bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic screening in a Brazilian cohort with inborn errors of immunity
Authors: Ferreira Cristina Santos , Francisco Junior Ronaldo da Silva , Gerber Alexandra Lehmkuhl , Guimarães Ana Paula de Campos , de Carvalho Flavia Amendola Anisio , dos Reis Bárbara Carvalho Santos , Pinto-Mariz Fernanda , de Souza Monica Soares , de Vasconcelos Zilton Farias Meira , Goudouris Ekaterini Simões , Vasconcelos Ana Tereza Ribeiro 
Published: August 2023

Abstract
Background
Inherited genetic defects in immune system-related genes can result in Inborn Errors of Immunity (IEI), also known as Primary Immunodeficiencies (PID). Diagnosis of IEI disorders is challenging due to overlapping clinical manifestations. Accurate identification of disease-causing germline variants is crucial for appropriate treatment, prognosis, and genetic counseling. However, genetic sequencing is challenging in low-income countries like Brazil. This study aimed to perform genetic screening on patients treated within Brazil's public Unified Health System to identify candidate genetic variants associated with the patient’s phenotype.

Methods
Thirteen singleton unrelated patients from three hospitals in Rio de Janeiro were enrolled in this study. Genomic DNA was extracted from the peripheral blood lymphocytes of each patient, and whole exome sequencing (WES) analyses were conducted using Illumina NextSeq. Germline genetic variants in IEI-related genes were prioritized using a computational framework considering their molecular consequence in coding regions; minor allele frequency ≤ 0.01; pathogenicity classification based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines gathered from the VarSome clinical database; and IEI-related phenotype using the Franklin tool. The genes classification into IEI categories follows internationally recognized guidelines informed by the International Union of Immunological Societies Expert Committee. Additional methods for confirmation of the variant included Sanger sequencing, phasing analysis, and splice site prediction.

Results
A total of 16 disease-causing variants in nine genes, encompassing six different IEI categories, were identified. X-Linked Agammaglobulinemia, caused by BTK variations, emerged as the most prevalent IEI disorder in the cohort. However, pathogenic and likely pathogenic variants were also reported in other known IEI-related genes, namely CD40LG, CARD11, WAS, CYBB, C6, and LRBA. Interestingly, two patients with suspected IEI exhibited pathogenic variants in non-IEI-related genes, ABCA12 and SLC25A13, potentially explaining their phenotypes.

Conclusions
Genetic screening through WES enabled the detection of potentially harmful variants associated with IEI disorders. These findings contribute to a better understanding of patients' clinical manifestations by elucidating the genetic basis underlying their phenotypes.
Trade-off in genome turnover events leading to adaptive evolution of Microcystis aeruginosa species complex
Authors: Zhang Xian , Xiao Lijun , Liu Jiahui , Tian Qibai , Xie Jiaqi 
Published: August 2023

Abstract
Background
Numerous studies in the past have expanded our understanding of the genetic differences of global distributed cyanobacteria that originated around billions of years ago, however, unraveling how gene gain and loss drive the genetic evolution of cyanobacterial species, and the trade-off of these evolutionary forces are still the central but poorly understood issues.

Results
To delineate the contribution of gene flow in mediating the hereditary differentiation and shaping the microbial evolution, a global genome-wide study of bloom-forming cyanobacterium, Microcystis aeruginosa species complex, provided robust evidence for genetic diversity, reflected by enormous variation in gene repertoire among various strains. Mathematical extrapolation showed an ‘open’ microbial pan-genome of M. aeruginosa species, since novel genes were predicted to be introduced after new genomes were sequenced. Identification of numerous horizontal gene transfer’s signatures in genome regions of interest suggested that genome expansion via transformation and phage-mediated transduction across bacterial lineage as an evolutionary route may contribute to the differentiation of Microcystis functions (e.g., carbohydrate metabolism, amino acid metabolism, and energy metabolism). Meanwhile, the selective loss of some dispensable genes at the cost of metabolic versatility is as a mean of adaptive evolution that has the potential to increase the biological fitness.

