bluuebunny/crossref_metadata_2025 huggingface dataset:
Study on the Development of a Conceptual Framework to Identify the Risk Factors of Diabetic Retinopathy among Diabetic Patients: A Concept Paper
Authors: Naserrudin Nurul Athirah , Jeffree Mohammad Saffree , Kaur Nirmal , Rahim Syed Sharizman Syed Abdul , Ibrahim Mohd Yusof
Published: September 2022

The most common complication of diabetes mellitus (DM) is diabetic retinopathy (DR). The control of DR risk factors is essential for the effective prevention of DR. There is currently a lack of research to guide DR-related research in Malaysia. This concept paper aimed to review published studies and propose a conceptual framework (CF) as a guide for future research to determine the prevalence of DR and its risk factors across DM patients. After a review of prior research, this study has presented a CF that takes into account these four key elements: the patient’s sociodemographic characteristics, comorbidities, complications, and diabetes conditions, namely, the length of the disease and glycaemic control. In the suggested CF, ethnicity was highlighted as a crucial risk factor for DR across lower- to middle-income countries (LMIC) and multiracial countries. In order to guide future studies, scientific guidance is essential. The proposed CF would help future research to conduct scientific research related to DR. Also, the proposed CF was tailored to suit research across LMIC and multiracial countries.
Adjunctive Bright Light Therapy for Non-Seasonal Major Depressive Disorder: A Randomized Controlled Trial
Authors: Chen I-Peng , Huang Chun-Chao , Huang Hui-Chun , Yang Fan-Pei Gloria , Ko Kai-Ting , Lee Yun-Tse , Sun Fang-Ju , Liu Shen-Ing
Published: September 2022

This double-blind, randomized controlled trial assessed bright light therapy (BLT) augmentation efficacy compared with placebo light in treating non-seasonal major depressive disorder. The study participants belonged to a subtropical area (24.5°–25.5°N) with extensive daylight and included outpatients who had received stable dosages and various regimens of antidepressive agents for 4 weeks before enrollment. The outcomes were the 17-item Hamilton Depression Rating Scale, Montgomery–Asberg Depression Rating Scale, and Patient Health Questionnaire-9, which were assessed at weeks 1, 2, and 4. A total of 43 participants (mean age 45 years, ranging from 22–81) were randomized into the BLT [n = 22] and placebo light groups [n = 21]. After a 4-week administration of morning light therapy (30 min/day), depressive symptoms did not reduce significantly, which might be due to the small sample size. Nonetheless, this study had some strengths because it was conducted in warmer climates, unlike other studies, and examined diverse Asians with depression. Our findings suggest that several factors, such as poor drug response, different antidepressive regimens, duration of BLT, and daylength variability (i.e., natural daylight in the environment) may influence the utility of add-on BLT. Researchers may consider these important factors for future non-seasonal depression studies in subtropical environments.
Distribution Characteristics and Source Analysis of Nitrogen and Phosphorus in Different Rivers in Two Water Period: A Case Study of Pi River and Shiting River in the Upper Reaches of Tuo River in China
Authors: Li Tongfei , Zhou Pingyan , Ding Yunchang , Tang Qiding , Zhou Shanshan , Liu Ying
Published: September 2022

In this paper, the distribution characteristics of total nitrogen (TN), total phosphorus (TP) and fractions of nitrogen and phosphorus in water and surface sediments of the Pi and Shiting rivers in the dry and wet seasons were studied by molybdenum blue/ascorbic acid spectrophotometry and Standard Measurements and Testing (SMT). Correlation analysis, cluster analysis and principal component analysis were used to identified nitrogen and phosphorus pollution sources. The results showed that: (1) nitrogen and phosphorus in water and surface sediments in the study area were at different levels. (2) In the Pi river, the decomposition of animal and plant residues, the leachate from the accumulation of aquaculture wastewater and urban domestic sewage were the main sources of nitrogen and phosphorus pollution, while in the Shiting river, the unreasonable application of pesticides and fertilizers, the degradation of animal and plant residues, agricultural wastewater from agricultural drainage channels, industrial production wastewater and the weathering of agricultural wastes had a great impact on the nitrogen and phosphorus pollution. The results in this study provide reliable experimental data and a reference to local relevant departments for the implementation of effective control measures for the reduction of the nitrogen and phosphorus pollution load in the river basin.
Bushfire Smoke and Children’s Health—Exploring a Communication Gap
Authors: Walsh Erin I. , Sargent Ginny , Cevik-Compiegne Burcu , Roberts Michelle , Palfrey Nicola , Gooyers-Bourke Laura , Vardoulakis Sotiris , Laachir Karima
Published: September 2022

The “Black Summer” bushfires of 2019/2020 in Australia generated smoke that persisted for over three months, mainly affecting Eastern Australia. Most communication strategies focused on the fire itself, revealing a knowledge gap in effective communication of the impact of bushfire smoke on health, especially for children and those living in non-English speaking minority groups. To address this, semi-structured qualitative interviews were undertaken with sixteen adults with caring (n = 11) or educational (n = 5) responsibilities for primary-school aged children (5–12 years, with some also having children up to 16 years) who had direct experience of the “Black Summer” bushfires. Overall, 43% (n = 7) of the sample spoke English as a first language, 25% (n = 4) spoke Turkish, with the remainder speaking Persian, Arabic, and Spanish. Thematic inductive qualitative content analysis revealed predominant themes of the role of parents and caregivers as conduits and curators of information. Air quality apps were the most common source of information. Language barriers and the lack of child-friendly methods of communication were highlighted as particular challenges. This qualitative study provides evidence for future development of communication strategies to better serve culturally and linguistically diverse individuals and the children in their care.
Factors Associated with Caregiver Burden in Caregivers of Older Patients with Dementia in Indonesia
Authors: Putri Yossie Susanti Eka , Putra I Gusti Ngurah Edi , Falahaini Annida , Wardani Ice Yulia
Published: September 2022

