bluuebunny/crossref_metadata_2025 huggingface dataset:
Border crossers: Feminist decolonial geography and climate change
Authors: Gay-Antaki Miriam
Published: July 2022

While more geographical studies around climate change incorporate gender in the climate debate, few of them explore the epistemological value of gendering climate knowledge, fewer, the potential of feminist decolonial climate knowledge. Using border thinking, this paper brings Feminist Science and Technology Studies, Decolonial Theory, and Feminist Political Ecology into conversation with human geography to stress how a Feminist Decolonial Geography is well suited to tackle climate change. This approach can trace the origin of dominant ideas around climate change and enunciate their location, challenging normative, disembodied, and universal claims. By delineating the power relationships that transform people into hierarchical categories, we can trace the socio-environmental relationships that also contribute to climate change. The identification of exclusionary structures and rules to participate in climate science and beyond can elucidate opportunities to create a more equitable knowledge base. Border crossers represent opportunities to expand our epistemological canon. To resolve the climate crisis, we must adopt the navigating and negotiating skills of border crossers, hybrid, and bilingual world travelers. An essential vantage point to resolve the climate crisis.
Proteomic and phosphoproteomic landscapes of acute myeloid leukemia
Authors: Kramer Michael H. , Zhang Qiang , Sprung Robert , Day Ryan B. , Erdmann-Gilmore Petra , Li Yang , Xu Ziheng , Helton Nichole M. , George Daniel R. , Mi Yiling , Westervelt Peter , Payton Jacqueline E. , Ramakrishnan Sai M. , Miller Christopher A. , Link Daniel C. , DiPersio John F. , Walter Matthew J. , Townsend R. Reid , Ley Timothy J.
Published: July 2022

We have developed a deep-scale proteome and phosphoproteome database from 44 representative acute myeloid leukemia (AML) patients from the LAML TCGA dataset and 6 healthy bone marrow–derived controls. After confirming data quality, we orthogonally validated several previously undescribed features of AML revealed by the proteomic data. We identified examples of posttranscriptionally regulated proteins both globally (ie, in all AML samples) and also in patients with recurrent AML driver mutations. For example, samples with IDH1/2 mutations displayed elevated levels of the 2-oxoglutarate–dependent histone demethylases KDM4A/B/C, despite no changes in messenger RNA levels for these genes; we confirmed this finding in vitro. In samples with NPMc mutations, we identified several nuclear importins with posttranscriptionally increased protein abundance and showed that they interact with NPMc but not wild-type NPM1. We identified 2 cell surface proteins (CD180 and MRC1/CD206) expressed on AML blasts of many patients (but not healthy CD34+ stem/progenitor cells) that could represent novel targets for immunologic therapies and confirmed these targets via flow cytometry. Finally, we detected nearly 30 000 phosphosites in these samples; globally, AML samples were associated with the abnormal phosphorylation of specific residues in PTPN11, STAT3, AKT1, and PRKCD. FLT3-TKD samples were associated with increased phosphorylation of activating tyrosines on the cytoplasmic Src-family tyrosine kinases FGR and HCK and related signaling proteins. PML-RARA–initiated AML samples displayed a unique phosphorylation signature, and TP53-mutant samples showed abundant phosphorylation of serine-183 on TP53 itself. This publicly available database will serve as a foundation for further investigations of protein dysregulation in AML pathogenesis.
Origin, evolution, and tissue-specific functions of the porcine repetitive element 1
Authors: Zheng Min , Guo Tianfu , Yang Bin , Zhang Zhiyan , Huang Lusheng
Published: July 2022

Background

The porcine repetitive element 1 (PRE1) is the most abundant short interspersed nuclear element (SINE) in the Sus scrofa genome and it has been suggested that some PRE1 can have regulatory functions. The million copies of PRE1 in the porcine genome have accumulated abundant CpG dinucleotides and unique structural variations, such as direct repeats and patterns of sequence degeneration. The aims of this study were to analyse these structural variations to trace the origin and evolutionary pattern of PRE1 and to investigate potential methylation-related functions of PRE1 based on methylation patterns of PRE1 CpG dinucleotides in different tissues.

Results

We investigated the evolutionary trajectory of PRE1 and found that PRE1 originated from the ancestral CHRS-S1 family through three main successive partial duplications. We found that the partial duplications and deletions of PRE1 were likely due to RNA splicing events during retrotransposition. Functionally, correlation analysis showed that the methylation levels of 103 and 261 proximal PRE1 were, respectively, negatively and positively correlated with the expression levels of neighboring genes (Spearman correlation, P < 0.01). Further epigenomic analysis revealed that, in the testis, demethylation of proximal PRE1 in the HORMAD1 and HACD3 genes had tissue-specific enhancer and promoter functions, while in the muscle, methylation of proximal PRE1 repeats in the TCEA3 gene had an enhancer function.

Conclusions

The characteristic sequences of PRE1 reflect unique patterns of origin and evolution and provide a structural basis for diverse regulatory functions.
SARS-CoV-2 in a tropical area of Colombia, a remarkable conversion of presymptomatic to symptomatic people impacts public health
Authors: Martínez Caty , Serrano-Coll Héctor , Faccini Álvaro , Contreras Verónica , Galeano Ketty , Botero Yesica , Herrera Yonairo , Garcia Alejandra , Garay Evelin , Rivero Ricardo , Contreras Héctor , López Yesica , Guzmán Camilo , Miranda Jorge , Arrieta Germán , Mattar Salim
Published: July 2022

Background

The ability of SARS-CoV-2 to remain in asymptomatic individuals facilitates its dissemination and makes its control difficult. Objective. To establish a cohort of asymptomatic individuals, change to the symptomatic status, and determine the most frequent clinical manifestations. 

