bluuebunny/crossref_metadata_2025 huggingface dataset:
Myeloma and DNA damage
Authors: Tonon Giovanni
Published: November 2023

DNA-damaging agents have represented the first effective treatment for the blood cancer multiple myeloma, and after 65 years since their introduction to the clinic, they remain one of the mainstay therapies for this disease. Myeloma is a cancer of plasma cells. Despite exceedingly slow proliferation, myeloma cells present extended genomic rearrangements and intense genomic instability, starting at the premalignant stage of the disease. Where does such DNA damage stem from? A reliable model argues that the powerful oncogenes activated in myeloma as well the phenotypic peculiarities of cancer plasma cells, including the dependency on the proteasome for survival and the constant presence of oxidative stress, all converge on modulating DNA damage and repair. Beleaguered by these contraposing forces, myeloma cells survive in a precarious balance, in which the robust engagement of DNA repair mechanisms to guarantee cell survival is continuously challenged by rampant genomic instability, essential for cancer cells to withstand hostile selective pressures. Shattering this delicate equilibrium has been the goal of the extensive use of DNA-damaging agents since their introduction in the clinic, now enriched by novel approaches that leverage upon synthetic lethality paradigms. Exploiting the impairment of homologous recombination caused by myeloma genetic lesions or treatments, it is now possible to design therapeutic combinations that could target myeloma cells more effectively. Furthermore, DNA-damaging agents, as demonstrated in solid tumors, may sensitize cells to immune therapies. In all, targeting DNA damage and repair remains as central as ever in myeloma, even for the foreseeable future.
A mechanism for hereditary angioedema caused by a methionine-379–to–lysine substitution in kininogens
Authors: Dickeson S. Kent , Kumar Sunil , Sun Mao-fu , Litvak Maxim , He Tracey Z. , Phillips Dennis R. , Roberts Elijah T. , Feener Edward P. , Law Ruby H. P. , Gailani David
Published: November 2023

Hereditary angioedema (HAE) is associated with episodic kinin-induced swelling of the skin and mucosal membranes. Most patients with HAE have low plasma C1-inhibitor activity, leading to increased generation of the protease plasma kallikrein (PKa) and excessive release of the nanopeptide bradykinin from high-molecular-weight kininogen (HK). However, disease-causing mutations in at least 10% of patients with HAE appear to involve genes for proteins other than C1-inhibitor. A point mutation in the Kng1 gene encoding HK and low–molecular weight kininogen (LK) was identified recently in a family with HAE. The mutation changes a methionine (Met379) to lysine (Lys379) in both proteins. Met379 is adjacent to the Lys380-Arg381 cleavage site at the N-terminus of the bradykinin peptide. Recombinant wild-type (Met379) and variant (Lys379) versions of HK and LK were expressed in HEK293 cells. PKa-catalyzed kinin release from HK and LK was not affected by the Lys379 substitutions. However, kinin release from HK-Lys379 and LK-Lys379 catalyzed by the fibrinolytic protease plasmin was substantially greater than from wild-type HK-Met379 and LK-Met379. Increased kinin release was evident when fibrinolysis was induced in plasma containing HK-Lys379 or LK-Lys379 compared with plasma containing wild-type HK or LK. Mass spectrometry revealed that the kinin released from wild-type and variant kininogens by PKa is bradykinin. Plasmin also released bradykinin from wild-type kininogens but cleaved HK-Lys379 and LK-Lys379 after Lys379 rather than Lys380, releasing the decapeptide Lys-bradykinin (kallidin). The Met379Lys substitutions make HK and LK better plasmin substrates, reinforcing the relationship between fibrinolysis and kinin generation.
The essential microenvironmental role of oligomannoses specifically inserted into the antigen-binding sites of lymphoma cells
Authors: Stevenson Freda K. , Forconi Francesco
Published: November 2023

There are 2 mandatory features added sequentially en route to classical follicular lymphoma (FL): first, the t(14;18) translocation, which upregulates BCL2, and second, the introduction of sequence motifs into the antigen-binding sites of the B-cell receptor (BCR), to which oligomannose-type glycan is added. Further processing of the glycan is blocked by complementarity-determining region–specific steric hindrance, leading to exposure of mannosylated immunoglobulin (Ig) to the microenvironment. This allows for interaction with the local lectin, dendritic cell–specific ICAM-3–grabbing nonintegrin (DC-SIGN), expressed by tissue macrophages and follicular dendritic cells. The major function of DC-SIGN is to engage pathogens, but this is subverted by FL cells. DC-SIGN induces tumor-specific low-level BCR signaling in FL cells and promotes membrane changes with increased adhesion to VCAM-1 via proximal kinases and actin regulators but, in contrast to engagement by anti-Ig, avoids endocytosis and apoptosis. These interactions appear mandatory for the early development of FL, before the acquisition of other accelerating mutations. BCR-associated mannosylation can be found in a subset of germinal center B-cell–like diffuse large B-cell lymphoma with t(14;18), tracking these cases back to FL. This category was associated with more aggressive behavior: both FL and transformed cases and, potentially, a significant number of cases of Burkitt lymphoma, which also has sites for N-glycan addition, could benefit from antibody-mediated blockade of the interaction with DC-SIGN.
A novel efficient drug repurposing framework through drug-disease association data integration using convolutional neural networks
Authors: Amiri Ramin , Razmara Jafar , Parvizpour Sepideh , Izadkhah Habib
Published: November 2023