This cross-sectional study aimed to identify caregiver burden and its determinants in the informal caregivers of older patients with dementia (PWDs) aged ≥ 60 years in Java, Indonesia. Data were collected from 207 caregivers of older PWDs using self-administered questionnaires. The dependent variable was caregiver subjective burden, assessed using the Zarit Burden Interview (ZBI). The independent variables included the socio-demographic characteristics of PWDs and caregivers, the caregiver’s perceived social support, and the behavioural and psychological symptoms of dementia (BPSD). Linear regression with a stepwise elimination method was used to identify the factors associated with caregiver burden. This study found that four factors were associated with the caregiver burden, such as the gender of PWDs, the educational level of caregivers, social support, and BPSD (R-squared = 27.78%). Higher burden was reported among the caregivers of female PWDs (β = 5.58; 95%CI = 2.16; 8.99) and PWDs with higher scores of BPSD (β = 0.34; 95%CI = 0.25; 0.43). Meanwhile, the caregivers with higher perceived social support (β = −0.26; 95%CI = −0.42; −0.10) and who completed high school education and above (β = −6.41; 95%CI = −10.07; −2.74) tended to have lower scores of subjective burden. These findings suggest that BPSD management and maintaining the resources of support may provide an opportunity to minimise caregiver burden and improve the quality of life of caregivers and PWDs.
Healthcare Workers’ Resilience Toolkit for Disaster Management and Climate Change Adaptation
Authors: Mohtady Ali Heba , Ranse Jamie , Roiko Anne , Desha Cheryl
Published: September 2022

Climate change has been recognised as a multiplier of risk factors affecting public health. Disruptions caused by natural disasters and other climate-driven impacts are placing increasing demands on healthcare systems. These, in turn, impact the wellness and performance of healthcare workers (HCWs) and hinder the accessibility, functionality and safety of healthcare systems. This study explored factors influencing HCWs’ disaster management capabilities with the aim of improving their resilience and adaptive capacity in the face of climate change. In-depth, semi-structured interviews were conducted with thirteen HCWs who dealt with disasters within two hospitals in Queensland, Australia. Analysis of the results identified two significant themes, HCWs’ disaster education and HCWs’ wellness and needs. The latter comprised five subthemes: HCWs’ fear and vulnerability, doubts and uncertainty, competing priorities, resilience and adaptation, and needs assessment. This study developed an ‘HCWs Resilience Toolkit’, which encourages mindfulness amongst leaders, managers and policymakers about supporting four priority HCWs’ needs: ‘Wellness’, ‘Education’, ‘Resources’ and ‘Communication’. The authors focused on the ‘Education’ component to detail recommended training for each of the pre-disaster, mid-disaster and post-disaster phases. The authors conclude the significance of the toolkit, which provides a timely contribution to the healthcare sector amidst ongoing adversity.
Heat Exposure, Heat-Related Symptoms and Coping Strategies among Elderly Residents of Urban Slums and Rural Vilages in West Bengal, India
Authors: Mukhopadhyay Barun , Weitz Charles A.
Published: September 2022

The impact of heat stress among the elderly in India—particularly the elderly poor—has received little or no attention. Consequently, their susceptibility to heat-related illnesses is virtually unknown, as are the strategies they use to avoid, or deal with, the heat. This study examined perceptions of comfort, heat-related symptoms, and coping behaviors of 130 elderly residents of Kolkata slums and 180 elderly residents of rural villages south of Kolkata during a 90-day period when the average 24-h heat indexes were between 38.6 °C and 41.8 °C. Elderly participants in this study reported being comfortable under relatively warm conditions—probably explained by acclimatization to the high level of experienced heat stress. The prevalence of most heat-related symptoms was significantly greater among elderly women, who also were more likely to report multiple symptoms and more severe symptoms. Elderly women in the rural villages were exposed to significantly hotter conditions during the day than elderly men, making it likely that gender differences in symptom frequency, number and severity were related to gender differences in heat stress. Elderly men and elderly village residents made use of a greater array of heat-coping behaviors and exhibited fewer heat-related symptoms than elderly women and elderly slum residents. Overall, heat measurements and heat-related symptoms were less likely to be significant predictors of most coping strategies than personal characteristics, building structures and location. This suggests that heat-coping behaviors during hot weather were the result of complex, culturally influenced decisions based on many different considerations besides just heat stress.
The Use of Different Anthropometric Indices to Assess the Body Composition of Young Women in Relation to the Incidence of Obesity, Sarcopenia and the Premature Mortality Risk
Authors: Gažarová Martina , Bihari Maroš , Lorková Marta , Lenártová Petra , Habánová Marta
Published: September 2022

