bluuebunny/crossref_metadata_2025 huggingface dataset:
Interplay between fatty acid desaturase2 (FADS2) rs174583 genetic variant and dietary antioxidant capacity: cardio-metabolic risk factors in obese individuals
Authors: Khodarahmi Mahdieh , Javidzade Parisa , Farhangi Mahdieh Abbasalizad , Hashemzehi Ahmad , Kahroba Houman
Published: June 2022

Objective

Polymorphisms of the fatty acid desaturase (FADS) gene cluster have been associated with obesity and its-related consequences. This cross-sectional study aimed to investigate whether the adherence to dietary non-enzymatic antioxidant capacity (NEAC), reflecting the antioxidant potential of the whole diet, modifies the association of FADS2 rs174583 polymorphism with cardio-metabolic risk factors in obese adults.

Methods

The present study included 347 healthy obese adults (aged 20–50 years). Dietary NEAC was assessed by a validated food frequency questionnaire with 147 items and estimated through total radical-trapping antioxidant parameters (TRAP), oxygen radical absorbance capacity (ORAC), and ferric reducing ability of plasma (FRAP) with the use of published databases. FADS2 rs174583 polymorphism was characterized using PCR–RFLP. ANCOVA multivariate interaction model was used to analyze gene-diet interactions.

Results

after adjustment for the confounding variables (age, physical activity, SES and WC), this study showed significant interactions between rs174583 polymorphism and adherence to dietary ORAC on the serum cholesterol (PInteraction = 0.029), LDL-C (PInteraction = 0.025) and HDL-C levels (PInteraction = 0.049) among the male group; minor allele carriers who had the highest adherence to the NEAC (ORAC) showed a better metabolic profile (lower TG and LDL-C and higher HDL-C) (P < 0.05). Among women, the dietary ORAC-rs174583 interactions were statistically significant for the serum insulin concentration (PInteraction = 0.020), QUICKI (PInteraction = 0.023) and HOMA-IR (PInteraction = 0.017); the highest QUICKI and the lowest HOMA-IR and serum insulin levels were observed in the CC homozygote carriers with the moderate compliance with the dietary ORAC (P < 0.05). In addition, the dietary TRAP modified the association between FADS2 variant and change in LDL-C levels (PInteraction = 0.037); the homozygous wild-type (CC) women who placed in the top tertile of TRAP had significantly the lowest LDL-C levels than those in the second tertile (P < 0.05).

Conclusion

These data indicate that the FADS2 rs174583 polymorphism interacts with the dietary NEAC to influence cardio-metabolic risk factors in obese subjects. Replication in prospective cohort studies among other populations is required to confirm the results of our study.
PBL teaching in ultrasonography resident standardization training in the COVID-19 pandemic
Authors: Lin Zi-mei , Hong Yu-rong , Liu Chun-mei , Luo Zhi-yan , Zhang Ying , Xie Xiao-jie , Huang Pin-tong
Published: June 2022

Objective

To study the effect of the problem-based learning (PBL) method in ultrasonography (US) resident standardization training during the COVID-19 pandemic.

Methods

Fifty residents were divided into two groups to participate in a 30-day US training program. The residents in the observation group underwent PBL combined with the lecture-based learning (LBL) method, while the residents in the control group experienced the LBL method alone, with 25 residents in each group. A basic theoretical test, practical examination, and questionnaire were used to evaluate the teaching effect of the PBL + LBL method and the LBL method alone.

Results

The basic theoretical pretest score of the observation group was not significantly different from that of the control group. However, the posttest theoretical score and practical score were significantly higher in the observation group than in the control group (P < 0.01). The results of the questionnaire showed that the resident satisfaction level in the observation group with PBL combined with the LBL method was 96%, which was significantly higher than that of the control group with the LBL method alone (80%) (P < 0.05).

Conclusion

The combination of PBL with the LBL method has obvious advantages over the LBL method alone in regard to the training of US residents during the COVID-19 pandemic.
Mental health clinicians’ perceptions of nature-based interventions within community mental health services: evidence from Australia
Authors: Tambyah Rachel , Olcoń Katarzyna , Allan Julaine , Destry Pete , Astell-Burt Thomas
Published: June 2022

Background

Mental health conditions are one of the largest burdens of disease in Australia and globally. There is a need to seek innovative and alternative interventions that can prevent and alleviate mental health symptoms. Nature-based interventions (NBIs), namely programs and activities where individuals engage with natural environments with the aim of improving their health and wellbeing (e.g., nature walking groups), may be such an alternative. This study aimed to explore the perceptions of mental health clinicians on the potential benefits of, and barriers to, implementing NBIs within a community mental health setting.

Methods

This study used a qualitative, exploratory research design. Fifteen mental health clinicians were recruited from the Illawarra Shoalhaven Local Health District, Australia, and interviewed (September–October 2021) about their perceptions of NBIs within mental health settings. The semi-structured interviews were analysed using an inductive thematic approach and managed with NVivo.

Results

Mental health clinicians viewed spending time in nature as relaxing, refreshing, and therapeutic. Many described it as part of their lifestyle and encouraged consumers to engage in nature-based activities on their own time. If NBIs were to be introduced as part of mental health services, clinicians expressed willingness to promote them to their consumers. Clinicians listed many potential benefits of NBIs for mental health consumers including improved mood, calmness and relaxation, a sense of empowerment, and social connections. Despite these benefits, clinicians were concerned about a variety of barriers to NBIs including consumers’ mental health symptoms such as anxiety or lack of motivation, scepticism, and geographic accessibility, as well as organisational barriers such as policies around safety risk.

