mapped to GET4) had a high shared environmental component accounting for 68% of the overall variance in methylation at the site. Utilising twin discordance analysis, we found 6 CpG sites (5 associated with PDS and 1 with PA) that had an environmentally driven association with puberty. Furthermore, genes with PDS- or PA-associated CpGs were consistently linked to various developmental processes and diseases such as breast, prostate and ovarian cancer, while methylation quantitative trait loci of associated CpG sites were enriched in immune pathways developing during puberty.

Conclusions

By identifying puberty-associated DNA methylation sites and examining the effects of sex, environment and genetics, we shed light on the intricate interplay between environment and genetics in the context of puberty. Through our comprehensive analysis, we not only deepen the understanding of the significance of both genetic and environmental factors in the complex processes of puberty and its timing, but also gain insights into potential links with disease risks.
Endothelial progenitor cells as biomarkers of diabetes-related cardiovascular complications
Authors: Benítez-Camacho Josefa , Ballesteros Antonio , Beltrán-Camacho Lucía , Rojas-Torres Marta , Rosal-Vela Antonio , Jimenez-Palomares Margarita , Sanchez-Gomar Ismael , Durán-Ruiz Mª Carmen
Published: November 2023

Diabetes mellitus (DM) constitutes a chronic metabolic disease characterized by elevated levels of blood glucose which can also lead to the so-called diabetic vascular complications (DVCs), responsible for most of the morbidity, hospitalizations and death registered in these patients. Currently, different approaches to prevent or reduce DM and its DVCs have focused on reducing blood sugar levels, cholesterol management or even changes in lifestyle habits. However, even the strictest glycaemic control strategies are not always sufficient to prevent the development of DVCs, which reflects the need to identify reliable biomarkers capable of predicting further vascular complications in diabetic patients. Endothelial progenitor cells (EPCs), widely known for their potential applications in cell therapy due to their regenerative properties, may be used as differential markers in DVCs, considering that the number and functionality of these cells are affected under the pathological environments related to DM. Besides, drugs commonly used with DM patients may influence the level or behaviour of EPCs as a pleiotropic effect that could finally be decisive in the prognosis of the disease. In the current review, we have analysed the relationship between diabetes and DVCs, focusing on the potential use of EPCs as biomarkers of diabetes progression towards the development of major vascular complications. Moreover, the effects of different drugs on the number and function of EPCs have been also addressed.

Graphical Abstract
Sex-differences in proteasome-dependent K48-polyubiquitin signaling in the amygdala are developmentally regulated in rats
Authors: Farrell Kayla , Auerbach Aubrey , Liu Catherine , Martin Kiley , Pareno Myasia , Ray W. Keith , Helm Richard F. , Biase Fernando , Jarome Timothy J.
Published: November 2023

Background

Sex differences have been observed in several brain regions for the molecular mechanisms involved in baseline (resting) and memory-related processes. The ubiquitin proteasome system (UPS) is a major protein degradation pathway in cells. Sex differences have been observed in lysine-48 (K48)-polyubiquitination, the canonical degradation mark of the UPS, both at baseline and during fear memory formation within the amygdala. Here, we investigated when, how, and why these baseline sex differences arise and whether both sexes require the K48-polyubiquitin mark for memory formation in the amygdala.

Methods

We used a combination of molecular, biochemical and proteomic approaches to examine global and protein-specific K48-polyubiquitination and DNA methylation levels at a major ubiquitin coding gene (Uba52) at baseline in the amygdala of male and female rats before and after puberty to determine if sex differences were developmentally regulated. We then used behavioral and genetic approaches to test the necessity of K48-polyubiquitination in the amygdala for fear memory formation.

Results

We observed developmentally regulated baseline differences in Uba52 methylation and total K48-polyubiquitination, with sexual maturity altering levels specifically in female rats. K48-polyubiquitination at specific proteins changed across development in both male and female rats, but sex differences were present regardless of age. Lastly, we found that genetic inhibition of K48-polyubiquitination in the amygdala of female, but not male, rats impaired fear memory formation.