The objective of the study was to evaluate the stratification of young women based on the assessment of body composition according to several currently recommended anthropometric indices and parameters, as well as the presence of obesity, sarcopenic obesity and the risk of premature death. Three hundred and three young Caucasian women aged 18–25 years were included in the cross-sectional observational study. For the purposes of the study, we used the bioelectrical impedance method and applied the obtained data to calculate indices defining obesity, sarcopenic obesity and premature mortality risk (ABSI z-score). We found significant differences between indicators of total and abdominal obesity when determining the rate of risk of premature death and diagnosis of obesity. Our results also suggest that FMI and FM/FFM indices correlate excellently with fat mass and visceral adipose tissue, better than BMI. Even in the case of abdominal obesity, FMI appears to correlate relatively strongly, more so than BMI. The results of the study support the opinion that in the assessment of body composition and health status, the presence of obesity (sarcopenic obesity) and the risk of premature death, anthropometric parameters and indices focusing not only on body weight (BMI, ABSI), but also on the proportionality and distribution of fat (WC, WHR, WHtR, VFA) and muscle tissue (FFMI, SMMI, FM/FFM ratio) should be used.
Oral-Health-Related Quality of Life as Measured with the Child-OIDP Index and Oral Health Status in Spanish Adolescents
Authors: Alvarez-Azaustre María Paloma , Greco Rossana , Llena Carmen
Published: September 2022

Background: Our aim was to analyze the relationship between OHRQoL (Oral-Health-Related Quality of Life) assessed by the C-OIDP (Child-Oral Impacts on Daily Performances) indexand oral health status in 13-15 years old Spanish population. Methods: A cross-sectional study was designed in a random sample of 337 adolescents. The C-OIDP and an oral health perception questionnaire were applied. ICDAS II (International Caries Detection and Assessment System) classification was used for assessing caries status, CPI (Community Periodontal Index) for periodontal status and discrepancy in the three planes for occlusal evaluation. Statistical analysis included Mann–Whitney, Kruskal–Wallis and Spearman correlation tests. Results: The prevalence of impact was 48.1%. The most frequently affected dimension was eating (21.4%). The overall mean C-OIDP index was 3.28. Higher DMFT (Decayed Missed Filled Tooth) was significantly associated with C-OIDP index (p = 0.03). Participants with CPI > 0 showed an impact index almost twice as high as those with CPI = 0 (p > 0.05). Significant association was found between quality of life and CPI for women (p < 0.01). Only the molar Angle’s class was associated with the impact index (p = 0.04). Conclusions: The OHRQoL in Spanish adolescents is good. The DMFT index had an impact on adolescents’ quality of life, showing a greater impact in men than in women. Periodontal status had a greater impact in women. No association between the extent of the caries lesion and the impact index was found.
Heart Rate Does Not Reflect the %VO2max in Recreational Runners during the Marathon
Authors: Billat Véronique , Palacin Florent , Poinsard Luc , Edwards Johnathan , Maron Michael
Published: September 2022

Exercise physiologists and coaches prescribe heart rate zones (between 65 and 80% of maximal heart rate, HRmax) during a marathon because it supposedly represents specific metabolic zones and the percentage of V˙O2max below the lactate threshold. The present study tested the hypothesis that the heart rate does not reflect the oxygen uptake of recreational runners during a marathon and that this dissociation would be more pronounced in the lower performers’ group (>4 h). While wearing a portable gas exchange system, ten male endurance runners performed an incremental test on the road to determine V˙O2max, HRmax, and anaerobic threshold. Two weeks later, the same subjects ran a marathon with the same device for measuring the gas exchanges and HR continuously. The %HRmax remained stable after the 5th km (between 88% and 91%, p = 0.27), which was not significantly different from the %HRmax at the ventilatory threshold (89 ± 4% vs. 93 ± 6%, p = 0.12). However, the %V˙O2max and percentage of the speed associated with V˙O2max decreased during the marathon (81 ± 5 to 74 ± 5 %V˙O2max and 72 ± 9 to 58 ± 14 %vV˙O2max, p < 0.0001). Hence, the ratio between %HRmax and %V˙O2max increased significantly between the 5th and the 42nd km (from 1.01 to 1.19, p = < 0.001). In conclusion, pacing during a marathon according to heart rate zones is not recommended. Rather, learning about the relationship between running sensations during training and racing using RPE is optimal.
Principals’ Perspectives on Joining a Kindergarten Outreach Dental Service: A Qualitative Study
Authors: Chai Hollis Haotian , Gao Sherry Shiqian , Fung Marcus Ho Tak , Duangthip Duangporn , Lo Edward Chin Man , Chu Chun-Hung
Published: September 2022

In this qualitative study, the researchers explored principals’ perspectives on a free outreach dental service with silver diamine fluoride (SDF) therapy for children in kindergarten. Two researchers recruited kindergarten principals using purposive sampling. They conducted individual semi-structured interviews to collect the principals’ perspectives regarding their adoption of and experience with the service. They manually transcribed the interview verbatim into text and followed a thematic approach for data analysis. The researchers interviewed eight principals. The principals identified the prevalent caries status and importance of oral health promotion for kindergarten children. They acknowledged that the service enhanced dental knowledge, fostered oral hygiene practice and improved children’s oral health. To adopt this service, they needed to ensure adequate capacity to perform the service. They had no concern with staining by SDF because the parents were informed and consented to the SDF therapy. They appreciated the free service provided by a professional team managed by a reputable university. In conclusion, the principals were generally satisfied with the outreach dental service. They realised the necessity of oral health promotion. They found that parents accepted the SDF therapy although the SDF stained their children’s carious teeth. They needed support from their teachers and the children’s parents to run the service.
Spatial–Temporal Variations of Water Quality in Urban Rivers after Small Sluices Construction: A Case in Typical Regions of the Taihu Lake Basin
Authors: Lan Feng , Haisen Wang , Yan Yan
Published: September 2022