Conclusion

Responding to the individual and organisational factors that could hinder the implementation of NBIs while building on the existing evidence of the positive impact of nature on health and wellbeing and, as demonstrated in this study, mental health clinicians’ interest and supportiveness of NBIs, mental health services should consider the implementation of NBIs as part of routine practice.
Investigation into the correlation between humanistic care ability and emotional intelligence of hospital staff
Authors: Ma Jingjing , Peng Wentao , Pan Jihong
Published: June 2022

Background

There are different degrees of flaws in the knowledge structure of humanistic medicine of medical staff. The level of emotional intelligence of medical staff affects their career development as well as their relationship with patients. Currently, the research on humanistic care ability (HCA) and emotional intelligence of medical staff in China and other countries is rare. This study aimed to investigate the correlation between the level of HCA and level of emotional intelligence of the whole hospital staff.

Methods

The questionnaire survey employed contained self-designed questions on the hospital staff members’ socio-demographic background, Caring Ability Inventory, and Wong and Law Emotional Intelligence Scale. The survey was conducted with the staff of West China Second University Hospital, Sichuan University in April 2020.

Results

The hospital staff’s average CAI score was 197.77 ± 20.30, and their average WLEIS score was 84.21 ± 13.48. The CAI and WLEIS scores of the hospital staff who chose their college majors on their own interests were higher than those who chose their majors for other reasons (employability, suggestions from family or others, etc.). The CAI and WLEIS scores of the hospital staff who had received more comprehensive and in-depth humanistic care training were higher than those who did not. The CAI score of the hospital staff who had participated in volunteer service activities was higher than those who did not. The WLEIS score of the Pediatrics Department staff was higher than that of the Outpatient and Emergency Department staff, and the difference was statistically significant (P < 0.05). The scores of emotional intelligence, self-emotion assessment and expression, self-emotion management, self-emotion utilization, emotion recognition of others, and HCA of the hospital staff were positively correlated (P < 0.001).

Conclusion

There were different levels of development of internal factors of emotional intelligence among the hospital staff, and their humanistic care ability was at a low level. Emotional intelligence was positively correlated to humanistic care ability. The findings suggest in-service training and education by healthcare institutions to enhance healthcare staff’s emotional intelligence for promoting the general health of the population.
Technology-assisted peer therapy: a new way of delivering evidence-based psychological interventions
Authors: Atif Najia , Nazir Huma , Sultan Zoone Hasan , Rauf Rabia , Waqas Ahmed , Malik Abid , Sikander Siham , Rahman Atif
Published: June 2022

In low-income settings, ninety percent of individuals with clinical depression have no access to evidence-based psychological interventions. Reasons include lack of funds for specialist services, scarcity of trained mental health professionals, and the stigma attached to mental illness. In recent years there have been many studies demonstrating effective delivery of psychological interventions through a variety of non-specialists. While these interventions are cost-effective and less stigmatising, efforts to scale-up are hampered by issues of quality-control, and what has been described by implementation scientists as ‘voltage-drop’ and ‘programme-drift.’ Using principles of Human Centred Design in a rural setting in Pakistan, we worked with potential users to co-design a Tablet or Smartphone-based App that can assist a lay-person deliver the Thinking Healthy Programme, a World Health Organization-endorsed evidence-based intervention for perinatal depression. The active ingredients of this cognitive-therapy based intervention are delivered by a virtual ‘avatar’ therapist incorporated into the App which is operated by a ‘peer’ (a woman from the neighbourhood with no prior experience of healthcare delivery). Using automated cues from the App, the peer reinforces key therapeutic messages, helps with problem-solving and provides the non-specific but essential therapeutic elements of empathy and support. The peer and App therefore act as co-therapists in delivery of the intervention. The peer can deliver the intervention with good fidelity after brief automated in-built training. This approach has the potential to be applied to other areas of mental health and help bridge the treatment gap, especially in resource-poor settings. This paper describes the process of co-development with end-users and key features of the App.
Relationship between moral sensitivity and the quality of nursing care for the elderly with Covid-19 in Iranian hospitals
Authors: Nazari Shima , Poortaghi Sarieh , Sharifi Farshad , Gorzin Shaghayegh , Afshar Pouya Farokhnezhad
Published: June 2022

Background

The quality of care has a significant impact on the condition of elderly patients. Many factors affect the quality of care, including ethical considerations. Ethical considerations, such as moral sensitivity, change in times of crisis. The present study was conducted to assess the relationship between moral sensitivity and the quality of nursing care for the elderly with Covid-19 in Iranian hospitals.

Methods

This was a cross-sectional descriptive correlational study. The participants included 445 nurses that were selected by quota sampling method from hospitals admitting COVID-19 patients. The data were collected using the Moral Sensitivity Questionnaire (MSQ) and Quality Patient Care Scale (QUALPAC) as self-reports. We used the SPSS software v.16 for statistical analysis.

Results

The total score of moral sensitivity and quality of care was 52.29 ± 16.44 and 2.83 ± 0.23, respectively. Moral sensitivity negatively correlates with psychological, social, and physical aspects (P < 0.05). Modifying autonomy, interpersonal orientation, and experiencing moral conflict predicted β = 0.10 of the psychosocial aspect of quality of care. Structural moral meaning and expressing benevolence predicted the changes in the physical dimension of quality of care (β = 0.02).