Conclusions
Now that the recruitment of novel genes was accompanied by a parallel loss of some other ones, a trade-off in gene content may drive the divergent differentiation of M. aeruginosa genomes. Our study provides a genetic framework for the evolution of M. aeruginosa species and illustrates their possible evolutionary patterns.
Dementia awareness among elderly at risk for developing mild cognitive impairment: a cross sectional study at a university-based primary care clinic
Authors: Ali Mohd Fairuz , Ja’afar Nur Iman Suraiya , Krishnan Thayaletchumy Gophala , Zulkifle Mohamad Azizi Mohamad , Khaidzir Nur Khairunnisa , Jamil Teh Rohila , Man Zuraidah Che , Aziz Aznida Firzah Abdul 
Published: August 2023

Abstract
Background
The number of people living with dementia in Malaysia is expected to increase with the nation’s growing elderly population and increased lifespan. The lack of public awareness of dementia is partly compounded by low personal health literacy, while scarce research on local patient awareness further impacts the execution of optimised healthcare services in Malaysia. Patients with chronic disease have an elevated risk of developing mild cognitive impairment (MCI). This study aimed to assess the level of awareness of basic knowledge on dementia among the elderly, especially those at risk of developing mild cognitive impairment and its associated factors.

Methods
A total of 207 elderly patients aged 60 years and above with chronic diseases attending a university-based primary care clinic were recruited via a systematic randomised sampling method from the clinic patient attendance registry. Respondents were assessed using self-administered online questionnaires distributed via mobile devices. The questionnaire assessed awareness, i.e. ability to correctly answer a self-reported questionnaire on basic dementia knowledge; (adapted from Northern Ireland Life and Times Survey 2010), risk of MCI; (using Towards Useful Aging (TUA)-WELLNESS screening questionnaire) and help-seeking behaviour. Bivariate analysis was used to determine factors associated with dementia awareness.

Results
The response rate was 77.1%, with the majority of participants were females, Chinese and had secondary school education. 39.1% of participants were categorised as high risk of developing MCI. The majority (92.8%) had low dementia awareness and had never shared their concerns regarding dementia (93.2%) nor had any discussion (87.0%) on cognitive impairment with their physicians. Three factors had an association with total dementia awareness score, i.e., younger age group, higher risk of MCI and presence of cardiovascular diseases have significantly lower awareness score (p < 0.05).

Conclusion
Awareness of dementia is low among elderly patients with potentially high risk of developing MCI. Efforts to improve awareness on dementia should focus on primary care doctors engaging with at-risk elderly patients to initiate discussion regarding dementia risk while managing modifiable risk factors i.e. hypertension control, diabetes, dyslipidaemia and obesity.
Combined influence of depression and low-grade inflammation on mortality in peritoneal dialysis patients
Authors: Zhang Yanxia , Chen Jiexin , Tang Ruiying , Deng Jihong , Guo Huankai , Wu Xianfeng , Xu Qingdong 
Published: August 2023

Abstract
Background
The relationship between depression and systemic inflammation as risk factors for mortality is not well understood and requires further investigation.

Methods
Patients undergoing continuous ambulatory peritoneal dialysis (CAPD) between July 01, 2015 to December 31, 2019, were analyzed and followed up until December 31, 2020. According to their status of depression (PHQ-9 score ≥ 5) and low-grade inflammation (hs-CRP level ≥ 3 mg/L), patients were divided into four groups (G1, without depression, nor inflammation; G2, with depression, without inflammation; G3, with inflammation, without depression; G4, with both depression and inflammation). We performed Kaplan–Meier and multivariable Cox proportional analyses of mortality for the combined influence of depression and systemic inflammation in this cohort.

Results
During the mean follow-up of 36.3 ± 14.8 months, 73 deaths were recorded in 358 participants. Compared with patients in group G1, patients in group G2 and G3 carried 137% {hazard ratio (HR): 2.37, 95% confidence interval (CI): 1.06—5.23, p = 0.035} and 140% (HR: 2.40, 95% CI: 1.01—5.69, p = 0.048) higher risk of mortality. Patients in group G4 (with both depression and inflammation) showed the highest risks of all-cause mortality with 276% higher mortality risk (HR: 3.76, 95% CI: 1.73—8.15, p = 0.001), respectively.