Drug repurposing is an exciting field of research toward recognizing a new FDA-approved drug target for the treatment of a specific disease. It has received extensive attention regarding the tedious, time-consuming, and highly expensive procedure with a high risk of failure of new drug discovery. Data-driven approaches are an important class of methods that have been introduced for identifying a candidate drug against a target disease. In the present study, a model is proposed illustrating the integration of drug-disease association data for drug repurposing using a deep neural network. The model, so-called IDDI-DNN, primarily constructs similarity matrices for drug-related properties (three matrices), disease-related properties (two matrices), and drug-disease associations (one matrix). Then, these matrices are integrated into a unique matrix through a two-step procedure benefiting from the similarity network fusion method. The model uses a constructed matrix for the prediction of novel and unknown drug-disease associations through a convolutional neural network. The proposed model was evaluated comparatively using two different datasets including the gold standard dataset and DNdataset. Comparing the results of evaluations indicates that IDDI-DNN outperforms other state-of-the-art methods concerning prediction accuracy.
Genome-wide identification, expression analysis, and functional study of the bZIP transcription factor family and its response to hormone treatments in pea (Pisum sativum L.)
Authors: Wu Xiaozong , Cheng Changhe , Ma Rui , Xu Jianbo , Ma Congcong , Zhu Yutao , Ren Yanyan
Published: November 2023

Background

Basic leucine zipper (bZIP) protein is a plant-specific transcription factor involved in various biological processes, including light signaling, seed maturation, flower development, cell elongation, seed accumulation protein, and abiotic and biological stress responses. However, little is known about the pea bZIP family.

Results

In this study, we identified 87 bZIP genes in pea, named PsbZIP1 ~ PsbZIP87, via homology analysis using Arabidopsis. The genes were divided into 12 subfamilies and distributed unevenly in 7 pea chromosomes. PsbZIPs in the same subfamily contained similar intron/exon organization and motif composition. 1 tandem repeat event and 12 segmental duplication events regulated the expansion of the PsbZIP gene family. To better understand the evolution of the PsbZIP gene family, we conducted collinearity analysis using Arabidopsis thaliana, Oryza sativa Japonica, Fagopyrum tataricum, Solanum lycopersicum, Vitis vinifera, and Brachypodium distachyon as the related species of pea. In addition, interactions between PsbZIP proteins and promoters containing hormone- and stress-responsive cis-acting elements suggest that the regulation of PsbZIP expression was complex. We also evaluated the expression patterns of bZIP genes in different tissues and at different fruit development stages, all while subjecting them to five hormonal treatments.

Conclusion

These results provide a deeper understanding of PsbZIP gene family evolution and resources for the molecular breeding of pea. The findings suggested that PsbZIP genes, specifically PSbZIP49, play key roles in the development of peas and their response to various hormones.
Lipopolysaccharide O-antigen profiles of Helicobacter pylori strains from Southwest China
Authors: Tang Xiaoqiong , Wang Peng , Shen Yalin , Song Xiaona , Benghezal Mohammed , Marshall Barry J. , Tang Hong , Li Hong
Published: November 2023

Background

Helicobacter pylori lipopolysaccharide (LPS) structures vary among strains of different geographic origin. The aim of this study was to characterize the LPS O-antigen profiles of H. pylori strains isolated from Southwest China, and to further analyze the association of Lewis antigen expression with clinical outcomes and antibiotic resistance.

Results

A total of 71 H. pylori isolates from Southwest China were included for LPS profiling by silver staining and Western blotting after SDS-PAGE electrophoresis. We demonstrated that all the clinical isolates had the conserved lipid A and core-oligosaccharide, whereas the O-antigen domains varied significantly among the isolates. Compared with the common presence of the glucan/heptan moiety in LPS O-antigen structure of European strains, the clinical isolates in this study appeared to lack the glucan/heptan moiety. The expression frequency of Lex, Ley, Lea, and Leb was 66.2% (47/71), 84.5% (60/71), 56.3% (40/71), and 31.0% (22/71), respectively. In total, the expression of type II Lex and/or Ley was observed in 69 (97.2%) isolates, while type I Lea and/or Leb were expressed in 49 (69.0%) isolates. No association of Lewis antigen expression with clinical outcomes or with antibiotic resistance was observed.

Conclusions

H. pylori strains from Southwest China tend to produce heptan-deficient LPS and are more likely to express type I Lewis antigens as compared with Western strains. This may suggest that H. pylori evolves to change its LPS structure for adaptation to different hosts.
Isolation of virulent phages against multidrug-resistant Acinetobacter baumannii recovered from inanimate objects of Jimma Medical Center, Southwest Ethiopia
Authors: Hailemichael Terefe , Girma Lencho , Fissiha Paulos , Geteneh Alene , Kassa Tesfaye
Published: November 2023

Background

Because of the multidrug resistance features of Acinetobacter baumannii, endurance to diverse conditions, and causing health fatalities in healthcare settings, the global health system is looking for the development of new antimicrobials for such bacteria. As the new antimicrobial drugs pipeline is running dry, it is imperative to look for eco-friendly bio-control strategies. In this regard, phages are one to combat the biofilm producer and MDR A. baumannii. Thus, the study aimed to isolate and examine the role of phages against biofilm producers and MDR A. baumannii from inanimate objects at Jimma Medical Center (JMC), Ethiopia.