Conclusions

These results suggest that K48-polyubiquitination differentially targets proteins in the amygdala in a sex-specific manner regardless of age. However, sexual maturity is important in the developmental regulation of K48-polyubiquitination levels in female rats. Consistent with these data, K48-polyubiquitin signaling in the amygdala is selectively required to form fear memories in female rats. Together, these data indicate that sex-differences in baseline K48-polyubiquitination within the amygdala are developmentally regulated, which could have important implications for better understanding sex-differences in molecular mechanisms involved in processes relevant to anxiety-related disorders such as post-traumatic stress disorder (PTSD).
Delta-Sincov mappings in Banach algebras
Authors: Fechner Włodzimierz , Świątczak Aleksandra
Published: November 2023

We study solutions and approximate solutions of the multiplicative Sincov equation $$ T(f, h) = T(f, g)T(g, h) $$
T
(
f
,
h
)
=
T
(
f
,
g
)
T
(
g
,
h
)
for mapping T taking values in a commutative Banach algebra.
In vitro evaluation of cell viability and expression profile of growth factors in mouse Sertoli cells exposed to Delta-9-tetrahydrocannabinol: a mechanistic insight into the cannabinoid-induced testicular toxicity
Authors: Mohammadpour-Asl Shadi , Roshan-Milani Shiva , Abdollahzade Fard Amin , Golchin Ali
Published: November 2023

The potentially adverse effects of cannabis (marijuana), a common leisure compound, on male reproductive performance are a reason for concern. δ-9-tetrahydrocannabinol (THC), the primary active component of marijuana alters testicular cells’ proliferation and function which affects male fertility and causes testicular cells dysfunction and apoptosis. The main objective of this study was to investigate the possible mechanism underlying the toxic effects of THC with a mechanistic insight into Sertoli cell-based reproductive dysfunction. The Mus musculus Sertoli cell line (TM4) was cultured and exposed to different concentrations of THC and, MTT (3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was then performed for evaluating cell viability. The expression of caspase-3 gene and genes related to growth factors were analyzed by real-time RT-PCR. Western blotting was performed for evaluating protein expression level. THC concentration-dependently decreased the TM4 viability with a significant effect starting at concentration of 1 μM and reaching about 75% of the control level at the concentration of 50 μM (IC25). Moreover, caspase-3 mRNA expression levels significantly increased while growth factors mRNA levels decreased in THC-exposed cells compared to unexposed cells. There was also a significant reduction in related protein levels in THC group. Administration of the THC promotes cytotoxic and apoptotic effects on TM4 cells partly through down-regulation of growth factors expression. Increased apoptosis, over expression of caspase-3, and down-regulation of growth factors expression in Sertoli cells exposed to THC may be a reflection of THC-induced testicular toxicity, which may be partly involved in infertility associated with marijuana smoking or medical cannabis use.
Lacosamide dosing in patients receiving continuous renal replacement therapy
Authors: Chaijamorn Weerachai , Phunpon Sathian , Sathienluckana Thanompong , Charoensareerat Taniya , Pattharachayakul Sutthiporn , Rungkitwattanakul Dhakrit , Srisawat Nattachai
Published: November 2023

Background

Lacosamide is one of the anticonvulsants used in critically ill patients. This study aimed to suggest appropriate lacosamide dosing regimens in critically ill patients receiving continuous renal replacement therapy (CRRT) via Monte Carlo simulations.

Methods

Mathematical models were created using published demographic and pharmacokinetics in adult critically ill patients. CRRT modalities with different effluent rates were added into the models. Lacosamide regimens were evaluated on the probability of target attainment (PTA) using pharmacodynamic targets of trough concentrations and area under the curve within a range of 5–10 mg/L and 80.25–143 and 143–231 mg*h/L for the initial 72 h-therapy, respectively. Optimal regimens were defined from regimens that yielded the highest PTA. Each dosing regimen was tested in a group of different 10,000 virtual patients.