Conclusion

The quality of care had a significant inverse correlation with moral sensitivity. Multiple regression analysis showed that modifying autonomy, interpersonal orientation, and experiencing moral conflict could predict the psychosocial dimensions. Structuring moral meaning could predict the physical dimension. The communication aspects were not related to any of the dimensions of moral sensitivity.
Identification of hub genes and regulatory networks in histologically unstable carotid atherosclerotic plaque by bioinformatics analysis
Authors: Guo Julong , Ning Yachan , Su Zhixiang , Guo Lianrui , Gu Yongquan
Published: June 2022

Objective

This study identified underlying genetic molecules associated with histologically unstable carotid atherosclerotic plaques through bioinformatics analysis that may be potential biomarkers and therapeutic targets.

Methods

Three transcriptome datasets (GSE41571, GSE120521 and E-MTAB-2055) and one non-coding RNA dataset (GSE111794) that met histological grouping criteria of unstable plaque were downloaded. The common differentially expressed genes (co-DEGs) of unstable plaques identified from three mRNA datasets were annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomics (KEGG). A protein–protein interaction (PPI) network was constructed to present the interaction between co-DEGs and screen out hub genes. MiRNet database and GSE111794 dataset were used to identify the miRNAs targeting hub genes. Associated transcription factors (TFs) and drugs were also predicted. These predicted results were used to construct miRNA/TFs-hub gene and drug-hub gene regulatory networks.

Results

A total of 105 co-DEGs were identified, including 42 up-regulated genes and 63 down-regulated genes, which were mainly enriched in collagen-containing extracellular matrix, focal adhesion, actin filament bundle, chemokine signaling pathway and regulates of actin cytoskeleton. Ten hub genes (up-regulated: HCK, C1QC, CD14, FCER1G, LCP1 and RAC2; down-regulated: TPM1, MYH10, PLS3 and FMOD) were screened. HCK and RAC2 were involved in chemokine signaling pathway, MYH10 and RAC2 were involved in regulation of actin cytoskeleton. We also predicted 12 miRNAs, top5 TFs and 25 drugs targeting hub genes. In the miRNA/TF-hub gene regulatory network, PLS3 was the most connected hub genes and was targeted by six miRNAs and all five screened TFs. In the drug-hub gene regulatory network, HCK was targeted by 20 drugs including 10 inhibitors.

Conclusions

We screened 10 hub genes and predicted miRNAs and TFs targeting them. These molecules may play a crucial role in the progression of histologically unstable carotid plaques and serve as potential biomarkers and therapeutic targets.
CircEZH2/miR-133b/IGF2BP2 aggravates colorectal cancer progression via enhancing the stability of m6A-modified CREB1 mRNA
Authors: Yao Bing , Zhang Qinglin , Yang Zhou , An Fangmei , Nie He , Wang Hui , Yang Cheng , Sun Jing , Chen Ke , Zhou Jingwan , Bai Bing , Gu Shouyong , Zhao Wei , Zhan Qiang
Published: June 2022

Background

Aberrant expression of circular RNAs (circRNAs) contributes to the initiation and progression of human malignancies, but the underlying mechanisms remain largely elusive.

Methods

High-throughput sequencing was performed to screen aberrantly expressed circRNAs or miRNAs in colorectal cancer (CRC) and adjacent normal tissues. A series of gain- and loss-of-function studies were conducted to evaluate the biological behaviors of CRC cells. RNA pulldown, mass spectrometry, RIP, qRT-PCR, Western blot, luciferase reporter assays and MeRIP-seq analysis were further applied to dissect the detailed mechanisms.

Results

Here, a novel circRNA named circEZH2 (hsa_circ_0006357) was screened out by RNA-seq in CRC tissues, whose expression is closely related to the clinicpathological characteristics and prognosis of CRC patients. Biologically, circEZH2 facilitates the proliferation and migration of CRC cells in vitro and in vivo. Mechanistically, circEZH2 interacts with m6A reader IGF2BP2 and blocks its ubiquitination-dependent degradation. Meanwhile, circEZH2 could serve as a sponge of miR-133b, resulting in the upregulation of IGF2BP2. Particularly, circEZH2/IGF2BP2 enhances the stability of CREB1 mRNA, thus aggravating CRC progression.

Conclusions

Our findings not only reveal the pivotal roles of circEZH2 in modulating CRC progression, but also advocate for attenuating circEZH2/miR-133b/IGF2BP2/ CREB1 regulatory axis to combat CRC.
An update of Nrf2 activators and inhibitors in cancer prevention/promotion
Authors: Pouremamali Farhad , Pouremamali Amir , Dadashpour Mehdi , Soozangar Narges , Jeddi Farhad
Published: June 2022