Methods

Between April 9 and August 9, 2020, molecular diagnosis of SARS-CoV-2 infection was confirmed in 154 asymptomatic people in contact with subjects diagnosed with COVID-19. Nasopharyngeal swabs were performed on these people in different hospitals in Córdoba, the Caribbean area of Colombia. The genes E, RdRp, and N were amplified with RT-qPCR. Based on the molecular results and the Cq values, the patients were subsequently followed up through telephone calls to verify their health conditions.

Results

Overall, of 154 asymptomatic individuals, 103 (66.9%) remained asymptomatic, and 51 (33.1%) changed to symptomatic. The most frequent clinical manifestations in young people were anosmia and arthralgia. Adults showed cough, ageusia, and odynophagia; in the elderly were epigastralgia, dyspnea, and headache. Mortality was 8%.

Conclusions

A proportion of 33% of presymptomatic individuals was found, of which four of them died. This high rate could indicate a silent transmission, contributing significantly to the epidemic associated with SARS-CoV-2.
Genomic signature of MTOR could be an immunogenicity marker in human colorectal cancer
Authors: Wang Chenxing , Aikemu Batuer , Shao Yanfei , Zhang Sen , Yang Guang , Hong Hiju , Huang Ling , Jia Hongtao , Yang Xiao , Zheng Minhua , Sun Jing , Li Jianwen
Published: July 2022

Background

The mTOR signaling pathway plays an important role in cancer. As a master regulator, the status of MTOR affects pathway activity and the efficacy of mTOR inhibitor therapy. However, little research has been performed to explore MTOR in colorectal cancer (CRC).

Methods

In this study, gene expression and clinical data were analyzed using The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Signaling pathways related to MTOR in CRC were identified by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). Somatic mutation data were downloaded from TCGA and analyzed using the maftools R package. Tumor Immune Estimation Resource (TIMER) and CIBERSORT were used to analyze correlations between MTOR and tumor-infiltrating immune cells (TIICs). Finally, we detected MTOR mutations in a CRC cohort from our database using whole-exome sequencing.

Results

We found that MTOR was overexpressed in Asian CRC patients and associated with a poor prognosis. Enrichment analysis showed that MTOR was involved in metabolism, cell adhesion, and translation pathways in CRC. High MTOR expression was correlated with high tumor mutation burden (TMB) and several TIICs. Finally, we found that the mTOR signaling pathway was activated in CRC lines characterized by microsatellite instability (MSI), and the frequency of MTOR mutations was higher in MSI-high (MSI-H) patients than in microsatellite stable (MSS) patients.

Conclusions

MTOR may represent a comprehensive indicator of prognosis and immunological status in CRC. The genomic signatures of MTOR may provide guidance for exploring the role of mTOR inhibitors in CRC.
Viral blood-borne infections testing and linkage to care cascade among persons who experience homelessness in the United States: a systematic review and meta-analysis
Authors: Saha Ria , Miller Amanda P. , Parriott Andrea , Horvath Hacsi , Kahn James G. , Malekinejad Mohsen
Published: July 2022

Background

Persons who experience homelessness remain at increased risk for three viral blood-borne infections: human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). We assessed the yield of testing and linkage to care programs targeting this population for these infections in the United States (US).

Methods

We searched PubMed, Embase, Web of Science, and Cochrane Central for peer-reviewed articles through August 27, 2020. Additionally, we searched the grey literature. Two individuals independently reviewed all relevant studies to check for eligibility and extracted data for each step in the care cascade. We used random-effects model to generate weighted pooled proportions to assess yield at each step. Cumulative proportions were calculated as products of adjacent-step pooled proportions. We quantitatively synthesized data from the studies that focused on non-drug injecting individuals.

Results

We identified 24 studies published between 1996–2019 conducted in 19 US states. Seventeen studies screened for HIV, 12 for HCV, and two screened for HBV. For HIV, 72% of approached were recruited, 64% had valid results, 4% tested positive, 2% were given results, and 1% were referred and attended follow-up. Of positives, 25% were referred to treatment and started care. For HCV, 69% of approached were recruited, 63% had valid results, 16% tested positive, 14% were given results, and 3% attended follow-up. Of positives, 30% were referred for treatment and 19% started care. The yield at each care cascade step differs widely by recruitment strategy (for example, for HIV: 71.6% recruited of reached under service-based with zero yield under healthcare facility-based and outreach).

Conclusions

A very large proportion of this population reached for HIV and HCV care were lost in the follow-up steps and never received treatment. Future programs should examine drop-out reasons and intervene to reduce health disparities in this population.
Teachers' characteristics predict students' guidance for healthy lifestyle: a cross-sectional study in Arab-speaking schools
Authors: Wilf-Miron Rachel , Kittany Roaa , Saban Mor , Kagan Ilya
Published: July 2022

Introduction

Schools are valuable settings for implementing healthy lifestyle interventions. Teachers' health behaviors affect their health and well-being and might affect their position as role models for students. This study aimed a) to assess health behaviors, health perceptions, burnout, job satisfaction, and organizational commitment among Arab school teachers in Israel; b) to examine the relationship between these variables; and c) to explain the variance of healthy lifestyle promotion among students.

Methods

A cross-sectional study using a structured questionnaire was conducted among 150 teachers (mean age 39 years, 85% women) in May-June 2020.