Conclusion
The combined of depression and inflammation is associated with all-cause mortality in peritoneal dialysis patients, suggesting a need for further study of depression and low-grade inflammation in PD patients and potential relationship between them.
The effects of environmental factors associated with childhood urbanicity on brain structure and cognition
Authors: Zhang Xiao , Yan Hao , Yu Hao , Zhang Yuyanan , Tan Hao Yang , Zhang Dai , Yue Weihua 
Published: August 2023

AbstractUrbanization is a trend lasting for more than one century worldwide. Four hundred ninety male and female adult Chinese Han participants with different urban and rural childhoods were included in this study. Early-life urban environment was found benefit for total grey matter volume (GMV), dorsolateral prefrontal cortex (DLPFC) GMV, temporal pole (TP) GMV and cognition function, and negatively correlated with medial prefrontal cortex (MPFC) GMV. Regression analysis showed that maternal education was a protective factor for total and DLPFC GMVs, while having siblings was better for MPFC GMV. Total, DLPFC and TP GMVs acts mediation effects between childhood urbanicity and different cognitive domains. These findings may suggest some pros and cons on brain structure associated with childhood urbanicity and related environmental factors.
Experiences of Egypt as a destination and transit country for Syrian refugee healthcare workers: a qualitative study
Authors: Ghobrial Andrew , Rayes Diana , Sabouni Ammar , Bdaiwi Yamama , Janoudi Saad , Howard Natasha , Abbara Aula 
Published: August 2023

Abstract
Background
Refugee healthcare workers (HCWs) can make important contributions in host countries, particularly in the wake of the ongoing COVID-19 pandemic, which has exacerbated existing shortages of frontline HCWs. However, refugee HCWs often face challenges entering the labour markets of such countries even where needs exist. Syria’s decade-long conflict has forced thousands of HCWs from their homes; however, data on this population are limited, impeding the formation of policies that can support them. This study explores the experiences of Syrian refugee HCWs in Egypt.

Methods
Key informants (KIs) were selected using purposive and snowball sampling method and semi-structured interviews were conducted in person in Cairo and remotely from the UK during July 2019. Interviews were conducted in Arabic and analysed using a combined deductive and inductive thematic analysis framework after transcription into English.

Results
Fifteen KI interviews were analysed. The main emerging themes from the qualitative interviews are those relating to 1. Education, training, and licensing 2. Politics and bureaucracy 3. Societal factors 4. Economic factors. Political changes in Egypt altered opportunities for Syrian HCWs over time; however, refugee HCWs broadly reported acceptance among Egyptian patients and colleagues. Bureaucratic factors which impede the ability of Syrian refugee HCWs to obtain a full license to practice and leave to remain and the absence of clearly defined policies were reported as barriers. Economic factors including the risk of economic exploitation e.g. in the informal sector and financial insecurity were noted to have a negative psychosocial impact.

Conclusions
This is the first qualitative research study which explores the experiences of Syrian refugee HCWs in Egypt. It adds to the sparse literature on the topic of Syrian refugee HCWs but provides evidence for further discussions on how to support refugee HCWs in Egypt and in other host countries in the region. Though interviews were conducted before the COVID-19 pandemic, the pandemic itself lends urgency to the discussion around refugee HCWs on an international level.
Early vascular aging as an index of cardiovascular risk in healthy adults: confirmatory factor analysis from the EVasCu study
Authors: Saz-Lara Alicia , Cavero-Redondo Iván , Pascual-Morena Carlos , Martínez-García Irene , Rodríguez-Gutiérrez Eva , Lucerón-Lucas-Torres Maribel , Bizzozero-Peroni Bruno , Moreno-Herráiz Nerea , Martínez-Rodrigo Arturo 
Published: August 2023

Abstract
Background
The concept of early vascular aging (EVA) represents a potentially beneficial model for future research into the pathophysiological mechanisms underlying the early manifestations of cardiovascular disease. For this reason, the aims of this study were to verify by confirmatory factor analysis the concept of EVA on a single factor based on vascular, clinical and biochemical parameters in a healthy adult population and to develop a statistical model to estimate the EVA index from variables collected in a dataset to classify patients into different cardiovascular risk groups: healthy vascular aging (HVA) and EVA.