NF-E2-related factor 2 (Nrf2) protein is a basic-region leucine zipper transcription factor that defends against endogenous or exogenous stressors. By inducing several cytoprotective and detoxifying gene expressions, Nrf2 can increase the sensitivity of the cells to oxidants and electrophiles. Transient Nrf2 activation, by its specific activators, has protective roles against carcinogenesis and cancer development. However, permanent activation of Nrf2 promotes various cancer properties, comprising malignant progression, chemo/radio resistance, and poor patient prognosis. Taken together, these findings suggest that reaching an optimal balance between paradoxical functions of Nrf2 in malignancy may render a selective improvement to identify therapeutic strategies in cancer treatment. In this review, we describe lately discovered Nrf2 inducers and inhibitors, and their chemopreventive and/or anticancer activities.
Aberrant SPOP-CHAF1A ubiquitination axis triggers tumor autophagy that endows a therapeutical vulnerability in diffuse large B cell lymphoma
Authors: Yan Wei , Shi Xue , Wang Huihan , Liao Aijun , Yang Wei
Published: June 2022

Purpose

Aberrant epigenetic changes, like DNA methylation, histone modifications, or ubiquitination, could trigger metabolic disorders in human cancer cells. This study planed to uncover the biological roles of epigenetic SPOP/CHAF1A axis in modulating tumor autophagy during Diffuse large B-cell lymphoma (DLBCL) tumorigenesis.

Materials and methods

The Immunohistochemistry (IHC) was performed to assess the CHAF1A expressions. The expression data of CHAF1A was derived from The Cancer Genome Atlas (TCGA), GSE32918 and GSE83632 datasets. Bioinformatic assays contain differential analysis, functional enrichment analysis and Kaplan–Meier survival curve analysis. The colony generation assay, Transwell assay and CCK-8 assays were conducted for the in vitro assays. The in vivo ubiquitination assays were used to assess regulations of SPOP on CHAF1A. The Chromatin immunoprecipitation (ChIP) assays were used to uncover epigenetic regulations of CHAF1A on TFEB. The relevant DLBCL cells were subcutaneously injected to SCID beige mice to establish the xenograft models.

Results

Bioinformatic results revealed that CHAF1A expressed highly in DLBCL that were validated in patients samples. Patients with high CHAF1A suffered from inferior prognosis with shorter survival months relative to those with low CHAF1A. High CHAF1A enhanced DLBCL aggressiveness, including cell proliferation, migration and in vivo growth. Mechanistically, E3 ubiquitin ligase SPOP binds to and induces the degradative ubiquitination of CHAF1A via recognizing a consensus SPOP-binding motif in CHAF1A. SPOP is down-regulated in DLBCL and habours two DLBCL-associated mutations. Deficient SPOP leads to accumulated CHAF1A proteins that promote malignant features of DLBCL. Subsequently, ChIP-qPCR assay revealed that CHAF1A directly binds to TFEB promoters to activate the expressions. High CHAF1A could enhance the transcriptional activity of TFEB and downstream genes. The SPOP/CHAF1A axis modulates TFEB-dependent transactivation to regulate the lysosomal biogenesis and autophagy. The in vivo models suggested that TFEB inhibition is effective to suppress growth of SPOP-deficient DLBCLs.

Conclusions

CHAF1A is aberrantly elevated in SPOP-deficient DLBCL. The in‐depth mechanism understanding of SPOP/CHAF1A/TFEB axis endows novel targets for DLBCL treatment.
White matter pathology in alzheimer’s transgenic mice with chronic exposure to low-level ambient fine particulate matter
Authors: Chen Ta-Fu , Lee Sheng-Han , Zheng Wan-Ru , Hsu Ching-Chou , Cho Kuan-Hung , Kuo Li-Wei , Chou Charles C.-K. , Chiu Ming-Jang , Tee Boon Lead , Cheng Tsun-Jen
Published: June 2022

Background

Air pollution, especially fine particulate matter (PM), can cause brain damage, cognitive decline, and an increased risk of neurodegenerative disease, especially alzheimer’s disease (AD). Typical pathological findings of amyloid and tau protein accumulation have been detected in the brain after exposure in animal studies. However, these observations were based on high levels of PM exposure, which were far from the WHO guidelines and those present in our environment. In addition, white matter involvement by air pollution has been less reported. Thus, this experiment was designed to simulate the true human world and to discuss the possible white matter pathology caused by air pollution.

Results

6 month-old female 3xTg-AD mice were divided into exposure and control groups and housed in the Taipei Air Pollutant Exposure System (TAPES) for 5 months. The mice were subjected to the Morris water maze test after exposure and were then sacrificed with brain dissection for further analyses. The mean mass concentration of PM2.5 during the exposure period was 13.85 μg/m3. After exposure, there was no difference in spatial learning function between the two groups, but there was significant decay of memory in the exposure group. Significantly decreased total brain volume and more neuronal death in the cerebral and entorhinal cortex and demyelination of the corpus callosum were noted by histopathological staining after exposure. However, there was no difference in the accumulation of amyloid or tau on immunohistochemistry staining. For the protein analysis, amyloid was detected at significantly higher levels in the cerebral cortex, with lower expression of myelin basic protein in the white matter. A diffuse tensor image study also revealed insults in multiple white matter tracts, including the optic tract.