Results

Most respondents (79%) were overweight and obese, 79% reported unhealthy nutrition and not reaching the recommended physical activity target, 47% slept >7 hours at night and 54% defined their health status as very good or excellent. Reported burnout levels were high. Organizational commitment and job satisfaction were high while students’ guidance towards a healthy lifestyle was moderate. Burnout was negatively correlated with health perception, organizational commitment, and job satisfaction. Health perception was positively correlated with organizational commitment, job satisfaction and promoting a healthy lifestyle among students. Logistic regression analysis revealed that job satisfaction, performance of PA according to the recommendations and burnout predicted 51% of the variance of healthy lifestyle promotion among students.

Conclusions

Teachers in Israeli Arab schools report unfavorable health behaviors and health perception as well as high burnout levels. The findings suggest implementing intervention programs to reduce teacher burnout and creating organizational conditions that would encourage teachers to adopt a healthy lifestyle and help them promote healthy lifestyle habits among their students.
Nonlinear association between changes in fasting plasma glucose and the incidence of diabetes in a nondiabetic Chinese cohort
Authors: Huang Chenghu , Ren Chenhong , Xuan Xiuping , Luo Yi , Peng Caibi
Published: July 2022

Background

Limited data show that changes in fasting plasma glucose (FPG changes) are related to the incidence of type 2 diabetes (T2D). We aimed to correlate FPG changes with incident diabetes and evaluate FPG changes as a marker to screen participants at high risk of T2D in China.

Methods

A total of 116,816 individuals were followed during a median follow-up of 3.10 years by secondary analysis in a nondiabetic Chinese cohort. The turning points were derived from a receiver operating characteristic curve. Hazard ratios (HRs) were evaluated by Cox proportional hazards models.

Results

A total of 2669 cases of T2D were identified (788 women and 1881 men). The age-standardized incidence of diabetes was 12.87 per 1000 person-years (women: 11.04; men: 14.69). A nonlinear relationship between FPG changes and incident diabetes is shown by the fitting curves. The curves were categorized into three stages by two turning points (-0.04 and 1.25 mmol/L) and conformed to the hook-like pattern: an initial decrease (stage-1), then a transient sharp elevation (stage-2), followed by a slow increase (stage-3). HRs per SD of FPG changes on incident diabetes varied with stage: stage-1: 0.16 (0.12, 0.23), stage-2: 0.20 (0.15, 0.28) and stage-3: 0.22 (0.16, 0.31). Compared with stage-1, the HR in stage-3 was significantly higher at 28.05 (23.99, 32.79), while the increase in stage-2 was slight at 2.16 (1.79, 2.61), and the HR in stage-3 rose to 30.09 (25.02, 36.19).

Conclusions

FPG changes had a strong correlation with the incidence of T2D and was a steady indicator that was used to distinguish the participants at high risk of diabetes.
The sonographic quantitative assessment of the deltoid muscle to detect type 2 diabetes mellitus: a potential noninvasive and sensitive screening method?
Authors: Rosen Kelli A. , Thodge Anay , Tang Amy , Franz Brendan M. , Klochko Chad L. , Soliman Steven B.
Published: July 2022

Background

In our previous published study, we demonstrated that a qualitatively assessed elevation in deltoid muscle echogenicity on ultrasound was both sensitive for and a strong predictor of a type 2 diabetes (T2DM) diagnosis. This study aims to evaluate if a sonographic quantitative assessment of the deltoid muscle can be used to detect T2DM.

Methods

Deltoid muscle ultrasound images from 124 patients were stored: 31 obese T2DM, 31 non-obese T2DM, 31 obese non-T2DM and 31 non-obese non-T2DM. Images were independently reviewed by 3 musculoskeletal radiologists, blinded to the patient’s category. Each measured the grayscale pixel intensity of the deltoid muscle and humeral cortex to calculate a muscle/bone ratio for each patient. Following a 3-week delay, the 3 radiologists independently repeated measurements on a randomly selected 40 subjects. Ratios, age, gender, race, body mass index, insulin usage and hemoglobin A1c were analyzed. The difference among the 4 groups was compared using analysis of variance or chi-square tests. Both univariate and multivariate linear mixed models were performed. Multivariate mixed-effects regression models were used, adjusting for demographic and clinical variables. Post hoc comparisons were done with Bonferroni adjustments to identify any differences between groups. The sample size achieved 90% power. Sensitivity and specificity were calculated based on set threshold ratios. Both intra- and inter-radiologist variability or agreement were assessed.

Results

A statistically significant difference in muscle/bone ratios between the groups was identified with the average ratios as follows: obese T2DM, 0.54 (P < 0.001); non-obese T2DM, 0.48 (P < 0.001); obese non-T2DM, 0.42 (P = 0.03); and non-obese non-T2DM, 0.35. There was excellent inter-observer agreement (intraclass correlation coefficient 0.87) and excellent intra-observer agreements (intraclass correlation coefficient 0.92, 0.95 and 0.94). Using threshold ratios, the sensitivity for detecting T2DM was 80% (95% CI 67% to 88%) with a specificity of 63% (95% CI 50% to 75%).