Urban river pollution is considered a ‘necessary evil’ consequence of disproportionate developmental expansion in metropolises. Unprecedented expansion and anthropic activities lead to the deterioration of urban rivers with municipal and industrial sewage. The construction of sluices is one of the irrefutable parts of the process. In order to prevent floods and drought, many cities build sluices and dams in rivers to balance water quantity in different seasons. To explore the change characteristics of the water quality in urban rivers after the construction of sluices and dams, the change in the total phosphorus (TP) and total nitrogen (TN) concentrations upstream and downstream of rivers was investigated under the condition of sluices closure in Wuxi. According to the results, when the sluices were closed, the pollutants of TP and TN would accumulate upstream in rivers, which caused the water quality in the upper reaches to be worse than that in the lower reaches. Specifically, the TN and TP concentrations downstream of urban rivers in Wuxi were approximately 14.42% and 13.80% lower than those upstream when the sluices were closed. Additionally, the water quality in urban rivers was usually better in summer and autumn than in the other seasons, showing obvious seasonality after the construction of the sluices. The research will provide a theoretical basis for future sluice operation and the water resources management of urban rivers.
Root-Related Genes in Crops and Their Application under Drought Stress Resistance—A Review
Authors: Qin Tianyuan , Kazim Ali , Wang Yihao , Richard Dormatey , Yao Panfeng , Bi Zhenzhen , Liu Yuhui , Sun Chao , Bai Jiangping
Published: September 2022

Crop growth and development are frequently affected by biotic and abiotic stresses. The adaptation of crops to stress is mostly achieved by regulating specific genes. The root system is the primary organ for nutrient and water uptake, and has an important role in drought stress response. The improvement of stress tolerance to increase crop yield potential and yield stability is a traditional goal of breeders in cultivar development using integrated breeding methods. An improved understanding of genes that control root development will enable the formulation of strategies to incorporate stress-tolerant genes into breeding for complex agronomic traits and provide opportunities for developing stress-tolerant germplasm. We screened the genes associated with root growth and development from diverse plants including Arabidopsis, rice, maize, pepper and tomato. This paper provides a theoretical basis for the application of root-related genes in molecular breeding to achieve crop drought tolerance by the improvement of root architecture.
Lipids Alterations Associated with Metformin in Healthy Subjects: An Investigation Using Mass Spectrometry Shotgun Approach
Authors: Dahabiyeh Lina A. , Mujammami Muhammad , AlMalki Reem H. , Arafat Tawfiq , Benabdelkamel Hicham , Alfadda Assim A. , Abdel Rahman Anas M.
Published: September 2022

Metformin is an orally effective insulin-sensitizing drug widely prescribed for treating type 2 diabetes mellitus (T2DM). Metformin has been reported to alter lipid metabolism. However, the molecular mechanisms behind its impact on lipid metabolism remain partially explored and understood. In the current study, mass spectrometry-based lipid profiling was used to investigate the lipidomic changes in the serum of 26 healthy individuals after a single-dose intake of metformin. Samples were analyzed at five-time points: preadministration, before the maximum concentration of metformin (Cmax), Cmax, after Cmax, and 36 h post-administration. A total of 762 molecules were significantly altered between the five-time points. Based on a comparison between baseline level and Cmax, metformin significantly increased and decreased the level of 33 and 192 lipids, respectively (FDR ≤ 0.05 and fold change cutoff of 1.5). The altered lipids are mainly involved in arachidonic acid metabolism, steroid hormone biosynthesis, and glycerophospholipid metabolism. Furthermore, several lipids acted in an opposed or similar manner to metformin levels and included fatty acyls, sterol lipids, glycerolipids, and glycerophospholipids. The significantly altered lipid species pointed to fundamental lipid signaling pathways that could be linked to the pleiotropic effects of metformin in T2DM, insulin resistance, polycystic ovary syndrome, cancer, and cardiovascular diseases.
Cardiac Mitochondria Dysfunction in Dyslipidemic Mice
Authors: Braczko Alicja , Kutryb-Zajac Barbara , Jedrzejewska Agata , Krol Oliwia , Mierzejewska Paulina , Zabielska-Kaczorowska Magdalena , Slominska Ewa M. , Smolenski Ryszard T.
Published: September 2022

Dyslipidemia triggers many severe pathologies, including atherosclerosis and chronic inflammation. Several lines of evidence, including our studies, have suggested direct effects of dyslipidemia on cardiac energy metabolism, but details of these effects are not clear. This study aimed to investigate how mild dyslipidemia affects cardiac mitochondria function and vascular nucleotide metabolism. The analyses were performed in 3- and 6-month-old knock-out mice for low-density lipoprotein receptor (Ldlr−/−) and compared to wild-type C57Bl/6J mice (WT). Cardiac isolated mitochondria function was analyzed using Seahorse metabolic flux analyzer. The mechanical function of the heart was measured using echocardiography. The levels of fusion, fission, and mitochondrial biogenesis proteins were determined by ELISA kits, while the cardiac intracellular nucleotide concentration and vascular pattern of nucleotide metabolism ecto-enzymes were analyzed using reverse-phase high-performance liquid chromatography. We revealed the downregulation of mitochondrial complex I, together with a decreased activity of citrate synthase (CS), reduced levels of nuclear respiratory factor 1 and mitochondrial fission 1 protein, as well as lower intracellular adenosine and guanosine triphosphates’ pool in the hearts of 6-month Ldlr−/− mice vs. age-matched WT. The analysis of vascular ecto-enzyme pattern revealed decreased rate of extracellular adenosine monophosphate hydrolysis and increased ecto-adenosine deaminase activity (eADA) in 6-month Ldlr−/− vs. WT mice. No changes were observed in echocardiography parameters in both age groups of Ldlr−/− mice. Younger hyperlipidemic mice revealed no differences in cardiac mitochondria function, CS activity, intracellular nucleotides, mitochondrial biogenesis, and dynamics but exhibited minor changes in vascular eADA activity vs. WT. This study revealed that dysfunction of cardiac mitochondria develops during prolonged mild hyperlipidemia at the time point corresponding to the formation of early vascular alterations.
SARS-CoV-2 Spatiotemporal Genomic and Molecular Analysis of the First Wave of the COVID-19 Pandemic in Macaé, the Brazilian Capital of Oil
Authors: da-Costa-Rodrigues Bruno , Cheohen Caio , Sciammarella Felipe , Pierre-Bonetti-Pozzobon Allan , Ribeiro Lupis , Nepomuceno-Silva José Luciano , Medeiros Marcio , Mury Flávia , Monteiro-de-Barros Cintia , Lazoski Cristiano , Leal-da-Silva Manuela , Tanuri Amilcar , Nunes-da-Fonseca Rodrigo
Published: September 2022