Conclusions

In conclusion, this pilot study showed that even chronic exposure to low PM2.5 concentrations still caused brain damage, such as gross brain atrophy, cortical neuron damage, and multiple white matter tract damage. Typical amyloid cascade pathology did not appear prominently in the vulnerable brain region after exposure. These findings imply that multiple pathogenic pathways induce brain injury by air pollution, and the optic nerve may be another direct invasion route in addition to olfactory nerve.
The Social Competence Promotion Program among Young Adolescents (SCPP-YA) in Chile (“Mi Mejor Plan”) for substance use prevention among early adolescents: study protocol for a randomized controlled trial
Authors: Gaete Jorge , Inzunza Constanza , Ramírez Saray , Valenzuela Daniela , Rojas Cristian , Araya Ricardo
Published: June 2022

Background

Substance use is highly prevalent among children and adolescents in Chile, and it is known how it impacts their health and social adjustment. The call for effective prevention of substance use among children adolescents has resulted in numerous school-based programs, and particularly, the Social Competence Promotion Program among Young Adolescents (SCPP-YA) has been proved to be successful for promoting social and problem-solving skills in addition to preventing substance abuse in the US population. The purpose of this study is to test the effectiveness of the Social Competence Promotion Program among Young Adolescents (SCPP-YA) in Chile (“Mi Mejor Plan”).

Methods

This is a cluster randomized controlled trial, parallel-group type, where “Mi Mejor Plan” is compared to standard school preventive curricula in control schools. A total of 10 schools and 600 adolescents are expected to be recruited and randomized with 1:1 allocation. During formative work, the SCPP-YA program was culturally adapted to Chile. The effectiveness of this program will be assessed using the European Drug Addiction Prevention Trial Questionnaire (EU-Dap), measuring substance use prevalence and risk and protective factors in baseline, post-intervention, and 4 months after the end of the intervention.

Discussion

The proposed study will be the first to test the effectiveness of the Social Competence Promotion Program among Young Adolescents (SCPP-YA) in Chile in a cluster randomized control trial and also the first study evaluating this program in Spanish-speaking Latin America. SCPP-YA has been implemented successfully in the USA. Thus, if the effects of the program are positive, wide implementation in Chile and Latin American countries is possible soon.

Trial registration

Clinical Trials NCT04236947. Registered on January 22, 2020.
pH regulatory divergent point for the selective bio-oxidation of primary diols during resting cell catalysis
Authors: Hua Xia , Zhang ChenHui , Han Jian , Xu Yong
Published: June 2022

Background

Hydroxyl acid is an important platform chemical that covers many industrial applications due to its dual functional modules. At present, the traditional technology for hydroxyl acid production mainly adopts the petroleum route with benzene, cyclohexane, butadiene and other non-renewable resources as raw materials which violates the development law of green chemistry. Conversely, it is well-known that biotechnology and bioengineering techniques possess several advantages over chemical methods, such as moderate reaction conditions, high chemical selectivity, and environmental-friendly. However, compared with chemical engineering, there are still some major obstacles in the industrial application of biotechnology. The critical issue of the competitiveness between bioengineering and chemical engineering is products titer and volume productivity. Therefore, based on the importance of hydroxyl acids in many fields, exploring a clean, practical and environmental-friendly preparation process of the hydroxyl acids is the core purpose of this study.

Results

To obtain high-purity hydroxyl acid, a microbiological regulation for its bioproduction by Gluconobacter oxydans was constructed. In the study, we found a critical point of chain length determine the end-products. Gluconobacter oxydans catalyzed diols with chain length ≤ 4, forming hydroxyl acids, and converting 1,5-pentylene glycol and 1,6-hexylene glycol to diacids. Based on this principle, we successfully synthesized 75.3 g/L glycolic acid, 83.2 g/L 3-hydroxypropionic acid, and 94.3 g/L 4-hydroxybutyric acid within 48 h. Furthermore, we directionally controlled the products of C5/C6 diols by adjusting pH, resulting in 102.3 g/L 5‑hydroxyvaleric acid and 48.8 g/L 6-hydroxycaproic acid instead of diacids. Combining pH regulation and cell-recycling technology in sealed-oxygen supply bioreactor, we prepared 271.4 g 5‑hydroxyvaleric acid and 129.4 g 6-hydroxycaproic acid in 6 rounds.

Conclusions

In this study, a green scheme of employing G. oxydans as biocatalyst for superior-quality hydroxyl acids (C2–C6) production is raised up. The proposed strategy commendably demonstrated a novel technology with simple pH regulation for high-value production of hydroxyl acids via green bioprocess developments.
3DFAACTS-SNP: using regulatory T cell-specific epigenomics data to uncover candidate mechanisms of type 1 diabetes (T1D) risk
Authors: Liu Ning , Sadlon Timothy , Wong Ying Y. , Pederson Stephen , Breen James , Barry Simon C.
Published: June 2022

Background

Genome-wide association studies (GWAS) have enabled the discovery of single nucleotide polymorphisms (SNPs) that are significantly associated with many autoimmune diseases including type 1 diabetes (T1D). However, many of the identified variants lie in non-coding regions, limiting the identification of mechanisms that contribute to autoimmune disease progression. To address this problem, we developed a variant filtering workflow called 3DFAACTS-SNP to link genetic variants to target genes in a cell-specific manner. Here, we use 3DFAACTS-SNP to identify candidate SNPs and target genes associated with the loss of immune tolerance in regulatory T cells (Treg) in T1D.