Conclusions

The sonographic quantitative assessment of the deltoid muscle by ultrasound is sensitive and accurate for the detection of T2DM. Following further studies, this process could translate into a dedicated, simple and noninvasive screening method to detect T2DM with the prospects of identifying even a fraction of the undiagnosed persons worldwide. This could prove especially beneficial in screening of underserved and underrepresented communities.
A Twitter-facilitated professional learning community: online participation, connectedness, and satisfaction
Authors: Zheng Binbin , Beck Dallaghan Gary
Published: July 2022

Background

Twitter has gained increasing popularity and attention as a professional learning environment to share knowledge, exchange information, make connections, and build networks. To evaluate the effectiveness of Twitter-facilitated online discussions, a community of inquiry framework could be used with the three key elements of online environments: cognitive presence, social presence, and teaching presence. This study aims to explore how medical educators participate in synchronous online discussions on Twitter using #MedEdChat, and how participants’ perceptions toward the three presences, sense of connectedness and interactions influenced their online satisfaction.

Methods

A survey invitation was emailed using the medical education email list DR-ED and was posted during the weekly Twitter conversations in December 2020, to solicit participants who have been involved in any kind of #MedEdChat activities (i.e., read transcripts or directly participate in discussions).

Results

A total of 68 people responded. Through descriptive analysis and path analysis, we found that almost half of the survey respondents were lurkers on #MedEdChat who read others’ tweets or transcripts. In addition, participants mainly used Twitter for resource sharing, collaborating with others, and networking. Participants rated teaching (i.e., moderator) presence the highest, followed by overall satisfaction, cognitive presence, sense of connectedness, social presence, and interactions. Among them, sense of connectedness and cognitive presence were significantly associated with participants’ overall satisfaction.

Conclusions

This study provided significant implications for using Twitter as a professional learning community to conduct online discussion activities. Facilitators could think of ways to improve participation by providing tutorials on how to participate on Twitter discussions, introduce or ask new participants to introduce themselves, facilitate discussion with intriguing questions, and invite medical educators of different roles as well as medical students and residents to join to bring in diverse perspectives.
Communication competence and resilience are modifiable factors for burnout of operating room nurses in South Korea
Authors: Lee Eun Yeong , Kim Kyoung-ja , Ko Sangjin , Song Eun Kyeung
Published: July 2022

Background

Burnout negatively impacts the personal and professional life of nurses. Job stress and resilience have been determined to be associated with nurse burnout. Given the importance of communication competence in operating room (OR) nurses, the associations of job stress, resilience, and communication competence with burnout have not been examined.

Purpose

To determine the relationships of job stress, resilience, and communication competence to burnout of OR nurses in South Korea.

Methods

This was a cross-sectional, descriptive study of 146 OR nurses. A series of self-reported questionnaires was used to assess job stress, resilience, communication competence, and burnout. Pearson correlation coefficient and a hierarchical linear regression were used for data analysis.

Results

Communication competence was correlated with resilience (r = 0.65, p < .001) and burnout (r = -0.44, p < .001), and resilience was correlated with burnout (r = -0.48, p < .001). Resilience (β = -0.22, p = .027) and communication competence (β = -0.33, p < .001) were associated with burnout of OR nurses in a hierarchical linear regression (F = 6.28, p < .001).

Conclusions

Increased resilience and communication competence were associated with lower burnout of perioperative nurses. To prevent and reduce burnout of OR nurses, it is necessary to develop and implement a program targeting for communication competence and resilience.

Implications for nursing management

Nurse leaders should provide programs fostering communication competence and resilience to OR nurses and encourage them to actively participate in such job trainings.
Triglyceride-glucose index trajectory and stroke incidence in patients with hypertension: a prospective cohort study
Authors: Huang Zegui , Ding Xiong , Yue Qing , Wang Xianxuan , Chen Zekai , Cai Zefeng , Li Weijian , Cai Zhiwei , Chen Guanzhi , Lan Yulong , Wu Weiqiang , Wu Shouling , Chen Youren
Published: July 2022

Background

It has been suggested that the baseline triglyceride-glucose (TyG) index, a simple surrogate measure for insulin resistance, is significantly associated with the occurrence of stroke. Nevertheless, the impact of longitudinal patterns of TyG on the stroke risk in hypertensive patients is still unknown. Hence, this study aimed to investigate the association between TyG index trajectory and stroke risk among hypertensive patients.

Methods

This prospective study included 19,924 hypertensive patients from the Kailuan Study who underwent three waves survey and were free of myocardial infarction, cancer and stroke before or during 2010. The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting plasma glucose (mg/dL)/2], and latent mixed modelling was used to identify the trajectory of TyG during the exposure period (2006–2010). Furthermore, the Cox proportional hazard models were applied to estimate the hazard ratio (HR) and 95% confidence interval (CI) for incident stroke of different trajectory groups.

Results

Five distinct TyG trajectory were identified during 2006–2010: low-stable (n = 2483; range, 8.03–8.06), moderate low-stable (n = 9666; range, 8.58–8.57), moderate high-stable (n = 5759; range, 9.16–9.09), elevated-stable (n = 1741; range, 9.79–9.75), and elevated-increasing (n = 275; range, 10.38–10.81). During the median follow-up of 9.97 years, 1,519 cases of incident stroke were identified, including 1,351 with ischemic stroke and 215 with hemorrhage stroke. After adjusting for confounding variables, the HR and 95% CI of stroke were 2.21 (1.49,3.28) for the elevated-increasing group, 1.43 (1.13,1.83) for the elevated-stable group, 1.35 (1.10,1.64) for the moderate high-stable group, 1.26 (1.06,1.52) for the moderate low-stable group, respectively, when compare with the low-stable group. Similar results were observed in ischemic stroke, but a significant association was not found between TyG trajectory and risk of hemorrhage stroke.