The SARS-CoV-2 virus infection led to millions of deaths during the COVID-19 pandemic. Hundreds of workers from several other Brazilian cities, as well as from other countries, arrive daily in Macaé to work in the oil supply chain, making this city a putative hotspot for the introduction of new viral lineages. In this study, we performed a genomic survey of SARS-CoV-2 samples from Macaé during the first outbreak of COVID-19, combined with clinical data and a molecular integrative analysis. First, phylogenomic analyses showed a high occurrence of viral introduction events and the establishment of local transmissions in Macaé, including the ingression and spread of the B.1.1.28 lineage in the municipality from June to August 2020. Second, SARS-CoV-2 mutations were identified in patients with distinct levels of COVID-19 severity. Third, molecular interactions of the mutated spike protein from three B.1.1.33 local samples and human ACE2 showed higher interactions than that of the wild-type spike protein from the ancestral virus. Altogether, these results elucidate the SARS-CoV-2 genomic profile in a strategic Brazilian city and further explore the functional aspects of SARS-CoV-2 with a characterization of emerging viral mutations associated with clinical data and the potential targets for drug development against SARS-CoV-2.
Increased Co-Occurrence of Pathogenic Variants in Hereditary Breast and Ovarian Cancer and Lynch Syndromes: A Consequence of Multigene Panel Genetic Testing?
Authors: Infante Mar , Arranz-Ledo Mónica , Lastra Enrique , Abella Luis Enrique , Ferreira Raquel , Orozco Marta , Hernández Lara , Martínez Noemí , Durán Mercedes
Published: September 2022

The probability of carrying two pathogenic variants (PVs) in dominant cancer-predisposing genes for hereditary breast and ovarian cancer and lynch syndromes in the same patient is uncommon, except in populations where founder effects exist. Two breast cancer women that are double heterozygotes (DH) for both BRCA1/BRCA2, one ovarian cancer case DH for BRCA1/RAD51C, and another breast and colorectal cancer who is DH for BRCA2/PMS2 were identified in our cohort. Ages at diagnosis and severity of disease in BRCA1/BRCA2 DH resembled BRCA1 single-carrier features. Similarly, the co-existence of the BRCA2 and PMS2 mutations prompted the development of breast and colorectal cancer in the same patient. The first BRCA1/BRCA2 DH was identified by HA-based and Sanger sequencing (1 of 623 families with BRCA PVs). However, this ratio has increased up to 2.9% (1 DH carrier vs. 103 single PV carriers) since using a custom 35-cancer gene on-demand panel. The type of cancer developed in each DH patient was consistent with the independently inherited condition, and the clinical outcome was no worse than in patients with single BRCA1 mutations. Therefore, the clinical impact, especially in patients with two hereditary syndromes, lies in genetic counseling tailor-made for each family based on the clinical guidelines for each syndrome. The number of DH is expected to be increased in the future as a result of next generation sequencing routines.
Prognostic Value of Albumin to Globulin Ratio in Non-Metastatic and Metastatic Prostate Cancer Patients: A Meta-Analysis and Systematic Review
Authors: Salciccia Stefano , Frisenda Marco , Bevilacqua Giulio , Viscuso Pietro , Casale Paolo , De Berardinis Ettore , Di Pierro Giovanni Battista , Cattarino Susanna , Giorgino Gloria , Rosati Davide , Del Giudice Francesco , Sciarra Alessandro , Mariotti Gianna , Gentilucci Alessandro
Published: September 2022

The aim of our meta-analysis is to analyze data available in the literature regarding a possible prognostic value of the albumin to globulin ratio (AGR) in prostate cancer (PC) patients. We distinguished our analysis in terms of PC staging, histologic aggressiveness, and risk of progression after treatments. A literature search process was performed (“prostatic cancer”, “albumin”, “globulin”, “albumin to globulin ratio”) following the PRISMA guidelines. In our meta-analysis, the pooled Event Rate (ER) estimate for each group of interest was calculated using a random effect model. Cases were distinguished in Low and High AGR groups based on an optimal cut-off value defined at ROC analysis. Four clinical trials were enclosed (sample size range from 214 to 6041 cases). The pooled Risk Difference for a non-organ confined PC between High AGR and Low AGR cases was −0.05 (95%CI: −0.12–0.01) with a very low rate of heterogeneity (I2 < 0.15%; p = 0.43) among studies (test of group differences p = 0.21). In non-metastatic PC cases, the pooled Risk Difference for biochemical progression (BCP) between High AGR and Low AGR cases was −0.05 (95%CI: −0.12–0.01) (I2 = 0.01%; p = 0.69) (test of group differences p = 0.12). In metastatic PC cases, AGR showed an independent significant (p < 0.01) predictive value either in terms of progression free survival (PFS) (Odds Ratio (OR): 0.642 (0.430–0.957)) or cancer specific survival (CSS) (OR: 0.412 (0.259–0.654)). Our meta-analysis showed homogeneous results supporting no significant predictive values for AGR in terms of staging, grading and biochemical progression in non-metastatic PC.
Characterization of Two Mouse Chd7 Heterozygous Loss-of-Function Models Shows Dysgenesis of the Corpus Callosum and Previously Unreported Features of CHARGE Syndrome
Authors: Collins Stephan C. , Vancollie Valerie E. , Mikhaleva Anna , Wagner Christel , Balz Rebecca , Lelliott Christopher J. , Yalcin Binnaz
Published: September 2022