Results

Using 3DFAACTS-SNP, we identified from a list of 1228 previously fine-mapped variants, 36 SNPs with plausible Treg-specific mechanisms of action. The integration of cell type-specific chromosome conformation capture data in 3DFAACTS-SNP identified 266 regulatory regions and 47 candidate target genes that interact with these variant-containing regions in Treg cells. We further demonstrated the utility of the workflow by applying it to three other SNP autoimmune datasets, identifying 16 Treg-centric candidate variants and 60 interacting genes. Finally, we demonstrate the broad utility of 3DFAACTS-SNP for functional annotation of all known common (> 10% allele frequency) variants from the Genome Aggregation Database (gnomAD). We identified 9376 candidate variants and 4968 candidate target genes, generating a list of potential sites for future T1D or other autoimmune disease research.

Conclusions

We demonstrate that it is possible to further prioritise variants that contribute to T1D based on regulatory function, and illustrate the power of using cell type-specific multi-omics datasets to determine disease mechanisms. Our workflow can be customised to any cell type for which the individual datasets for functional annotation have been generated, giving broad applicability and utility.
SNTA1-deficient human cardiomyocytes demonstrate hypertrophic phenotype and calcium handling disorder
Authors: Dong Tao , Zhao Yan , Jin Hai-Feng , Shen Lei , Lin Yan , Si Long-Long , Chen Li , Liu Ji-Cheng
Published: June 2022

Background

α-1-syntrophin (SNTA1), a protein encoded bySNTA1, is highly expressed in human cardiomyocytes. Mutations inSNTA1are associated with arrhythmia and cardiomyopathy. Previous research on SNTA1 has been based on non-human cardiomyocytes. This study was designed to identify the phenotype ofSNTA1-deficiency using human cardiomyocytes.

Methods

SNTA1was knocked out in the H9 embryonic stem cell line using the CRISPR-Cas9 system. H9SNTA1KO cells were then induced to differentiate into cardiomyocytes using small molecule inhibitors. The phenotypic discrepancies associated withSNTA1-deficient cardiomyocytes were investigated.

Results

SNTA1was truncated at the 149th amino acid position of PH1 domain by a stop codon (TGA) using the CRISPR-Cas9 system.SNTA1-deficiency did not affect the pluripotency of H9SNTA1KO, and they retain their in vitro ability to differentiate into cardiomyocytes. However, H9SNTA1KO derived cardiomyocytes exhibited hypertrophic phenotype, lower cardiac contractility, weak calcium transient intensity, and lower level of calcium in the sarcoplasmic reticulum. Early treatment ofSNTA1-deficient cardiomyocytes with ranolazine improved the calcium transient intensity and cardiac contractility.

Conclusion

SNTA1-deficient cardiomyocytes can be used to research the etiology, pathogenesis, and potential therapies for myocardial diseases. TheSNTA1-deficient cardiomyocyte model suggests that the maintenance of cardiac calcium homeostasis is a key target in the treatment of myocardial-related diseases.
Morphological characteristics of the surgical neck region in the proximal humerus at different ages
Authors: Guo Jialiang , Zhou Yali , Shang Meishuang , Chen Wei , Hou Zhiyong , Zhang Yingze , Dong Weichong
Published: June 2022

Background

The objective of the study was to demonstrate the cortical thickness character in the humeral surgical neck region using 3D cortical bone mapping technique and try to illustrate its morphological changes with age.

Material and methods

Normal individuals, including 11 volunteers younger than 18 years, 87 adult men and 46 adult women, were enrolled. The cortical thickness and height of the surgical neck region was measured with Mimic and 3 Matic software. The height of the region was compared and measured. People with an age of 18–30 years was identified as Group I, people in 31–40 years as Group II, people in 41–50 years as Group III, people in 51–60 years as Group IV, and Group V including people ≥ 61 years.

Results

Compared with the baseline Group I, cortical thickness was significantly decreased by 0.52 mm (P = 0.006) in Group III, by 0.76 mm (P < 0.001) in Group IV, and by 0.77 mm (P < 0.001) in Group V. Age moderately predicted cortical thickness withr = −0.5481. The height of the cortical change region was significantly decreased by 2.25 mm (P = 0.007) in Group II, by 2.98 mm (P < 0.001) in Group III, and by 2.07 mm (P = 0.02) in Group IV. However, no significant decrease was illustrated in Group V (0.57 mm) (P = 0.891). The relation between age and the height of the cortical thickness change region was nonlinear.

Conclusions

This study identified an obvious decrease in cortical thickness with aging, and the height was curve fitted with aging in surgical neck region.
A confirmation of vertical acoustic resonance and field-aligned current generation just after the 2022 Hunga Tonga Hunga Ha’apai volcanic eruption
Authors: Iyemori Toshihiko , Nishioka Michi , Otsuka Yuichi , Shinbori Atsuki
Published: June 2022