Results

Our results revealed the optimal lacosamide dosing regimen of 300–450 mg/day is recommended for adult patients receiving both CRRT modalities with 20–25 effluent rates. The dose of 600 mg/day was suggested in higher effluent rate of 35 mL/kg/h. Moreover, a patient with body weight > 100 kg was less likely to attain the targets.

Conclusions

Volume of distribution, total clearance, CRRT clearance and body weight were significantly contributed to lacosamide dosing. Clinical validation of the finding is strongly indicated.
Insights into the underlying pathogenesis and therapeutic potential of endoplasmic reticulum stress in degenerative musculoskeletal diseases
Authors: Wen Ze-Qin , Lin Jun , Xie Wen-Qing , Shan Yun-Han , Zhen Ge-Hua , Li Yu-Sheng
Published: November 2023

Degenerative musculoskeletal diseases are structural and functional failures of the musculoskeletal system, including osteoarthritis, osteoporosis, intervertebral disc degeneration (IVDD), and sarcopenia. As the global population ages, degenerative musculoskeletal diseases are becoming more prevalent. However, the pathogenesis of degenerative musculoskeletal diseases is not fully understood. Previous studies have revealed that endoplasmic reticulum (ER) stress is a stress response that occurs when impairment of the protein folding capacity of the ER leads to the accumulation of misfolded or unfolded proteins in the ER, contributing to degenerative musculoskeletal diseases. By affecting cartilage degeneration, synovitis, meniscal lesion, subchondral bone remodeling of osteoarthritis, bone remodeling and angiogenesis of osteoporosis, nucleus pulposus degeneration, annulus fibrosus rupture, cartilaginous endplate degeneration of IVDD, and sarcopenia, ER stress is involved in the pathogenesis of degenerative musculoskeletal diseases. Preclinical studies have found that regulation of ER stress can delay the progression of multiple degenerative musculoskeletal diseases. These pilot studies provide foundations for further evaluation of the feasibility, efficacy, and safety of ER stress modulators in the treatment of musculoskeletal degenerative diseases in clinical trials. In this review, we have integrated up-to-date research findings of ER stress into the pathogenesis of degenerative musculoskeletal diseases. In a future perspective, we have also discussed possible directions of ER stress in the investigation of degenerative musculoskeletal disease, potential therapeutic strategies for degenerative musculoskeletal diseases using ER stress modulators, as well as underlying challenges and obstacles in bench-to-beside research.
Dietary counselling plus omega-3 supplementation in the treatment of generalized anxiety disorder: protocol for a randomized wait-list controlled pilot trial (the “EASe-GAD Trial”)
Authors: Aucoin Monique , LaChance Laura , van der Wurff Inge , Miller Sean , Naidoo Umadevi , Jenkins Andrew , Cooley Kieran
Published: November 2023

Background

Anxiety disorders are prevalent and disabling conditions involving excessive worry and tension. Generalized anxiety disorder (GAD), the most common anxiety disorder, affects 5% of individuals from high-income countries and many individuals report that treatment options are not accessible, effective, or tolerable. Clinical evidence suggests that nutrition interventions, based on the Mediterranean diet and supplementation of omega-3 fatty acids, can significantly improve symptoms of depression; however, the effect of nutrition interventions on anxiety symptoms has not been studied in a clinical population. The primary objective of the present study is to assess the feasibility and acceptability of a dietary counselling and omega-3 fatty acid supplementation intervention delivered to adult women with GAD. The secondary objectives include assessing changes in anxiety symptom severity, assessing changes in quality of life, assessing changes in biomarkers, and evaluating the components of the program.