CHARGE syndrome is a rare congenital disorder frequently caused by mutations in the chromodomain helicase DNA-binding protein-7 CHD7. Here, we developed and systematically characterized two genetic mouse models with identical, heterozygous loss-of-function mutation of the Chd7 gene engineered on inbred and outbred genetic backgrounds. We found that both models showed consistent phenotypes with the core clinical manifestations seen in CHARGE syndrome, but the phenotypes in the inbred Chd7 model were more severe, sometimes having reduced penetrance and included dysgenesis of the corpus callosum, hypoplasia of the hippocampus, abnormal retrosplenial granular cortex, ventriculomegaly, hyperactivity, growth delays, impaired grip strength and repetitive behaviors. Interestingly, we also identified previously unreported features including reduced levels of basal insulin and reduced blood lipids. We suggest that the phenotypic variation reported in individuals diagnosed with CHARGE syndrome is likely due to the genetic background and modifiers. Finally, our study provides a valuable resource, making it possible for mouse biologists interested in Chd7 to make informed choices on which mouse model they should use to study phenotypes of interest and investigate in more depth the underlying cellular and molecular mechanisms.
What Do the Transcriptome and Proteome of Menstrual Blood-Derived Mesenchymal Stem Cells Tell Us about Endometriosis?
Authors: Penariol Letícia B. C. , Thomé Carolina H. , Tozetti Patrícia A. , Paier Carlos R. K. , Buono Fabiana O. , Peronni Kamila C. , Orellana Maristela D. , Covas Dimas T. , Moraes Maria E. A. , Silva Wilson A. , Rosa-e-Silva Júlio C. , Ferriani Rui A. , Faça Vitor M. , Poli-Neto Omero B. , Tiezzi Daniel G. , Meola Juliana
Published: September 2022

Given the importance of menstrual blood in the pathogenesis of endometriosis and the multifunctional roles of menstrual mesenchymal stem cells (MenSCs) in regenerative medicine, this issue has gained prominence in the scientific community. Moreover, recent reviews highlight how robust the integrated assessment of omics data are for endometriosis. To our knowledge, no study has applied the multi-omics approaches to endometriosis MenSCs. This is a case-control study at a university-affiliated hospital. MenSCs transcriptome and proteome data were obtained by RNA-seq and UHPLC-MS/MS detection. Among the differentially expressed proteins and genes, we emphasize ATF3, ID1, ID3, FOSB, SNAI1, NR4A1, EGR1, LAMC3, and ZFP36 genes and MT2A, TYMP, COL1A1, COL6A2, and NID2 proteins that were already reported in the endometriosis. Our functional enrichment analysis reveals integrated modulating signaling pathways such as epithelial–mesenchymal transition (↑) and PI3K signaling via AKT to mTORC1 (↓ in proteome), mTORC1 signaling, TGF beta signaling, TNFA signaling via NFkB, IL6 STAT3 signaling, and response to hypoxia via HIF1A targets (↑ in transcriptome). Our findings highlight primary changes in the endometriosis MenSCs, suggesting that the chronic inflammatory endometrial microenvironment can modulate these cells, providing opportunities for endometriosis etiopathogenesis. Moreover, they identify challenges for future research leveraging knowledge for regenerative and precision medicine in endometriosis.
Experimental and Clinical Evidence Suggests That Treatment with Betacellulin Can Alleviate Th2-Type Cytokine-Mediated Impairment of Skin Barrier Function
Authors: Peng Ge , Tsukamoto Saya , Umehara Yoshie , Kishi Ryoma , Tominaga Mitsutoshi , Takamori Kenji , Okumura Ko , Ogawa Hideoki , Ikeda Shigaku , Niyonsaba François
Published: September 2022