Method

Institution-based cross-sectional study was conducted from June to November 2019. A total of 309 swab samples were collected from inanimate objects and the environment in JMC. Isolation of A. baumannii, antimicrobial susceptibility testing, and biofilm detection were carried out according to standard protocol. Kirby Bauer disk diffusion and microliter plate were methods for AST and biofilm detection, respectively. Specific phage was isolated and characterized from sewage at JMC compound. The data were analyzed by SPSS version 25.0, and chi-square (X2) cross-tabulation was used to determine the correlation of variables. A P-value of < 0.05 was considered a statistically significant association.

Result

A. baumannii from inanimate objects and surfaces of different environments at JMC was detected in 6.5% of the samples. From 20 of the isolates, 85% were biofilm producers, and 60% were MDR. The lytic phage isolated specifically against A. baumannii was found host specific, and thermally stable ranging from 10–50°C. The phage was active against 42% of MDR A. baumannii, 40% of both biofilm-producing and MDR A. baumannii (MDRAB), and 35.3% of the biofilm-producing isolates.

Conclusion

The good activity of phages towards MDRAB isolates, its biofilm degradation capability, thermal stability, and host specificity in our study encourages viewing the potential use of phages as a bio-control agent besides the routine cleansing agents. Therefore, we recommend isolation of specific phages in the eradication of MDRAB from health facilities with additional efforts to characterize in detail and assess their efficacy in animal models.
Polygamy and safe sex negotiation among married women: evidence from Cameroon
Authors: Dhillon Satveer , Amoak Daniel , Chidimbah Munthali George N. , Sano Yujiro , Antabe Roger , Luginaah Isaac
Published: November 2023

Background

Research indicates that women in polygamous relationships may be exposed to unique sexual and reproductive health challenges. However, there are very few studies that examine whether polygamy is associated with safe sex negotiation among married women in sub-Saharan Africa, including Cameroon.

Methods

Using the 2018 Cameroon Demographic and Health Survey, we apply logistic regression analysis to compare two indicators of safe sex negotiation (i.e., the ability to ask for condom use and refuse sex against their partner) between polygamous (n = 1,628) and monogamous (n = 5,686) women aged 15–49 years old.

Results

We find that 67% and 50% of married women can ask for condom use and refuse sex against their partner, respectively. Multivariate analysis further reveals that women in polygamous relationships are less likely to report they can ask for condom use (OR = 0.71, p < 0.001) and refuse sex (OR = 0.64, p < 0.001) in comparison to their monogamous counterparts.

Conclusions

Our analysis found that in Cameroon, women in polygamous relationships, Muslim women, married women with inadequate HIV knowledge, those who had never been tested for HIV and women with lower socioeconomic status are less likely to negotiate for safe sex. Based on these findings, we discuss several implications for policymakers, including the establishment of a comprehensive family planning educational program and the deployment of community health workers to disseminate educational initiatives pertaining to safe sex negotiation to community members.
Proteomic analysis investigating kidney transplantation outcomes- a scoping review
Authors: Rainey Anna , McKay Gareth J. , English Jane , Thakkinstian Ammarin , Maxwell Alexander Peter , Corr Michael
Published: November 2023

Background

Kidney transplantation is the optimal treatment option for most patients with end-stage kidney disease given the significantly lower morbidity and mortality rates compared to remaining on dialysis. Rejection and graft failure remain common in transplant recipients with limited improvement in long-term transplant outcomes despite therapeutic advances. There is an unmet need in the development of non-invasive biomarkers that specifically monitor graft function and predict transplant pathologies that affect outcomes. Despite the potential of proteomic investigatory approaches, up to now, no candidate biomarkers of sufficient sensitivity or specificity have translated into clinical use. The aim of this review was to collate and summarise protein findings and protein pathways implicated in the literature to date, and potentially flag putative biomarkers worth validating in independent patient cohorts.

Methods

This review followed the Joanna Briggs’ Institute Methodology for a scoping review. MedlineALL, Embase, Web of Science Core Collection, Scopus and Google Scholar databases were searched from inception until December 2022. Abstract and full text review were undertaken independently by two reviewers. Data was collated using a pre-designed data extraction tool.

Results

One hundred one articles met the inclusion criteria. The majority were single-centre retrospective studies of small sample size. Mass spectrometry was the most used technique to evaluate differentially expressed proteins between diagnostic groups and studies identified various candidate biomarkers such as immune or structural proteins.

Discussion

Putative immune or structural protein candidate biomarkers have been identified using proteomic techniques in multiple sample types including urine, serum and fluid used to perfuse donor kidneys. The most consistent findings implicated proteins associated with tubular dysfunction and immunological regulatory pathways such as leukocyte trafficking. However, clinical translation and adoption of candidate biomarkers is limited, and these will require comprehensive evaluation in larger prospective, multicentre trials.
High sensitivity and specificity in fetal gender identification in the first trimester, using ultrasound and Noninvasive Prenatal Screening (NIPS) in twin pregnancies, a prospective study
Authors: Svirsky Ran , Sharabi-Nov Adi , Sagi Tal , Meiri Hamutal , Adi Orenstein , Kugler Nadav , Maymon Ron
Published: November 2023

Introduction

Determination of the fetal gender in the first trimester is important in twin pregnancy cases of familial X-linked genetic syndromes and helps determine chorionicity. We assessed and compared the accuracy of first-trimester ultrasound scans, and cell-free fetal DNA (CfDNA) in determining fetal gender in the first trimester of twin pregnancies.

Methods

Women with twin pregnancies were recruited prospectively during the first trimester. Fetal gender was determined using both ultrasound scans and CfDNA screening. Both results were compared to the newborn gender after delivery.