A strong volcanic eruption caused a clear vertical acoustic resonance between the sea surface and the thermosphere. Its effects are observed as geomagnetic and GPS-TEC oscillations near the volcano and its geomagnetic conjugate area. The geomagnetic oscillations are observed at Apia and Honolulu geomagnetic observatories with amplitude of about 2 nT and 0.2 nT, respectively. The volcanic eruption started around 04:14 UT on January 15, 2022. The oscillations appeared at 04:21UT at Apia, Samoa, only about 7 min after the start of eruption. Because the distance between the volcano and Apia is about 841 km, it takes about 40 min for a sound wave to propagate from the volcano to Apia. Therefore, it is more plausible to assume that the magnetic oscillation observed at Apia about 7 min after the eruption is caused by the sound waves propagated vertically upward to the ionosphere and generated an electric current. The coherent appearance of geomagnetic oscillation at Honolulu located near the geomagnetic conjugate point of the volcano strongly support the idea that the ionospheric current generated over the volcano diverted as a field-aligned current which flew to the opposite hemisphere and caused the geomagnetic oscillation at Honolulu. The earliest start of GPS-TEC oscillation was around 04:15UT near the volcanic eruption, and it was around 04:20 UT at KOKV station in Hawaii. The time-lag of the TEC variations between Samoa and Hawaii obtained by a cross-correlation analysis is 4.5 min or 8.5 min. These time differences are much smaller than the travel time of the seismic waves from the volcano to Hawaii islands. Therefore, it is suggested that the electric field transmitted along geomagnetic field caused the TEC variation observed over Hawaii Islands. A sawtooth waveform of geomagnetic oscillation observed at Apia and Honolulu is analyzed and a possible generation mechanism is discussed.

Graphical Abstract
Safety and pharmacokinetics of a highly bioavailable resveratrol preparation (JOTROL TM)
Authors: Kemper Christopher , Behnam Dariush , Brothers Shaun , Wahlestedt Claes , Volmar Claude-Henry , Bennett Daniel , Hayward Marshall
Published: June 2022

Resveratrol exhibits a wide range of biological properties, including anti-glycation, antioxidant, anti-inflammation, neuroprotective (including against advanced dementia and Alzheimer’s disease), anti-cancer, and anti-aging activity in experimental models (Galiniak et al., Acta Biochim Pol 66:13-21, 2019). Unfortunately, this compound exhibits low bioavailability and solubility (Galiniak et al., Acta Biochim Pol 66:13-21, 2019), requiring large doses that can cause nausea and GI distress. JOTROLTM is a micellar 10% resveratrol solubilization formulation that is thought to increase bioavailability of resveratrol via lymphatic system absorption. Jupiter Neurosciences (formerly Jupiter Orphan Therapeutics; “Jupiter”) is pursuing the use of resveratrol in mucopolysaccharidosis type 1 (MPS 1), Friedreich’s ataxia, and Alzheimer’s disease/mild cognitive impairment. This paper describes a first in human study (FIH) to evaluate the bioavailability of resveratrol after ascending, single oral doses up to 700 mg resveratrol as JOTROLTM. After a single 500 mg dose of JOTROLTM, a Cmax of 455 ng/mL was observed, vs. 85 ng/mL Cmax after a 1 g encapsulated dose (Turner et al., Neurology 85:1383-91, 2015) and 1942 ng/mL after a 2.5 g micronized dose (Howells et al., Cancer Prev Res (Phila) 4:1419-1425, 2011). In this study, resveratrol exposures (AUCs and Cmax) increased with increasing doses. This increase appears to be higher than dose-proportional for AUC0-t and Cmax. Resveratrol and its three major conjugates accounted for 40 to 55% of the dose in urine, consistent with a high extent of absorption, but < 1% of drug-related material was intact relative to key metabolites in plasma and urine. Studies in Alzheimer’s patients and in MPS 1 are currently in development to test the effect this improved bioavailability has on those patient populations (Clintrials.gov, NCT04668274, 12/16/2020, https://clinicaltrials.gov/ct2/show/NCT04668274).
Association between non-alcoholic fatty liver disease and epicardial adipose tissue volume with cardiometabolic risk in coronary heart disease
Authors: Rasmy Hany Samir , Hamed Ahmed Shaaban , Demerdash Salah El , Zeidan Hanan Hafez , Amin Sameh Attia
Published: June 2022

Background

Regional adiposity has a significant impact on the formation of adverse metabolic and cardiovascular risk profiles. While much of the attention was directed to the importance of intra-abdominal adipose tissue, there were several new investigations about mediastinal and epicardial regions’ visceral adiposity. Our study aimed to determine the association between non-alcoholic fatty liver and increased epicardial adipose tissue mass with coronary artery disease severity.

Methods

This study was conducted on sixty patients who presented with symptoms of coronary artery disease and attended elective coronary angiography to rule out coronary artery disease. All patients have been subjected to full hepatic profile, noninvasive scoring system such as Fibrosis-4 and non-alcoholic fatty liver disease fibrosis score and abdominal ultrasound for diagnosis of non-alcoholic fatty liver disease and trans-thoracic echocardiography for measurement of average epicardial adipose tissue thickness. Student T test, analysis of variance test, chi-square test, and Fisher’s exact test were used for statistical analysis.

Results

According to the severity of coronary artery disease, patients with significant coronary stenosis had statistically significant higher degree of hepatic steatosis in abdominal ultrasound (P value < 0.001) while regarding the non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 for non-alcoholic fatty liver disease diagnosis, there was no significance between both groups. Also, the epicardial adipose tissue mean thickness was found to be statistically significantly higher among those with significant coronary stenosis than those without [7.859 ± 0.691 mm versus 5.600 ± 0.386 mm]. Moreover, statistically significant higher epicardial adipose tissue thickness values were found among grade 3 hepatic steatosis than in grades 2, 1, or 0 (P value < 0.001). At a cutoff > 6.1 mm, epicardial adipose tissue thickness was a valuable tool in discrimination between significant and non-significant coronary artery disease with specificity and sensitivity of 100%.