Betacellulin (BTC) is a peptide ligand that belongs to the epidermal growth factor family, the members of which have been implicated in skin morphogenesis, homeostasis, repair, and angiogenesis; however, the role of BTC in the regulation of the skin barrier remains unknown. To examine the role of BTC in skin barrier function, we analyzed atopic dermatitis (AD) transcriptomic data from Gene Expression Omnibus (GEO) datasets, performed BTC immunohistochemistry using human skin tissues, and evaluated the effects of BTC on primary human keratinocytes by real-time PCR, Western blotting, and assay of the transepidermal electrical resistance (TER), a functional parameter to monitor the tight junction barrier. We found that the gene expression of BTC was downregulated in skin lesions from patients with AD, and this downregulated expression recovered following biological treatments. Consistently, the BTC protein levels were downregulated in the lesional skin of AD patients compared with the normal skin of healthy participants, suggesting that the BTC levels in skin might be a biomarker for the diagnosis and therapy of AD. Furthermore, in human keratinocytes, BTC knockdown reduced the levels of skin-derived antimicrobial peptides and skin barrier-related genes, whereas BTC addition enhanced their levels. Importantly, in human skin equivalents, BTC restored the increased tight junction permeability induced by Th2 cytokine IL-4/IL-13 treatment. In addition, specific inhibitors of epidermal growth factor receptor (EGFR) and protein kinase C (PKC) abolished the BTC-mediated improvement in skin barrier-related proteins in keratinocyte monolayers. Collectively, our findings suggest that treatment with BTC might improve the Th2-type cytokine-mediated impairment of skin barrier function through the EGFR/PKC axis and that BTC might be a novel potential biomarker and therapeutic target for the treatment of skin conditions characterized by the overproduction of Th2 cytokines and dysfunctional skin barriers, such as AD.
Tumor-Informed Approach Improved ctDNA Detection Rate in Resected Pancreatic Cancer
Authors: Watanabe Kazunori , Nakamura Toru , Kimura Yasutoshi , Motoya Masayo , Kojima Shigeyuki , Kuraya Tomotaka , Murakami Takeshi , Kaneko Tsukasa , Shinohara Yoshihito , Kitayama Yosuke , Fukuda Keito , Hatanaka Kanako C. , Mitsuhashi Tomoko , Pittella-Silva Fabio , Yamaguchi Toshikazu , Hirano Satoshi , Nakamura Yusuke , Low Siew-Kee
Published: September 2022

Pancreatic cancer is one of the cancers with very poor prognosis; there is an urgent need to identify novel biomarkers to improve its clinical outcomes. Circulating tumor DNA (ctDNA) from liquid biopsy has arisen as a promising biomarker for cancer detection and surveillance. However, it is known that the ctDNA detection rate in resected pancreatic cancer is low compared with other types of cancer. In this study, we collected paired tumor and plasma samples from 145 pancreatic cancer patients. Plasma samples were collected from 71 patients of treatment-naïve status and from 74 patients after neoadjuvant therapy (NAT). Genomic profiling of tumor DNA and plasma samples was conducted using targeted next-generation sequencing (NGS). Somatic mutations were detected in 85% (123/145) of tumors. ctDNA was detected in 39% (28/71) and 31% (23/74) of treatment-naïve and after-NAT groups, respectively, without referring to the information of tumor profiles. With a tumor-informed approach (TIA), ctDNA detection rate improved to 56% (40/71) and 36% (27/74) in treatment-naïve and after-NAT groups, respectively, with the detection rate significantly improved (p = 0.0165) among the treatment-naïve group compared to the after-NAT group. Cases who had detectable plasma ctDNA concordant to the corresponding tumor showed significantly shorter recurrence-free survival (RFS) (p = 0.0010). We demonstrated that TIA improves ctDNA detection rate in pancreatic cancer, and that ctDNA could be a potential prognostic biomarker for recurrence risk prediction
Directional Submicrofiber Hydrogel Composite Scaffolds Supporting Neuron Differentiation and Enabling Neurite Alignment
Authors: Mungenast Lena , Züger Fabian , Selvi Jasmin , Faia-Torres Ana Bela , Rühe Jürgen , Suter-Dick Laura , Gullo Maurizio R.
Published: September 2022

Cell cultures aiming at tissue regeneration benefit from scaffolds with physiologically relevant elastic moduli to optimally trigger cell attachment, proliferation and promote differentiation, guidance and tissue maturation. Complex scaffolds designed with guiding cues can mimic the anisotropic nature of neural tissues, such as spinal cord or brain, and recall the ability of human neural progenitor cells to differentiate and align. This work introduces a cost-efficient gelatin-based submicron patterned hydrogel–fiber composite with tuned stiffness, able to support cell attachment, differentiation and alignment of neurons derived from human progenitor cells. The enzymatically crosslinked gelatin-based hydrogels were generated with stiffnesses from 8 to 80 kPa, onto which poly(ε-caprolactone) (PCL) alignment cues were electrospun such that the fibers had a preferential alignment. The fiber–hydrogel composites with a modulus of about 20 kPa showed the strongest cell attachment and highest cell proliferation, rendering them an ideal differentiation support. Differentiated neurons aligned and bundled their neurites along the aligned PCL filaments, which is unique to this cell type on a fiber–hydrogel composite. This novel scaffold relies on robust and inexpensive technology and is suitable for neural tissue engineering where directional neuron alignment is required, such as in the spinal cord.
Improved Trimethylangelicin Analogs for Cystic Fibrosis: Design, Synthesis and Preliminary Screening
Authors: Vaccarin Christian , Gabbia Daniela , Franceschinis Erica , De Martin Sara , Roverso Marco , Bogialli Sara , Sacchetti Gianni , Tupini Chiara , Lampronti Ilaria , Gambari Roberto , Cabrini Giulio , Dechecchi Maria Cristina , Tamanini Anna , Marzaro Giovanni , Chilin Adriana
Published: September 2022