Results

A total of 113 women with twin pregnancies were enrolled. There was 100% sensitivity and specificity in Y chromosome detection using CfDNA.

Gender assignment using ultrasound in any first-trimester scans was 79.7%. Accuracy level increased from 54.2% in CRL 45-54 mm to 87.7% in CRL 55-67 mm and 91.5% in CRL 67-87 mm. Male fetuses had significantly higher chances of a gender assignment error compared to female fetuses, odds ratio = 23.574 (CI 7.346 - 75.656).

Conclusions

CfDNA is highly sensitive and specific in determining the presence of the Y chromosome in twin pregnancies in the first trimester. Between CRL 55-87 mm, ultrasound scanning offers a highly accurate determination of fetal gender in twin pregnancies.
Development and post-Kasai procedure prognostic relevance of histological features for biliary atresia
Authors: Xu Xiaodan , Wang Xueting , Ding Meiyun , Zhao Yilin , Zhao Li , Zhao Linsheng , Li Mengdi , Zhao Fangyuan , Sun Rongjuan , Wang Zhiru , Zhang Ruifeng , Zhang Shujian , Ge Liang , Sun Yan , Zhan Jianghua
Published: November 2023

Objectives

To validate an appropriate evaluation method of liver fibrosis assessment based on the unique pathological features of biliary atresia (BA) that could well predict its prognosis.

Methods

A total of 68 patients with BA who underwent Kasai procedure (KP) and an intraoperative liver biopsy, followed up from January 2019 to December 2021, were recruited in a retrospective analysis. Ishak, Metavir, and BA-specific staging systems in relation to outcomes were analyzed using logistic regression, COX proportional hazard regression, Kaplan-Meier analysis, etc.

Results

Kaplan-Meier analysis determined a significant difference in native liver survival according to the BA-specific stage (p = 0.002). The ROC curve analysis for predicting prognosis showed that the AUC of BA-specific staging combined with iBALF and severe bile duct proliferation (BDP) (0.811, 95% CI: 0.710–0.913, p < 0.0001) was higher than BA-specific staging alone (0.755, 95% CI: 0.639–0.872, p < 0.001).

Conclusions

The BA-specific staging system reflects the condition of the liver fibrosis, and its combination with iBALF and severe BDP helps to better evaluate the prognosis of patients with BA.
Pre-pandemic trends and Black:White inequities in life expectancy across the 30 most populous U.S. cities: a population-based study
Authors: Silva Abigail , Saiyed Nazia S. , Canty Emma , Benjamins Maureen R.
Published: November 2023

Background

Racial inequities in life expectancy, driven by structural racism, have been documented at the state and county levels; however, less information is available at the city level where local policy change generally happens. Furthermore, an assessment of life expectancy during the decade preceding COVID-19 provides a point of comparison for life expectancy estimates and trends post COVID-19 as cities recover.

Methods

Using National Vital Statistics System mortality data and American Community Survey population estimates, we calculated the average annual city-level life expectancies for the non-Hispanic Black (Black), non-Hispanic White (White), and total populations. We then calculated the absolute difference between the Black and White life expectancies for each of the 30 cities and the U.S. We analyzed trends over four time periods (2008-2010, 2011-2013, 2014-2016, and 2017-2019).

Results

In 2017-2019, life expectancies ranged from 72.75 years in Detroit to 83.15 years in San Francisco (compared to 78.29 years for the U.S.). Black life expectancy ranged from 69.94 years in Houston to 79.04 years in New York, while White life expectancy ranged from 75.18 years in Jacksonville to 86.42 years in Washington, DC. Between 2008-2010 and 2017-2019, 17 of the biggest cities experienced a statistically significant improvement in life expectancy, while 9 cities experienced a significant decrease. Black life expectancy increased significantly in 14 cities and the U.S. but decreased significantly in 4 cities. White life expectancy increased significantly in 17 cities and the U.S. but decreased in 8 cities. In 2017-2019, the U.S. and all but one of the big cities had a significantly longer life expectancy for the White population compared to the Black population. There was more than a 13-year difference between Black and White life expectancies in Washington, DC (compared to 4.18 years at the national level). From 2008-2010 to 2017-2019, the racial gap decreased significantly for the U.S. and eight cities, while it increased in seven cities.

Conclusion

Urban stakeholders and equity advocates need data on mortality inequities that are aligned with city jurisdictions to help guide the allocation of resources and implementation of interventions.
Interleukin-6 upregulates extracellular matrix gene expression and transforming growth factor β1 activity of tendon progenitor cells
Authors: Altmann Nadine , Bowlby Charles , Coughlin Haley , Belacic Zarah , Sullivan Stasia , Durgam Sushmitha
Published: November 2023

Background

Prolonged inflammation during tendon healing and poor intrinsic healing capacity of tendon are causal factors associated with tendon structural and functional degeneration. Tendon cells, consisting of mature tenocytes and tendon progenitor cells (TPC) function to maintain tendon structure via extracellular matrix (ECM) synthesis. Tendon cells can succumb to tissue cytokine/chemokine alterations during healing and consequently contribute to tendon degeneration. Interleukin-(IL-)1β, IL-6 and TNFα are key cytokines upregulated in injured tendons; the specific effects of IL-6 on flexor tendon-derived TPC have not been discerned.