Conclusion

High epicardial adipose tissue thickness may represent a marker of severity of non-alcoholic fatty liver disease as well as an independent predictor of coronary artery disease risk.
Second-order approximate expressions of P- and SV-plane-wave reflection coefficients at the solid/solid media interface
Authors: Zhou Dongyong , Wen Xiaotao , He Xilei , He Zhenhua
Published: June 2022

To completely use large incident angle seismic data and improve the accuracy of amplitude-variation-with-offset inversion, especially for density information, we have derived second-order approximate expressions of the P- and SV-wave reflection coefficients at the solid/solid media interface. Vectors and Hessian matrices are used to describe the first- and second-order terms of the approximate expressions. The second-order approximations are then rewritten in a simple form. Furthermore, different pseudosecond-order approximations with different power series of the ray parameter p are derived based on the Taylor expansion of the second-order approximation of the P-wave reflection coefficient for the incident P wave (PP-wave reflection coefficient) according to the ray parameter p. By establishing four different single-phase medium models, we have verified that the accuracies of the second-order approximate expressions were remarkably higher than those of the first-order approximations. Furthermore, the pseudo p2 second-order approximation of the PP-wave reflection coefficient is highly consistent with the exact analytical expression.
Clinical Characteristics and Outcomes of Acute Lymphoblastic Leukemia in Adolescents and Young Adults in Malawi
Authors: Kasonkanji Edwards , Kimani Stephen , Skiver Brent , Ellis Grace , Seguin Ryan , Kaimila Bongani , Tomoka Tamiwe , Mulenga Maurice , Montgomery Nathan , Fedoriw Yuri , Gopal Satish , Westmorland Katherine D. , Painschab Matthew S.
Published: June 2022

PURPOSE

There are limited data on treatment and outcomes for acute lymphoblastic leukemia (ALL) among adolescents and young adults in sub-Saharan Africa. We describe a prospective observational cohort in Malawi.

METHODS

Patients age 15-39 years with newly diagnosed ALL at Kamuzu Central Hospital, Malawi, were enrolled from 2013 to 2019; follow-up was censored on December 2020. ALL diagnosis was confirmed on-site using immunohistochemistry and telepathology consultation involving pathologists in Malawi and the United States. All but four patients were treated with a modified pediatric-inspired regimen (Cancer and Leukemia Group B 10403 protocol). Key modifications included omission of asparaginase and no dose escalation for methotrexate.

RESULTS

Of 19 participants, the median age was 22 (range 15-36) years. Of the 15 patients who initiated treatment, 11 (73%) achieved remission after induction, one (7%) died during induction, two (13%) had refractory disease, and one (7%) absconded. No patients were lost to follow-up. Eventually, 10 of 11 patients (91%) with confirmed remission relapsed. The median duration of first remission was 10 (range 3-22) months. Twelve of 15 treated patients (80%) had died at the time of censoring. Among treated patients, the 12- and 24-month overall survival was 50% (95% CI, 23 to 72) and 17% (95% CI, 3 to 42), respectively. CNS involvement was associated with worse survival.

CONCLUSION

It is possible to treat adolescents and young adults with ALL in low-resource settings using a low-cost, pediatric-inspired regimen; however, outcomes are poor. Both cost and limitations in supportive care infrastructure limit intensive cytotoxic approaches such as asparaginase. Patient-reported outcomes are needed to understand the quality of life and cost-effectiveness. Critically, innovative, leap-frog therapies, such as monoclonal or bispecific antibodies, and feasible economic models for resource-limited settings are urgently needed.
Incidence of Cardiovascular Events in Patients Treated With Immune Checkpoint Inhibitors
Authors: Laenens Dorien , Yu Yuling , Santens Béatrice , Jacobs Johanna , Beuselinck Benoit , Bechter Oliver , Wauters Els , Staessen Jan , Janssens Stefan , Van Aelst Lucas
Published: June 2022

PURPOSE

In rare cases, immune checkpoint inhibitors (ICIs) cause immune-mediated myocarditis. However, true incidence of other major adverse cardiovascular events (MACEs) after ICI treatment remains unknown, mainly because late occurring side effects are rarely reported in prospective clinical trials. The aims of this study were (1) to identify incidence and risk factors of MACE in a real-life ICI-treated cancer cohort and (2) to compare incidence rates with patients with cancer who are not treated with ICIs and population controls.

METHODS

In total, 672 patients treated with ICIs were included. The primary end point was MACE, a composite of acute coronary syndrome, heart failure (HF), stroke, and transient ischemic attack. Secondary outcomes were acute coronary syndrome and HF separately. Incidence rates were compared between groups after matching according to age, sex, cardiovascular history, and cancer type.

RESULTS

The incidence of MACE was 10.3% during a median follow-up of 13 (interquartile range, 6-22) months. In multivariable analysis, a history of HF (hazard ratio 2.27; 95% CI, 1.03 to 5.04; P = .043) and valvular heart disease (hazard ratio 3.01; 95% CI, 1.05 to 8.66; P = .041) remained significantly associated with MACE. Cumulative incidence rates were significantly higher in the ICI group compared with the cancer cohort not exposed to ICI and the population controls, mainly driven by a higher risk of HF events.

CONCLUSION

Cardiovascular events during and after ICI treatment are more common than currently appreciated. Patients at risk are those with a history of cardiovascular disease. Compared with matched cancer and population controls, MACE incidence rates are significantly higher, suggesting a potential harmful effect of ICI treatment besides the underlying risk.