Methods
The EVasCu study, a cross-sectional study, was based on data obtained from 390 healthy adults. To examine the construct validity of a single-factor model to measure accelerated vascular aging, different models including vascular, clinical and biochemical parameters were examined. In addition, unsupervised clustering techniques (using both K-means and hierarchical methods) were used to identify groups of patients sharing similar characteristics in terms of the analysed variables to classify patients into different cardiovascular risk groups: HVA and EVA.

Results
Our data show that a single-factor model including pulse pressure, glycated hemoglobin A1c, pulse wave velocity and advanced glycation end products shows the best construct validity for the EVA index. The optimal value of the risk groups to separate patients is K = 2 (HVA and EVA).

Conclusions
The EVA index proved to be an adequate model to classify patients into different cardiovascular risk groups, which could be valuable in guiding future preventive and therapeutic interventions.
The tyrosine kinase inhibitor Dasatinib reduces cardiac steatosis and fibrosis in obese, type 2 diabetic mice
Authors: Gu Yue , Avolio Elisa , Alvino Valeria V , Thomas Anita C , Herman Andrew , Miller Poppy J , Sullivan Niall , Faulkner Ashton , Madeddu Paolo 
Published: August 2023

Abstract
Background
Cardiac steatosis is an early yet overlooked feature of diabetic cardiomyopathy. There is no available therapy to treat this condition. Tyrosine kinase inhibitors (TKIs) are used as first or second-line therapy in different types of cancer. In cancer patients with diabetes mellitus, TKIs reportedly improved glycemic control, allowing insulin discontinuation. They also reduced liver steatosis in a murine model of non-alcoholic fatty liver disease. The present study aimed to determine the therapeutic effect of the second-generation TKI Dasatinib on lipid accumulation and cardiac function in obese, type 2 diabetic mice. We also assessed if the drug impacts extra-cardiac fat tissue depots.

Methods
Two studies on 21-week-old male obese leptin receptor mutant BKS.Cg-+Leprdb/+Leprdb/OlaHsd (db/db) mice compared the effect of Dasatinib (5 mg/kg) and vehicle (10% DMSO + 90% PEG-300) given via gavage once every three days for a week or once every week for four weeks. Functional and volumetric indices were studied using echocardiography. Post-mortem analyses included the assessment of fat deposits and fibrosis using histology, and senescence using immunohistochemistry and flow cytometry. The anti-adipogenic action of Dasatinib was investigated on human bone marrow (BM)-derived mesenchymal stem cells (MSCs). Unpaired parametric or non-parametric tests were used to compare two and multiple groups as appropriate.

Results
Dasatinib reduced steatosis and fibrosis in the heart of diabetic mice. The drug also reduced BM adiposity but did not affect other fat depots. These structural changes were associated with improved diastolic indexes, specifically the E/A ratio and non-flow time. Moreover, Dasatinib-treated mice had lower levels of p16 in the heart compared with vehicle-treated controls, suggesting an inhibitory impact of the drug on the senescence signalling pathway. In vitro, Dasatinib inhibited human BM-MSC viability and adipogenesis commitment.

Conclusions
Our findings suggest that Dasatinib opposes heart and BM adiposity and cardiac fibrosis. In the heart, this was associated with favourable functional consequences, namely improvement in an index of diastolic function. Repurposing TKI for cardiac benefit could address the unmet need of diabetic cardiac steatosis.
Kinetics of COVID-19 mRNA primary and booster vaccine-associated neutralizing activity against SARS-CoV-2 variants of concern in long-term care facility residents: a prospective longitudinal study in Japan
Authors: Kakugawa Tomoyuki , Doi Keiko , Ohteru Yuichi , Kakugawa Hiroyuki , Oishi Keiji , Kakugawa Masahiro , Hirano Tsunahiko , Mimura Yusuke , Matsunaga Kazuto 
Published: August 2023