Methods

Passage 3 equine superficial digital flexor tendon (SDFT)-derived TPC were isolated from 6 horses. IL-6 impact on the viability (MMT assay with 0, 1, 5 and 10 ng/mL concentrations), migration (scratch motility assay at 0, 10ng/mL concentration) of TPC in monolayer culture were assessed. IL-6 effect on tendon ECM and chondrogenic gene expression (qRT-PCR), TGFβ1 gene expression and activity (ELISA), and MMP-1, -3 and − 13 gene expression of TPC was evaluated.

Results

IL-6 decreased TPC viability and migration. IL-6 treatment at 10 ng/mL significantly up-regulated TGFβ1 gene expression (6.3-fold; p = 0.01) in TPC, and significantly increased the TGFβ1 concentration in cell culture supernates. IL-6 (at 10 ng/mL) significantly up-regulated both tendon ECM (COL1A1:5.3-fold, COL3A1:5.4-fold, COMP 5.5-fold) and chondrogenic (COL2A1:3.9-fold, ACAN:6.2-fold, SOX9:4.8-fold) mRNA expression in TPC. Addition of SB431542, a TGFβ1 receptor inhibitor, to TPC in the presence of IL-6, attenuated the up-regulated tendon ECM and chondrogenic genes.

Conclusion

IL-6 alters TPC phenotype during in vitro monolayer culture. Pro- and anti-inflammatory roles of IL-6 have been implicated on tendon healing. Our findings demonstrate that IL-6 induces TGFβ1 activity in TPC and affects the basal TPC phenotype (as evidenced via increased tendon ECM and chondrogenic gene expressions). Further investigation of this biological link may serve as a foundation for therapeutic strategies that modulate IL-6 to enhance tendon healing.
Reduced burnout in medical and health science students during the pandemic COVID-19 - a follow-up study of a single institution in Hungary
Authors: Sipos David , Biro Anett Anna , Busa Flora , Freihat Omar , Tollár József , Pandur Attila András , Kovács Árpád , Deutsch Krisztina , Csima Melinda Petőné
Published: November 2023

Background

The coronavirus pandemic has significantly impacted lives worldwide, especially of medical and health science students. In Hungary, education has been relegated to the online space, with a substantial proportion of students having to attend medical secondments. Increased stress, uncertainty, and the presence of medical secondments can have an impact on students’ premature burnout.

Methods

In 2021, we conducted a follow-up survey among students of the University of Pécs studying medicine and health sciences in two data collection periods (from March to May and September to November). Our online questionnaire consisted of the Maslach Burnout Inventory General Survey for Students and our self-designed questionnaire. We used descriptive and paired two-sample t-tests for data analysis at a 95% confidence interval (p ≤ 0.05).

Results

We excluded from our survey respondents whose data we could not follow-up; finally, 183 students’ responses were analyzed. The majority of students were female (n = 148; 80.9%). Overall, there was a significant decrease in both exhaustion (EX) and cynicism (CY) scores (p = 0.001; p = 0.004). Female respondents had higher EX scores, but a significant decrease was observed for both genders (p ≤ 0.05). Excluding paramedic students, a significant decrease in EX scores was observed for the specialties we studied (p ≤ 0.05). General medicine students’ CY scores decreased; physiotherapy students’ profesisonal efficacy (PE) scores increased significantly (p ≤ 0.05). Students who were on medical secondments (n = 127; 69. 4%) were found to be more affected by burnout, but in all cases, these scores significantly improved (p ≤ 0.05). Students serving in the National Ambulance Service (n = 76; 41.5%), Hospitals (n = 44; 24.0%), or both (n = 7; 3.8%) had a significant decrease in their burnout score (p ≤ 0.05). Students who served in either a hospital or a hospital and National Ambulance Service had significantly improved CY and PE scores (p ≤ 0.05). Students concerned about their health had elevated EX and CY scores, which also improved (p ≤ 0.05).

Conclusions

In conclusion, medical secondments positively affected student burnout scores for medicine and health sciences students at our institution. This fact implies that it is necessary to have more internships in real-life settings during the training.

Trial registration

Our survey has been approved by the Medical Research Council (Case No IV/4573-1/2021/ECU).
Epididymal RNase T2 contributes to astheno-teratozoospermia and intergenerational metabolic disorder through epididymosome-sperm interaction
Authors: Ma Zhuoyao , Li Jinyu , Fu Li , Fu Rong , Tang Ningyuan , Quan Yanmei , Xin Zhixiang , Ding Zhide , Liu Yue
Published: November 2023

Background

The epididymis is crucial for post-testicular sperm development which is termed sperm maturation. During this process, fertilizing ability is acquired through the epididymis-sperm communication via exchange of protein and small non-coding RNAs (sncRNAs). More importantly, epididymal-derived exosomes secreted by the epididymal epithelial cells transfer sncRNAs into maturing sperm. These sncRNAs could mediate intergenerational inheritance which further influences the health of their offspring. Recently, the linkage and mechanism involved in regulating sperm function and sncRNAs during epididymal sperm maturation are increasingly gaining more and more attention.

Methods

An epididymal-specific ribonuclease T2 (RNase T2) knock-in (KI) mouse model was constructed to investigate its role in developing sperm fertilizing capability. The sperm parameters of RNase T2 KI males were evaluated and the metabolic phenotypes of their offspring were characterized. Pandora sequencing technology profiled and sequenced the sperm sncRNA expression pattern to determine the effect of epididymal RNase T2 on the expression levels of sperm sncRNAs. Furthermore, the expression levels of RNase T2 in the epididymal epithelial cells in response to environmental stress were confirmed both in vitro and in vivo.