A small library of new angelicin derivatives was designed and synthesized with the aim of bypassing the side effects of trimethylangelicin (TMA), a promising agent for the treatment of cystic fibrosis. To prevent photoreactions with DNA, hindered substituents were inserted at the 4 and/or 6 positions. Unlike the parent TMA, none of the new derivatives exhibited significant cytotoxicity or mutagenic effects. Among the synthesized compounds, the 4-phenylderivative 12 and the 6-phenylderivative 25 exerted a promising F508del CFTR rescue ability. On these compounds, preliminary in vivo pharmacokinetic (PK) studies were carried out, evidencing a favorable PK profile per se or after incorporation into lipid formulations. Therefore, the selected compounds are good candidates for future extensive investigation to evaluate and develop novel CFTR correctors based on the angelicin structure.
Developmental Transcriptome Analysis of Red-Spotted Apollo Butterfly, Parnassius bremeri
Authors: Lee Kang-Woon , Denison Michael Immanuel Jesse , Veerappan Karpagam , Srinivasan Sridhar , Park Bohyeon , Natarajan Sathishkumar , Chung Hoyong , Park Junhyung
Published: September 2022

Parnassius bremeri (P. bremeri), a member of the genus Snow Apollo in the swallowtail family (Papilionidae), is a high alpine butterfly that lives in Russia, Korea, and China. It is an endangered wildlife (Class I) in South Korea and is a globally endangered species. The lack of transcriptomic and genomic resources of P. bremeri significantly hinders the study of its population genetics and conservation. The detailed information of the developmental stage-specific gene expression patterns of P. bremeri is of great demand for its conservation. However, the molecular mechanism underlying the metamorphic development of P. bremeri is still unknown. In the present study, the differentially expressed genes (DEGs) across the metamorphic developmental stages were compared using high-throughput transcriptome sequencing. We identified a total of 72,161 DEGs from eight comparisons. GO enrichment analysis showed that a range of DEGs were responsible for cuticle development and the melanin biosynthetic pathway during larval development. Pathway analysis suggested that the signaling pathways, such as the Wnt signaling pathway, hedgehog signaling pathway and Notch signaling pathway, are regulated during the developmental stages of P. bremeri. Furthermore, sensory receptors were also activated, especially during the larval to adult transition stage. Collectively, the results of this study provide a preliminary foundation and understanding of the molecular mechanism in their transcriptomes for further research on the metamorphic development of P. bremeri.
Rho/SRF Inhibitor Modulates Mitochondrial Functions
Authors: Patyal Pankaj , Nguyen Bachkhoa , Zhang Xiaomin , Azhar Gohar , Ameer Fathima S. , Verma Ambika , Crane Jasmine , KC Grishma , Che Yingni , Wei Jeanne Y.
Published: September 2022

CCG-1423 is a Rho A pathway inhibitor that has been reported to inhibit Rho/SRF-mediated transcriptional regulation. Serum response factor and its cofactors, which include ternary complex factors and myocardin-related transcription factors, regulate various cellular functions. In this study, we observed that CCG-1423 modulates the mitochondrial functions. The effect of this small molecule drug was determined by measuring mitochondrial function using an XFe96 Analyzer and an Oxygraph 2k (O2k) high-resolution respirometer. CCG-1423 treatment significantly reduced oxidative phosphorylation in a dose-dependent manner. However, CCG-1423 increased the glycolytic rate. We also observed that histone 4 at lysine-16 underwent hyperacetylation with the treatment of this drug. Immunolabeling with F-actin and MitoTracker revealed the alteration in the actin cytoskeleton and mitochondria. Taken together, our findings highlight a critical role of CCG-1423 in inhibiting the transcription of SRF/p49 and PGC-1α, β, resulting in the downregulation of mitochondrial genes, leading to the repression of mitochondrial oxidative phosphorylation and overall ATP reduction. This study provides a better understanding of the effects of CCG-1423 on mitochondria, which may be useful for the assessment of the potential clinical application of CCG-1423 and its derivatives.
Oligonucleotide-Recognizing Topoisomerase Inhibitors (OTIs): Precision Gene Editors for Neurodegenerative Diseases?
Authors: Bax Ben D. , Sutormin Dmitry , McDonald Neil Q. , Burley Glenn A. , Shelkovnikova Tatyana
Published: September 2022

Topoisomerases are essential enzymes that recognize and modify the topology of DNA to allow DNA replication and transcription to take place. Topoisomerases are divided into type I topoisomerases, that cleave one DNA strand to modify DNA topology, and type II, that cleave both DNA strands. Topoisomerases normally rapidly religate cleaved-DNA once the topology has been modified. Topoisomerases do not recognize specific DNA sequences, but actively cleave positively supercoiled DNA ahead of transcription bubbles or replication forks, and negative supercoils (or precatenanes) behind, thus allowing the unwinding of the DNA-helix to proceed (during both transcription and replication). Drugs that stabilize DNA-cleavage complexes with topoisomerases produce cytotoxic DNA damage and kill fast-dividing cells; they are widely used in cancer chemotherapy. Oligonucleotide-recognizing topoisomerase inhibitors (OTIs) have given drugs that stabilize DNA-cleavage complexes specificity by linking them to either: (i) DNA duplex recognizing triplex forming oligonucleotide (TFO-OTIs) or DNA duplex recognizing pyrrole-imidazole-polyamides (PIP-OTIs) (ii) or by conventional Watson–Crick base pairing (WC-OTIs). This converts compounds from indiscriminate DNA-damaging drugs to highly specific targeted DNA-cleaving OTIs. Herein we propose simple strategies to enable DNA-duplex strand invasion of WC-OTIs giving strand-invading SI-OTIs. This will make SI-OTIs similar to the guide RNAs of CRISPR/Cas9 nuclease bacterial immune systems. However, an important difference between OTIs and CRISPR/Cas9, is that OTIs do not require the introduction of foreign proteins into cells. Recent successful oligonucleotide therapeutics for neurodegenerative diseases suggest that OTIs can be developed to be highly specific gene editing agents for DNA lesions that cause neurodegenerative diseases.