Methods

This study is a randomized, wait-list controlled pilot trial delivering a 12-week, dietary counselling intervention and omega-3 supplementation to 50 adult women with GAD. Participants will complete seven individual counselling sessions which include education, personalized recommendations, mindful eating techniques, motivational interviewing, and goal setting. They will be provided with recipes, instructional videos, and food items. The intervention is designed based on the Social Cognitive Theory and previous research that has been done by the author team to identify dietary constituents with the most evidence to support their use in the treatment of anxiety disorders. Questionnaires and blood work will be completed at baseline, after the waiting period (for those in the waitlist group), and after the intervention.

Discussion

Results from this study will lay the foundation for future large-scale studies in this area and may provide preliminary evidence of the role of diet counselling and omega-3 supplementation in the management of GAD. Research on the role of nutrition in psychiatric care has been identified as a priority by a number of international organizations. The present trial directly addresses the call for the research that is most needed to advance the field.

Trial registration

This protocol was registered at ClinicalTrials.gov on October 10, 2022; NCT05573672.

Trial sponsor: The Canadian College of Naturopathic Medicine, 1255 Sheppard Ave E, Toronto, ON M2K 1E2, 416–498-1255.

Steering committee: Composed of MA, LL, KC, IvdW, SM, UN, AJ. The committee meets monthly to oversee the trial.

Protocol identifier: CCNM_EASe-GADCT_2201v4.
Not quite eye to A.I.: student and teacher perspectives on the use of generative artificial intelligence in the writing process
Authors: Barrett Alex , Pack Austin
Published: November 2023

Generative artificial intelligence (GenAI) can be used to author academic texts at a similar level to what humans are capable of, causing concern about its misuse in education. Addressing the role of GenAI in teaching and learning has become an urgent task. This study reports the results of a survey comparing educators’ (n = 68) and university students’ (n = 158) perceptions on the appropriate use of GenAI in the writing process. The survey included representations of user prompts and output from ChatGPT, a GenAI chatbot, for each of six tasks of the writing process (brainstorming, outlining, writing, revising, feedback, and evaluating). Survey respondents were asked to differentiate between various uses of GenAI for these tasks, which were divided between student and teacher use. Results indicate minor disagreement between students and teachers on acceptable use of GenAI tools in the writing process, as well as classroom and institutional-level lack of preparedness for GenAI. These results imply the need for explicit guidelines and teacher professional development on the use of GenAI in educational contexts. This study can contribute to evidence-based guidelines on the integration of GenAI in teaching and learning.
The holistic effects of medical cannabis compared to opioids on pain experience in Finnish patients with chronic pain
Authors: Jylkkä Jussi , Hupli Aleksi , Nikolaeva Aleksandra , Alanen Sandra , Back Anna Erika , Lindqvist Sara , Krabbe Andreas , Lavie-Ajayi Maya , Kantonen Oskari
Published: November 2023

Background

Medical cannabis (MC) is increasingly used for chronic pain, but it is unclear how it aids in pain management. Previous literature suggests that MC could holistically alter the pain experience instead of only targeting pain intensity. However, this hypothesis has not been previously systematically tested.

Method

A retrospective internet survey was used in a sample of Finnish chronic pain patients (40 MC users and 161 opioid users). The patients evaluated statements describing positive and negative phenomenological effects of the medicine. The two groups were propensity score matched to control for possible confounding factors.

Results

Exploratory factor analysis revealed three experience factors: Negative Side Effects, Positive Holistic Effects, and Positive Emotional Effects. The MC group (matched n = 39) received higher scores than the opioid group (matched n = 39) in Positive Emotional Effects with large effect size (Rank-Biserial Correlation RBC = .71, p < .001), and in Holistic Positive Effects with medium effect size (RBC = .47, p < .001), with no difference in Negative Side Effects (p = .13). MC and opioids were perceived as equally efficacious in reducing pain intensity. Ratings of individual statements were exploratively examined in a post hoc analysis.

Conclusion

MC and opioids were perceived to be equally efficacious in reducing pain intensity, but MC additionally positively affected broader pain-related factors such as emotion, functionality, and overall sense of wellbeing. This supports the hypothesis that MC alleviates pain through holistically altering the pain experience.