Results

Overexpression of RNase T2 caused severe subfertility associated with astheno-teratozoospermia in mice caput epididymis, and furthermore contributed to the acquired metabolic disorders in the offspring, including hyperglycemia, hyperlipidemia, and hyperinsulinemia. Pandora sequencing showed altered profiles of sncRNAs especially rRNA-derived small RNAs (rsRNAs) and tRNA-derived small RNAs (tsRNAs) in RNase T2 KI sperm compared to control sperm. Moreover, environmental stress upregulated RNase T2 in the caput epididymis.

Conclusions

The importance was demonstrated of epididymal RNase T2 in inducing sperm maturation and intergenerational inheritance. Overexpressed RNase T2 in the caput epididymis leads to astheno-teratozoospermia and metabolic disorder in the offspring.
Association between the triglyceride–glucose index and left ventricular global longitudinal strain in patients with coronary heart disease in Jilin Province, China: a cross-sectional study
Authors: Na Lin , Cui Wenjing , Li Xinqi , Chang Jing , Xue Xin
Published: November 2023

Background

This study aimed to investigate the association between the triglyceride–glucose (TyG) index and left ventricular global longitudinal strain (GLS) in patients with coronary heart disease and to examine the role of left ventricular GLS in detecting early changes in cardiac function in patients with coronary heart disease in the subclinical stage.

Methods

A cross-sectional study involving 178 participants with symptomatic coronary artery disease excluding myocardial infarction or left ventricular dysfunction was conducted in Jilin Province, China. Basic clinical, biochemical, and echocardiographic data were obtained from all participants. Myocardial strain parameters were compared between patients with higher TyG index and those with lower TyG index, and the association between the gradually elevated TyG index and on subclinical cardiac function in patients with coronary heart disease was evaluated.

Results

The GLS of left ventricle was lower in the higher TyG index group than in the lower TyG index group. As the TyG index increases, the GLS progressively decreases. The results remained stable after adjusting for confounding factors.

Conclusions

A higher TyG index maybe independently associated with subclinical left ventricular dysfunction in patients with coronary heart disease.
Potentiating humoral and cellular immunity using a novel hybrid polymer-lipid nanoparticle adjuvant for HBsAg-VLP vaccine
Authors: Liu Xuhan , Min Qiuxia , Song Huiping , Yue Aochun , Li Qin , Zhou Qing , Han Wei
Published: November 2023

Aluminium adjuvants are commonly used in vaccines to stimulate the immune system, but they have limited ability to promote cellular immunity which is necessary for clearing viral infections like hepatitis B. Current adjuvants that do promote cellular immunity often have undesired side effects due to the immunostimulants they contain. In this study, a hybrid polymer lipid nanoparticle (HPLNP) was developed as an efficient adjuvant for the hepatitis B surface antigen (HBsAg) virus-like particle (VLP) vaccine to potentiate both humoral and cellular immunity. The HPLNP is composed of FDA approved polyethylene glycol-b-poly (l-lactic acid) (PEG-PLLA) polymer and cationic lipid 1, 2-dioleoyl-3-trimethylammonium-propane (DOTAP), and can be easily prepared by a one-step method. The cationic optimised vaccine formulation HBsAg/HPLNP (w/w = 1/600) can maximise the cell uptake of the antigen due to the electrostatic adsorption between the vaccine nanoparticle and the cell membrane of antigen-presenting cells. The HPLNP prolonged the retention of the antigen at the injection site and enhanced the lymph node drainage of antigen, resulting in a higher concentration of serum anti-HBsAg IgG compared to the HBsAg group or the HBsAg/Al group after the boost immunisation in mice. The HPLNP also promoted a strong Th1-driven immune response, as demonstrated by the significantly improved IgG2a/IgG1 ratio, increased production of IFN-γ, and activation of CD4 + and CD8 + T cells in the spleen and lymph nodes. Importantly, the HPLNP demonstrated no systemic toxicity during immunisation. The advantages of the HPLNP, including good biocompatibility, easy preparation, low cost, and its ability to enhance both humoral and cellular immune responses, suggest its suitability as an efficient adjuvant for protein-based vaccines such as HBsAg-VLP. These findings highlight the promising potential of the HPLNP as an HBV vaccine adjuvant, offering an alternative to aluminium adjuvants currently used in vaccines.
TMT quantitative proteomics reveals key proteins relevant to microRNA-1-mediated regulation in osteoarthritis
Authors: Jiang Pinpin , Liang Dan , Wang Hang , Zhou Raorao , Che Xianda , Cong Linlin , Li Penghua , Wang Chunfang , Li Wenjin , Wei Xiaochun , Li Pengcui
Published: November 2023