Conclusion

A long-term elevated TyG index in hypertensive patients is associated with an increased risk of stroke, especially ischemic stroke. This finding implies that regular monitoring of TyG index may assist in identifying individuals at a higher risk of stroke among patients with hypertension.
Combined effect of pancreatic lipid content and gene variants (TCF7L2, WFS1 and 11BHSD1) on B-cell function in Middle Aged Women in a Post Hoc Analysis
Authors: Nádasdi Ákos , Gál Viktor , Masszi Tamás , Patócs Attila , Igaz Peter , Somogyi Anikó , Firneisz Gábor
Published: July 2022

Background

TCF7L2 rs7903146 and PNPLA3 rs738409 gene variants confer the strongest risk for type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD), respectively. Pancreatic triacylglycerol content (PTGC) was reported to have a role in T2DM development. We aimed to assess the correlation between PTGC and hepatic triacylglycerol content (HTGC) stratified by PNPLA3 rs738409 genotype and subsequently interactions between PTGC and gene variants associated with β-cell dysfunction (TCF7L2, WFS1) and visceral adiposity (11ΒHSD1) on β-cell function were also tested.

Methods

PTGC and HTGC were assessed using MR in a post-hoc analysis of a genotype-based (PNPLA3 rs738409) recall study of 39 (lipid- and glucose lowering) drug-naïve women. Oral glucose tolerance test, HbA1c, insulin indices, anthropometric data were evaluated. The effect of minor allele carrying of TCF7L2 (rs7903146); WFS1 (rs1801214) and 11ΒHSD1 (rs4844880) variants in combination with PTGC was studied on surrogate markers of β-cell function. We used Spearman’s rank-order, Mann-Whitney-U tests, and linear regression models.

Results

PTGC and HTGC values were correlated after stratification by the rs738409 variant (only in CC genotype group R = 0.67, p = 10− 4). PTGC and HbA1c values correlated in the entire study population (R = 0.58, p = 10− 4). Insulin resistance, sensitivity and disposition indices were correlated with PTGC (HOMA2-IR: R = 0.42, p = 0.008; TyG: R = 0.38, p = 0.018; Matsuda: R= − 0.48, p = 0.002; DIbasal: R=−0.33, p = 0.039; ISSI-2: R=−0.35, p = 0.028). Surrogate markers of β-cell function (HOMA2-B, AUCinsulin/AUCglucose) correlated significantly with PTGC in subjects with the following genotypes rs7903146: CC R = 0.51, p = 0.022; rs18001214: CT + CC R = 0.55, p = 0.013; rs4844880: TA + AA R = 0.56, p = 0.016. The strongest interactions were found between PTGC and TCF7L2 rs7903146 effect on HOMA2-B (p = 0.001) and AUCinsulin/AUCglucose (p = 0.013).

Conclusions

The PNPLA3 rs738409 genotype has a major effect on the correlation between PTGC and HTGC. Furthermore we first report the combined effect of PTGC and individual risk gene variants of TCF7L2, WFS1 and 11ΒHSD1 on β-cell dysfunction. The correlation between pancreatic lipid accumulation and HbA1c also indicates an important role for the latter pathology.
C/EBPα regulates the fate of bone marrow mesenchymal stem cells and steroid-induced avascular necrosis of the femoral head by targeting the PPARγ signalling pathway
Authors: Duan Ping , Wang Hanyu , Yi Xinzeyu , Zhang Hao , Chen Hui , Pan Zhenyu
Published: July 2022

Background

The imbalance of osteogenic/adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is closely related to steroid-induced avascular necrosis of the femoral head (SANFH). We aimed to investigate the epigenetic mechanism of intramedullary fat accumulation and continuous osteonecrosis after glucocorticoid (GC) withdrawal in SANFH.

Methods

An SANFH model was established in SD rats, which received an intermittent high GC dose for the first 4 weeks followed by an additional 4 weeks without GC. We explored the synergistic effects and mechanisms of C/EBPα and PPARγ on the differentiation of BMSCs by lentivirus-mediated gene knockdown and overexpression assays. A chromatin immunoprecipitation assay was performed to identify epigenetic modification sites on PPARγ in vivo and in vitro.

Results

In the SANFH model, intramedullary fat was significantly increased, and the transcription factors C/EBPα and PPARγ were upregulated simultaneously in the femoral head. In vitro, C/EBPα promoted adipogenic differentiation of BMSCs by targeting the PPARγ signalling pathway, while overexpression of C/EBPα significantly impaired osteogenic differentiation. Further studies demonstrated that histone H3K27 acetylation of PPARγ played an important role in the epigenetic mechanism underlying SANFH. C/EBPα upregulates the histone H3K27 acetylation level in the PPARγ promoter region by inhibiting HDAC1. Additionally, inhibiting the histone acetylation level of PPARγ effectively prevented adipogenic differentiation, thus slowing the progression of SANFH.

Conclusions

Our results demonstrate the molecular mechanism by which C/EBPα regulates PPARγ expression by acetylating histones and revealed the epigenetic phenomenon in SANFH for the first time.

Graphical abstract
Ectoderm-derived frontal bone mesenchymal stem cells promote traumatic brain injury recovery by alleviating neuroinflammation and glutamate excitotoxicity partially via FGF1
Authors: Qin Qiaozhen , Wang Ting , Xu Zhenhua , Liu Shuirong , Zhang Heyang , Du Zhangzhen , Wang Jianing , Wang Yadi , Wang Zhenning , Yuan Shanshan , Wu Jiamei , He Wenyan , Wang Changzhen , Yan Xinlong , Wang Yan , Jiang Xiaoxia
Published: July 2022

Background

Traumatic brain injury (TBI) leads to cell and tissue impairment, as well as functional deficits. Stem cells promote structural and functional recovery and thus are considered as a promising therapy for various nerve injuries. Here, we aimed to investigate the role of ectoderm-derived frontal bone mesenchymal stem cells (FbMSCs) in promoting cerebral repair and functional recovery in a murine TBI model.