Abstract
Background
Coronavirus disease 2019 (COVID-19) remains a threat to vulnerable populations such as long-term care facility (LTCF) residents, who are often older, severely frail, and have multiple comorbidities. Although associations have been investigated between COVID-19 mRNA vaccine immunogenicity, durability, and response to booster vaccination and chronological age, data on the association of clinical factors such as performance status, nutritional status, and underlying comorbidities other than chronological age are limited. Here, we evaluated the anti-spike IgG level and neutralizing activity against the wild-type virus and Delta and Omicron variants in the sera of LTCF residents, outpatients, and healthcare workers before the primary vaccination; at 8, 12, and 24 weeks after the primary vaccination; and approximately 3 months after the booster vaccination. This 48-week prospective longitudinal study was registered in the UMIN Clinical Trials Registry (Trial ID: UMIN000043558).

Results
Of 114 infection-naïve participants (64 LTCF residents, 29 outpatients, and 21 healthcare workers), LTCF residents had substantially lower anti-spike IgG levels and neutralizing activity against the wild-type virus and Delta variant than outpatients and healthcare workers over 24 weeks after the primary vaccination. In LTCF residents, booster vaccination elicited neutralizing activity against the wild-type virus and Delta variant comparable to that in outpatients, whereas neutralizing activity against the Omicron variant was comparable to that in outpatients and healthcare workers. Multiple regression analyses showed that age was negatively correlated with anti-spike IgG levels and neutralizing activity against the wild-type virus and Delta variant after the primary vaccination. However, multivariate regression analysis revealed that poor performance status and hypoalbuminemia were more strongly associated with a lower humoral immune response than age, number of comorbidities, or sex after primary vaccination. Booster vaccination counteracted the negative effects of poor performance status and hypoalbuminemia on the humoral immune response.

Conclusions
LTCF residents exhibited suboptimal immune responses following primary vaccination. Although older age is significantly associated with a lower humoral immune response, poor performance status and hypoalbuminemia are more strongly associated with a lower humoral immune response after primary vaccination. Thus, booster vaccination is beneficial for older adults, especially those with a poor performance status and hypoalbuminemia.
Combinatorial engineering of betalain biosynthesis pathway in yeast Saccharomyces cerevisiae
Authors: Babaei Mahsa , Thomsen Philip Tinggaard , Dyekjær Jane Dannow , Glitz Christiane Ursula , Pastor Marc Cernuda , Gockel Peter , Körner Johann Dietmar , Rago Daniela , Borodina Irina 
Published: August 2023

Abstract
Background
Betalains, comprising red–violet betacyanins and yellow–orange betaxanthins, are the hydrophilic vacuolar pigments that provide bright coloration to roots, fruits, and flowers of plants of the Caryophyllales order. Betanin extracted from red beets is permitted quantum satis as a natural red food colorant (E162). Due to antioxidant activity, betanin has potential health benefits.

Results
We applied combinatorial engineering to find the optimal combination of a dozen tyrosine hydroxylase (TyH) and 4,5-dopa-estradiol-dioxygenase (DOD) variants. The best-engineered Saccharomyces cerevisiae strains produced over six-fold higher betaxanthins than previously reported. By genome-resequencing of these strains, we found out that two copies of DOD enzyme from Bougainvillea glabra together with TyH enzymes from Abronia nealleyi, Acleisanthes obtusa, and Cleretum bellidiforme were present in the three high-betaxanthin-producing isolates. Next, we expressed four variants of glucosyltransferases from Beta vulgaris for betanin biosynthesis. The highest titer of betanin (30.8 ± 0.14 mg/L after 48 h from 20 g/L glucose) was obtained when completing the biosynthesis pathway with UGT73A36 glucosyltransferase from Beta vulgaris. Finally, we investigated betalain transport in CEN.PK and S288C strains of Saccharomyces cerevisiae and identified a possible role of transporter genes QDR2 and APL1 in betanin transport.

Conclusions
This study shows the potential of combinatorial engineering of yeast cell factories for the biotechnological production of betanin.