Osteoarthritis (OA) is the second-commonest arthritis, but pathogenic and regulatory mechanisms underlying OA remain incompletely understood. Here, we aimed to identify the mechanisms associated with microRNA-1 (miR-1) treatment of OA in rodent OA models using a proteomic approach. First, N = 18 Sprague Dawley (SD) rats underwent sham surgery (n = 6) or ACL transection (n = 12), followed at an interval of one week by randomization of the ACL transection group to intra-articular administration of either 50 µL placebo (control group) or miR-1 agomir, a mimic of endogenous miR-1 (experimental group). After allowing for eight weeks of remodeling, articular cartilage tissue was harvested and immunohistochemically stained for the presence of MMP-13. Second, N = 30 Col2a1-cre-ERT2 /GFPf1/fl -RFP-miR-1 transgenic mice were randomized to intra-articular administration of either placebo (control group, N = 15) or tamoxifen, an inducer of miR-1 expression (experimental group, N = 15), before undergoing surgical disruption of the medial meniscus (DMM) after an interval of five days. After allowing for eight weeks of remodeling, articular cartilage tissue was harvested and underwent differential proteomic analysis. Specifically, tandem mass tagging (TMT) quantitative proteomic analysis was employed to identify inter-group differentially-expressed proteins (DEP), and selected DEPs were validated using real-time quantitative polymerase chain reaction (RT-qPCR) technology. Immunohistochemically-detected MMP-13 expression was significantly lower in the experimental rat group, and proteomic analyses of mouse tissue homogenate demonstrated that of 3526 identified proteins, 345 were differentially expressed (relative up- and down-regulation) in the experimental group. Proteins Fn1, P4ha1, P4ha2, Acan, F2, Col3a1, Fga, Rps29, Rpl34, and Fgg were the *top ten most-connected proteins, implying that miR-1 may regulate an expression network involving these proteins. Of these ten proteins, three were selected for further validation by RT-qPCR: the transcript of Fn1, known to be associated with OA, exhibited relative upregulation in the experimental group, whereas the transcripts of P4ha1 and Acan exhibited relative downregulation. These proteins may thus represent key miR-1 targets during OA-regulatory mechanisms, and may provide additional insights regarding therapeutic mechanisms of miR-1 in context of OA.
A comprehensive model for assessing and classifying patients with thrombotic microangiopathy: the TMA-INSIGHT score
Authors: Addad Vanessa Vilani , Palma Lilian Monteiro Pereira , Vaisbich Maria Helena , Pacheco Barbosa Abner Mácola , da Rocha Naila Camila , de Almeida Cardoso Marilia Mastrocolla , de Almeida Juliana Tereza Coneglian , de Paula de Sordi Monica AP , Machado-Rugolo Juliana , Arantes Lucas Frederico , de Andrade Luis Gustavo Modelli
Published: November 2023

Background

Thrombotic Microangiopathy (TMA) is a syndrome characterized by the presence of anemia, thrombocytopenia and organ damage and has multiple etiologies. The primary aim is to develop an algorithm to classify TMA (TMA-INSIGHT score).

Methods

This was a single-center retrospective cohort study including hospitalized patients with TMA at a single center. We included all consecutive patients diagnosed with TMA between 2012 and 2021. TMA was defined based on the presence of anemia (hemoglobin level < 10 g/dL) and thrombocytopenia (platelet count < 150,000/µL), signs of hemolysis, and organ damage. We classified patients in eight categories: infections; Malignant Hypertension; Transplant; Malignancy; Pregnancy; Thrombotic Thrombocytopenic Purpura (TTP); Shiga toxin-mediated hemolytic uremic syndrome (STEC-SHU) and Complement Mediated TMA (aHUS). We fitted a model to classify patients using clinical characteristics, biochemical exams, and mean arterial pressure at presentation.

Results

We retrospectively retrieved TMA phenotypes using automatic strategies in electronic health records in almost 10 years (n = 2407). Secondary TMA was found in 97.5% of the patients. Primary TMA was found in 2.47% of the patients (TTP and aHUS). The best model was LightGBM with accuracy of 0.979, and multiclass ROC-AUC of 0.966. The predictions had higher accuracy in most TMA classes, although the confidence was lower in aHUS and STEC-HUS cases.

Conclusion

Secondary conditions were the most common etiologies of TMA. We retrieved comorbidities, associated conditions, and mean arterial pressure to fit a model to predict TMA and define TMA phenotypic characteristics. This is the first multiclass model to predict TMA including primary and secondary conditions.
The role of Nurr1-miR-30e-5p-NLRP3 axis in inflammation-mediated neurodegeneration: insights from mouse models and patients’ studies in Parkinson’s disease
Authors: Li Tianbai , Tan Xiang , Tian Lulu , Jia Congcong , Cheng Cheng , Chen Xi , Wei Min , Wang Yuanyuan , Hu Yiying , Jia Qiqi , Ni Yang , Al-Nusaif Murad , Li Song , Le Weidong
Published: November 2023