Methods

A murine TBI model was established by injuring C57BL/6 N mice with moderate-controlled cortical impact to evaluate the extent of brain damage and behavioral deficits. Ectoderm-derived FbMSCs were isolated from the frontal bone and their characteristics were assessed using multiple differentiation assays, flow cytometry and microarray analysis. Brain repairment and functional recovery were analyzed at different days post-injury with or without FbMSC application. Behavioral tests were performed to assess learning and memory improvements. RNA sequencing analysis, immunofluorescence staining, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were used to examine inflammation reaction and neural regeneration. In vitro co-culture analysis and quantification of glutamate transportation were carried out to explore the possible mechanism of neurogenesis and functional recovery promoted by FbMSCs.

Results

Ectoderm-derived FbMSCs showed fibroblast like morphology and osteogenic differentiation capacity. FbMSCs were CD105, CD29 positive and CD45, CD31 negative. Different from mesoderm-derived MSCs, FbMSCs expressed the ectoderm-specific transcription factor Tfap2β. TBI mice showed impaired learning and memory deficits. Microglia and astrocyte activation, as well as neural damage, were significantly increased post-injury. FbMSC application ameliorated the behavioral deficits of TBI mice and promoted neural regeneration. RNA sequencing analysis showed that signal pathways related to inflammation decreased, whereas those related to neural activation increased. Immunofluorescence staining and qRT-PCR data revealed that microglial activation and astrocyte polarization to the A1 phenotype were suppressed by FbMSC application. In addition, FGF1 secreted from FbMSCs enhanced glutamate transportation by astrocytes and alleviated the cytotoxic effect of excessive glutamate on neurons.

Conclusions

Ectoderm-derived FbMSC application significantly alleviated neuroinflammation, brain injury, and excitatory toxicity to neurons, improved cognition and behavioral deficits in TBI mice. Therefore, ectoderm-derived FbMSCs could be ideal therapeutic candidates for TBI which mostly affect cells from the same embryonic origins as FbMSCs.
Generation of an mESC model with a human hemophilia B nonsense mutation via CRISPR/Cas9 technology
Authors: Ma Yanchun , Sun Wenwen , Zhao Lidong , Yao Mingze , Wu Changxin , Su Pengfei , Yang Linhua , Wang Gang
Published: July 2022

Background

Hemophilia B is a rare inherited genetic bleeding disorder caused by a deficiency or lack of coagulation factor IX, the gene for which (F9) is located on the X chromosome. Hemophilia B is currently incurable and the standard treatment is coagulation factor replacement therapy. Although gene therapy has the potential to cure hemophilia, significant barriers are still needed to be overcome, e.g., off-target effects and immunoreactivity, so new approaches must be explored. Nonsense mutations account for 8% of all the hemophilia B mutation types and can result in the development of coagulation factor inhibitors. In this study, CRISPR/Cas9 technology was used to construct a mouse embryonic stem cell model with a hemophilia B nonsense mutation (F9 c.223C > T) in humans to investigate the pathogenesis and treatment of nonsense mutations in hemophilia B.

Methods

First, a donor plasmid with a mutation (F9 c.223 C > T) and sgRNAs were constructed. Second, both the donor plasmid and the px330-sgRNA were electroporated into mouse embryonic stem cell, and the mutant cells were then screened using puromycin and red fluorescence. Third, the mutant cell lines were tested for pluripotency and the ability to differentiate into three layers. Finally, the effect of mutation on gene function was studied in the differentiation system.

Results

The mutant vector and effective sgRNA were constructed, and the mutant cell line was screened. This mutant cell line exhibited pluripotency and the ability to differentiate into three layers. This point mutation affects F9 expression at both the RNA and protein levels in the differentiation system.

Conclusions

The mutant cell line obtained in the current study had a single-base mutation rather than a base deletion or insertion in the exon, which is more similar to clinical cases. In addition, the mutant has the characteristics of mouse embryonic stem cells, and this point mutation affects F9 gene transcription and translation, which can be used as a disease model for studying the pathogenesis and treatment of hemophilia at the stem cell level.
Increased arginine, lysine, and methionine levels can improve the performance, gut integrity and immune status of turkeys but the effect is interactive and depends on challenge conditions
Authors: Konieczka Paweł , Tykałowski Bartłomiej , Ognik Katarzyna , Kinsner Misza , Szkopek Dominika , Wójcik Maciej , Mikulski Dariusz , Jankowski Jan
Published: July 2022

Arginine (Arg), lysine (Lys), and methionine (Met) can be used to support the health status of turkeys. The present study investigated selected performance, gut integrity, and immunological parameters in turkeys reared in optimal or challenge conditions. The experiment lasted for 28 days, and it had a completely randomized 2 × 3 factorial design with two levels of dietary Arg, Lys and Met (high or low) and challenge with Clostridium perfringens (C. perfringens), Escherichia coli lipopolysaccharide (LPS) or no challenge (placebo). Increased dietary levels of Arg, Lys and Met had a beneficial effect on turkey performance and immunological parameters, and it improved selected indicators responsible for maintaining gut integrity in different challenge conditions. Under optimal conditions (with no challenge), high ArgLysMet diets did not compromise bird performance and they improved selected performance parameters in challenged birds. The immune system of turkeys was not excessively stimulated by high ArgLysMet diets, which did not disrupt the redox balance and had no negative effect on gut integrity. High ArgLysMet diets increased the expression levels of selected genes encoding nutrient transporters and tight junction proteins. However, the influence exerted by different dietary inclusion levels of Arg, Lys and Met on gut integrity was largely determined by the stressor (C. perfringens vs. LPS). Further studies are required to investigate the role of Arg, Lys and Met levels in the diet on the immune response, gut function and performance of turkeys in different challenge conditions.
Fine-grained precise-bone age assessment by integrating prior knowledge and recursive feature pyramid network
Authors: Jia Yang , Zhang Xinmeng , Du Hanrong , Chen Weiguang , Jin Xiaohui , Qi Wei , Yang Bin , Zhang Qiujuan , Wei Zhi
Published: July 2022

Bone age assessment (BAA) evaluates individual skeletal maturity by comparing the characteristics of skeletal development to the standard in a specific population. The X-ray image examination for bone age is tedious and subjective, and it requires high professional skills. Therefore, AI techniques are desired to innovate and improve BAA methods. Most of the BAA method use the whole X-ray image in an end-to-end model directly. Such whole-image-based approaches fail to characterize local changes and provide limited aid for diagnosis and understanding disease progress. To address these issues, we collected and curated a dataset of 2129 cases for the study of BAA with fine-grained skeletal maturity level labels of the 13 ROIs in hand bone based on the expert knowledge from TW method. We designed a four-stage automatic BAA model based on recursive feature pyramid network. Firstly, the palm region was segmented using U-Net, followed by the extraction of multi-target ROIs of hand bone using a recursive feature pyramid network. Given the extracted ROIs, we employed a transfer learning model with attention mechanism to predict the skeletal maturity level of each ROI. Finally, the bone age is assessed based on the percentile curve of bone maturity. The proposed BAA model can automate the BAA. In addition, it provides the detection result of the 13 ROIs and their ROI-level skeletal maturity. The MAE can reach 0.61 years on the dataset with the labeling precision of one year. All the data and annotations used in this paper are released publicly.
5mC and H3K9me3 of TRAF3IP2 promoter region accelerates the progression of translocation renal cell carcinoma
Authors: Yang Lei , Chen Yi , Liu Ning , Lu Yanwen , Li Xin , Ma Wenliang , Gan Weidong , Li Dongmei
Published: July 2022

Background

In our previous study, we found that lncRNA TRAF3IP2 antisense RNA 1 (TRAF3IP2-AS1) could play a critical role in the progression of NONO-TFE3 translocation renal cell carcinoma (NONO-TFE3 tRCC). However, the function of TRAF3IP2 (TRAF3 interacting protein 2), encoded by the complementary strand of TRAF3IP2-AS1, remains poorly understood in NONO-TFE3 tRCC.

Methods

Immunohistochemistry, western blot, and qRT-PCR were undertaken to study the expression and clinical significance of TRAF3IP2 in Xp11.2 tRCC tissues and cells. The functions of TRAF3IP2 in tRCC were investigated by proliferation analysis, EdU staining, colony and sphere formation assay, Transwell assay, and apoptosis analysis. The regulatory mechanisms among TRAF3IP2, NOTCH1, and TRAF3IP2-AS1 were investigated by luciferase assay, RNA immunoprecipitation, western blot, methylated DNA Immunoprecipitation, and CRISPR/dCas9-based system.

Results

The results showed that TRAF3IP2 was highly expressed in NONO-TFE3 tRCC tissues and cells, and the silence of TRAF3IP2 inhibited the proliferation, migration, and invasion of UOK109 cells which were derived from cancer tissue of patient with NONO-TFE3 tRCC. Mechanistic studies revealed that TRAF3IP2 functioned as a co-activator of NOTCH1 to activate the NOTCH1 pathway. Meanwhile, HNRNPK, DNMT1 and SETDB1 could be recruited by TRAF3IP2-AS1 to the promoter region of TRAF3IP2, which mediated 5-hydroxymethylcytosine (5mC) on DNA and trimethylated lysine 9 of histone H3 (H3K9me3) at transcriptional level to repress the expression of TRAF3IP2.

Conclusions

TRAF3IP2 functions as an oncogene in NONO-TFE3 tRCC progression and might serve as a novel target for NONO-TFE3 tRCC therapy.
Communicating to connect with patients
Authors: McCabe Rose
Published: July 2022

Michaelson & Rahim describe a very welcome sustainable training framework for teaching clinical communication skills to trainees on MRCPsych courses. This commentary expands on their article, noting how psychiatrists listen and ask questions affects the therapeutic relationship and patients’ willingness or ability to disclose sensitive information, which is particularly important in risk assessment. Extending videorecording role-plays in training to routine (including remote) clinical consultations and involving patients and carers in training will be key to identifying communication that has a positive impact on patient experience and outcomes.
A Unique Mechanism of a Novel SynonymousPHEXVariant Causing X-Linked Hypophosphatemia
Authors: Alhamoudi Kheloud M , Alghamdi Balgees , Alswailem Meshael , Nasir Abdul , Aljomaiah Abeer , Al-Hindi Hindi , Alzahrani Ali S
Published: July 2022

Context

Synonymous mutations are usually nonpathogenic.

Objective

We report here a family with X-linked hypophosphatemia (XLH) due to a novel synonymous PHEX variant with a unique mechanism.