Nuclear receptor related-1 (Nurr1), a ligand-activated transcription factor, is considered a potential susceptibility gene for Parkinson’s disease (PD), and has been demonstrated to possess protective effects against inflammation-induced neuronal damage. Despite the evidence showing decreased NURR1 level and increased pro-inflammatory cytokines in cell and animal models as well as in PD patients’ peripheral blood mononuclear cells (PBMCs), the underlying mechanism remains elusive. In this study, we investigated the molecular mechanism of Nurr1 in PD-related inflammation. Through the miRNA-sequencing and verification in PBMCs from a cohort of 450 individuals, we identified a significant change of a Nurr1-dependent miRNA miR-30e-5p in PD patients compared to healthy controls (HC). Additionally, PD patients exhibited an elevated plasma interleukin-1β (IL-1β) level and increased nucleotide-binding domain-like receptor protein 3 (NLRP3) expression in PBMCs compared to HC. Statistical analyses revealed significant correlations among NURR1, miR-30e-5p, and NLRP3 levels in the PBMCs of PD patients. To further explore the involvement of Nurr1-miR-30e-5p-NLRP3 axis in the inflammation-mediated PD pathology, we developed a mouse model (Nurr1flox+/Cd11b−cre+, Nurr1cKO) conditionally knocking out Nurr1 in Cd11b-expressing cells. Our investigations in Nurr1cKO mice unveiled significant dopaminergic neurodegeneration following lipopolysaccharide-induced inflammation. Remarkably, Nurr1 deficiency triggered microglial activation and activated NLRP3 inflammasome, resulting in increased IL-1β secretion. Coincidently, we found that miR-30e-5p level was significantly decreased in the PBMCs and primary microglia of Nurr1cKO mice compared to the controls. Furthermore, our in vitro experiments demonstrated that miR-30e-5p specifically targeted NLRP3. In Nurr1-knockdown microglia, NLRP3 expression was upregulated via miR-30e-5p. In summary, our findings highlight the involvement of Nurr1-miR-30e-5p-NLRP3 axis in the inflammation-mediated neurodegeneration in PD, the results of which may offer promising prospects for developing PD biomarkers and targeted therapeutic interventions.
Impact of the COVID-19 pandemic on the sexual and reproductive health of adolescents in Alberta, Canada
Authors: Meherali Salima , Rehmani Amyna Ismail , Ahmad Mariam , Adewale Bisi , Kauser Samar , Lebeuf Simone , Benoit James , Scott Shannon D.
Published: November 2023

Purpose

The COVID-19 pandemic led to major service disruptions in the healthcare sector, especially regarding sexual and reproductive health services. However, the impact of the pandemic on Canadian adolescents is relatively unknown. This study aimed to investigate the impacts of the COVID-19 pandemic and associated public health measures on the sexual and reproductive health (SRH) of adolescents in Alberta, Canada.

Methods

A qualitative study using an interpretive description (ID) approach and community-based participatory research principles was conducted to capture the subjective experience and perceptions of adolescents and service providers. With the collaboration of the Adolescent Advisory Group and community partners, 18 adolescents and 15 service providers were recruited for the study through purposive sampling. Findings from the qualitative interviews were analyzed using thematic analysis.

Results

Three major themes emerged from the analysis: (1) COVID-19 SRH experience, (2) barriers to SRH, and (3) adolescent SRH strategies. Our findings highlight numerous barriers and challenges that prevented adolescents from accessing SRH education, products, and services.

Conclusion

The COVID-19 pandemic had a profound impact on the SRH and the well-being of adolescents. Our study reflects the need for diverse SRH strategies to maintain continued access to SRH resources during disruptive events, such as the pandemic.
Examining the militarised hierarchy of Sierra Leone’s Ebola response and implications for decision making during public health emergencies
Authors: Boland Samuel T. , Balabanova Dina , Mayhew Susannah
Published: November 2023

Background

In September, 2014, Médecins Sans Frontières (MSF) called for militarised assistance in response to the rapidly escalating West Africa Ebola Epidemic. Soon after, the United Kingdom deployed its military to Sierra Leone, which (among other contributions) helped to support the establishment of novel and military-led Ebola Virus Disease (Ebola) response centres throughout the country. To examine these civil-military structures and their effects, 110 semi-structured interviews with civilian and military Ebola Response Workers (ERWs) were conducted and analysed using neo-Durkheimian theory.

Results

The hierarchical Ebola response centres were found to be spaces of ‘conflict attenuation’ for their use of ‘rule-bound niches’, ‘neutral zones’, ‘co-dependence’, and ‘hybridity’, thereby not only easing civil-military relationships (CMRel), but also increasing the efficiency of their application to Ebola response interventions. Furthermore, the hierarchical response centres were also found to be inclusive spaces that further increased efficiency through the decentralisation and localisation of these interventions and daily decision making, albeit for mostly privileged groups and in limited ways.

Conclusions

This demonstrates how hierarchy and localisation can (and perhaps should) go hand-in-hand during future public health emergency responses as a strategy for more robustly including typically marginalised local actors, while also improving necessary efficiency—in other words, an ‘inclusive hierarchical coordination’ that is both operationally viable and an ethical imperative.
Effect of 10.6-μm CO2 laser moxibustion on the fastest 15-m walking time in patients with knee osteoarthritis: a double-blind, sham-controlled, multi-site randomized trial
Authors: Chen Lusheng , Zhao Ling , Cheng Ke , Lin Lin , Wu Fan , Shen Xueyong
Published: November 2023

Background

In this study, we investigated the impact of 10.6-μm CO2 laser moxibustion (LM) on the fastest 15-m walking time in individuals suffering from knee osteoarthritis (KOA).

Methods

A total of 392 individuals diagnosed with KOA and meeting the specified eligibility criteria were assigned randomly into two groups: the LM treatment group and the sham LM control group (ratio 1:1). Both groups received either LM therapy or simulated LM therapy to address the affected area of the knee joint. This treatment was administered three times a week for a duration of 4 weeks.

Results

In the LM group, the fastest 15-m walking times at both Week 4 and Week 12 were significantly reduced compared to the times before treatment (all P < 0.05). However, in the sham LM group, there were no notable differences in the fastest 15-m walking times after treatment (all P > 0.05). Moreover, the LM group exhibited shorter 15-m walking times than the sham LM group at both Week 4 and Week 12 (all P < 0.05).

Conclusion

The use of CO2 LM can lead to a substantial enhancement in the fastest 15-m walking time of individuals suffering from KOA, and its therapeutic impact can last for a minimum of 8 weeks post-treatment. The fastest 15-m walking time serves as an indicator of alterations in the walking capacity of patients with KOA.