Methods

We studied a 4-member family (a mother, a son, and 2 daughters), all affected with XLH. Genomic DNA was extracted from peripheral leucocytes. Whole exome sequencing (WES) was used to identify the underlying genetic variant in the proband (the son). Sanger sequencing was used to confirm this variant in the proband and his family members. RT-PCR and sequencing of the cDNA revealed the effect of this variant on the PHEX structure and function

Results

A synonymous variant in the PHEX gene (c.1701A>C) was identified in all affected members. This variant changes the first nucleotide of exon 17 from adenine to cytosine. Using RT-PCR, this variant was shown to interfere with splicing of exons 16 with 17 resulting in a single shorter PHEX transcript in the proband compared to normal control. Sanger sequencing of the cDNA revealed a complete skipping of exon 17 and direct splicing of exons 16 and 18. This led to a frameshift and an introduction of a new stop codon in the next codon (codon 568), which ultimately led to truncation and loss of the final 183 amino acids of PHEX.

Conclusion

This novel variant shows how a synonymous exonic mutation may induce a complex series of changes in the transcription and translation of the gene and causes a disease, a mechanism that is not commonly recognized.
FCHSD2 is required for stereocilia maintenance in mouse cochlear hair cells
Authors: Zhai Xiaoyan , Du Haibo , Shen Yuxin , Zhang Xiujuan , Chen Zhengjun , Wang Yanfei , Xu Zhigang
Published: July 2022

Stereocilia are F-actin-based protrusions on the apical surface of inner-ear hair cells and are indispensable for hearing and balance perception. The stereocilia of each hair cell are organized into rows of increasing heights, forming a staircase-like pattern. The development and maintenance of stereocilia are tightly regulated, and deficits in these processes lead to stereocilia disorganization and hearing loss. Previously, we showed that the F-BAR protein FCHSD2 is localized along the stereocilia of cochlear hair cells and cooperates with CDC42 to regulate F-actin polymerization and cell protrusion formation in cultured COS-7 cells. In the present work, Fchsd2 knockout mice were established to investigate the role of FCHSD2 in hearing. Our data show that stereocilia maintenance is severely affected in cochlear hair cells of Fchsd2 knockout mice, which leads to progressive hearing loss. Moreover, Fchsd2 knockout mice show increased acoustic vulnerability. Noise exposure causes robust stereocilia degeneration as well as enhanced hearing threshold elevation in Fchsd2 knockout mice. Lastly, Fchsd2/Cdc42 double knockout mice show more severe stereocilia deficits and hearing loss, suggesting that FCHSD2 and CDC42 cooperatively regulate stereocilia maintenance.
The Human Side of Structural Transformation
Authors: Porzio Tommaso , Rossi Federico , Santangelo Gabriella
Published: July 2022

We document that nearly half of the global decline in agricultural employment was driven by new cohorts entering the labor market. A new dataset of policy reforms supports an interpretation of these cohort effects as human capital. Using a model of frictional labor reallocation, we conclude that human capital growth led to a sharp decline in the agricultural labor supply, accounting, at fixed prices, for 40 percent of the decrease in agricultural employment. This aggregate effect is halved in general equilibrium and it reflects the role of human capital as both a mediating factor and an independent driver of labor reallocation. (JEL J22, J24, J43, L16, O13, O14, Q10)
Market Access and Quality Upgrading: Evidence from Four Field Experiments
Authors: Bold Tessa , Ghisolfi Selene , Nsonzi Frances , Svensson Jakob
Published: July 2022

Smallholder farming in many developing countries is characterized by low productivity and low-quality output. Low quality limits the price farmers can command and their potential income. We conduct a series of experiments among maize farmers in Uganda to shed light on the barriers to quality upgrading and to study its potential. We find that the causal return to quality is zero. Providing access to a market where quality is paid a market premium led to an increase in farm productivity and income from farming. Our findings reveal the importance of demand-side constraints in limiting rural income and productivity growth. (JEL C93, L14, L15, L22, O13, Q12, Q13)
Appraisal on patient compliance and factors influencing the daily regimen of anti-tubercular drugs in Mangalore city: A cross-sectional study
Authors: Motappa Rohith , Fathima Tuba , Kotian Himani
Published: July 2022

Background: Globally, India is the country with the highest tuberculosis (TB) burden with respect to the number of new cases occurring each year. Annual incident cases of TB in India accounts for more than 25% of total TB morbidity and mortality worldwide. Several factors have been associated with the adherence of TB medication, which can be broadly classified as patient/personal, social, structural and health service. The aims of the present study were to determine the compliance to daily regimen of directly observed treatment, short-course (DOTS) therapy among TB patients registered at the Tuberculosis Unit (TU) of Mangalore and to identify the factors influencing non-compliance for treatment.

Methods: A cross sectional study was performed. The study sample was drawn from the TUs, General Hospital, Mangalore, after taking permission from District TB Officer. The names and addresses of TB patients were collected from treatment cards. The TB patients were approached at their homes/DOTS centers/Primary Health Centre’s (PHCs) with the help of senior treatment supervisors.

Results: It was found that patients positive for human immunodeficiency virus (HIV) were more likely to be non-adherent, which was statistically significant. Amongst the participants, 66 (33%) were diabetic and 28.8% of them were found to be non-adherent. The proportion of non-adherence was 27 times higher in those with poor patient provider relationships. Patients who reported to have side effects of TB medication were 5.23 times more likely to be non-adherent.

Conclusions: Advice on routine consultation with the health care facility, adherence to treatment regimen and education about its benefits should be the prime focus of providing health education to all TB patients, both at the individual and community levels.