bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma phosphate and all-cause mortality in individuals with and without type 2 diabetes: the Dutch population-based lifelines cohort study
Authors: van der Vaart Amarens , Cai Qingqing , Nolte Ilja M. , van Beek André P. J. , Navis Gerjan , Bakker Stephan J. L. , van Dijk Peter R. , de Borst Martin H. 
Published: April 2022

Abstract
Introduction
Individuals with type 2 diabetes have a substantially elevated cardiovascular risk. A higher plasma phosphate level promotes vascular calcification, which may adversely affect outcomes in individuals with type 2 diabetes. We hypothesized that the association between plasma phosphate and all-cause mortality is stronger in individuals with type 2 diabetes, compared to those without diabetes.

Methods
We analysed the association between plasma phosphate and all-cause mortality in the Dutch population-based Lifelines cohort and in subgroups with and without type 2 diabetes, using multivariable Cox regression adjusted for potential confounders. Effect modification was tested using multiplicative interaction terms.

Results
We included 57,170 individuals with 9.4 [8.8–10.4] years follow-up. Individuals within the highest phosphate tertile (range 1.00–1.83 mmol/L) were at higher risk of all-cause mortality (fully adjusted HR 1.18 [95% CI 1.02–1.36], p = 0.02), compared with the intermediate tertile (range 0.85–0.99 mmol/L). We found significant effect modification by baseline type 2 diabetes status (p-interaction = 0.003). Within the type 2 diabetes subgroup (N = 1790), individuals within the highest plasma phosphate tertile had an increased mortality risk (HR 1.73 [95% CI 1.10–2.72], p = 0.02 vs intermediate tertile). In individuals without diabetes at baseline (N = 55,380), phosphate was not associated with mortality (HR 1.12 [95% CI 0.96–1.31], p = 0.14). Results were similar after excluding individuals with eGFR < 60 mL/min/1.73 m2.

Discussion
High-normal plasma phosphate levels were associated with all-cause mortality in individuals with type 2 diabetes. The association was weaker and non-significant in those without diabetes. Measurement of phosphate levels should be considered in type 2 diabetes; whether lowering phosphate levels can improve health outcomes in diabetes requires further study.
Cell type-specific response of colon cancer tumor cell lines to oncolytic HSV-1 virotherapy in hypoxia
Authors: Shayan Sara , Arashkia Arash , Bahramali Golnaz , Abdoli Asghar , Nosrati Mohammad Sadegh Shams , Azadmanesh Kayhan 
Published: April 2022

AbstractBackgroundNovel strategies are required since the hypoxic tumor microenvironment is one of the important impediments for conventional cancer therapy. High mobility group box 1 (HMGB1) protein can block aerobic respiration in cancer cells. We hypothesized that HMGB1could also kill the colorectal cancer cells during hypoxia.MethodsIn this study, we developed oncolytic herpes simplex virus type 1 expressing HMGB1 protein (HSV-HMGB1) and investigated the cytotoxic effect of HSV-HMGB1 and its parental virus (HSV-ble) on three colorectal cancer cells (HCT116, SW480, and HT29) under normoxic (20% oxygen) and hypoxic (1% oxygen) conditions. We further identified potential autophagy- related genes in HT29 cells by retrieving mRNA expression microarray datasets from the Gene Expression Omnibus database. These genes were then detected in HT29 cells infected with HSV-HMGB1 and HSV-ble during normoxia and hypoxia by Real-Time quantitative PCR (qRT-PCR).ResultsThe cytotoxic effect of HSV-HMGB1 was significantly higher than that of HSV-ble during normoxia; however, during hypoxia, HSV-HMGB1 enhanced the viability of HT29 cells at MOI 0.1. Analyzing the cell death pathway revealed that HSV-HMGB1 induced autophagy in HT29 cells under hypoxic conditions.ConclusionIn conclusion, it appears that oncolytic virotherapy is cell context-dependent. Therefore, understanding the cancer cells’ characteristics, microenvironment, and cell signaling are essential to improve the therapeutic strategies.
Epidemic malaria dynamics in Ethiopia: the role of self-limiting, poverty, HIV, climate change and human population growth
Authors: Krsulovic Felipe Augusto Maurin , Moulton Timothy Peter , Lima Mauricio , Jaksic Fabian 
Published: April 2022

Abstract
Background
During the last two decades, researchers have suggested that the changes of malaria cases in African highlands were driven by climate change. Recently, a study claimed that the malaria cases (Plasmodium falciparum) in Oromia (Ethiopia) were related to minimum temperature. Critics highlighted that other variables could be involved in the dynamics of the malaria. The literature mentions that beyond climate change, trends in malaria cases could be involved with HIV, human population size, poverty, investments in health control programmes, among others.

Methods
Population ecologists have developed a simple framework, which helps to explore the contributions of endogenous (density-dependent) and exogenous processes on population dynamics. Both processes may operate to determine the dynamic behaviour of a particular population through time. Briefly, density-dependent (endogenous process) occurs when the per capita population growth rate (R) is determined by the previous population size. An exogenous process occurs when some variable affects another but is not affected by the changes it causes. This study explores the dynamics of malaria cases (Plasmodium falciparum and Plasmodium vivax) in Oromia region in Ethiopia and explores the interaction between minimum temperature, HIV, poverty, human population size and social instability.

Results
The results support that malaria dynamics showed signs of a negative endogenous process between R and malaria infectious class, and a weak evidence to support the climate change hypothesis.

Conclusion
Poverty, HIV, population size could interact to force malaria models parameters explaining the dynamics malaria observed at Ethiopia from 1985 to 2007.
Long noncoding RNA TLNC1 promotes the growth and metastasis of liver cancer via inhibition of p53 signaling
Authors: Yuan Kefei , Lan Jiang , Xu Lin , Feng Xuping , Liao Haotian , Xie Kunlin , Wu Hong , Zeng Yong 
Published: April 2022

Abstract
Background
Long non-coding RNAs (lncRNAs) have been demonstrated to play vital roles in cancer development and progression. However, their biological roles and function mechanisms in liver cancer remain largely unknown.

Methods
RNA-seq was performed with clinical hepatoma tissues and paired adjacent normal liver tissues to identify differentially expressed lncRNAs. qPCR was utilized to examine the expression levels of lncRNAs. We studied the function of TLNC1 in cell growth and metastasis of hepatoma with both cell and mouse models. RNA-seq, RNA pull-down coupled with mass spectrometry, RNA immunoprecipitation, dual luciferase reporter assay, and surface plasmon resonance analysis were used to analyze the functional mechanism of TLNC1.

Results
Based on the intersection of our own RNA-seq, TCGA RNA-seq, and TCGA survival analysis data, TLNC1 was identified as a potential tumorigenic lncRNA of liver cancer. TLNC1 significantly enhanced the growth and metastasis of hepatoma cells both in vitro and in vivo. TLNC1 exerted its tumorigenic function through interaction with TPR and inducing the TPR-mediated transportation of p53 from nucleus to cytoplasm, thus repressing the transcription of p53 target genes and finally contributing to the progression of liver cancer.

Conclusions
TLNC1 is a promising prognostic factor of liver cancer, and the TLNC1-TPR-p53 axis can serve as a potential therapeutic target for hepatoma treatment.
A critical review of definitions of rural areas in Indonesia and implications for health workforce policy and research
Authors: Putri Likke Prawidya , Russell Deborah Jane , O’Sullivan Belinda Gabrielle , Meliala Andreasta , Kippen Rebecca 
Published: April 2022

Abstract
Background
Choosing the appropriate definition of rural area is critical to ensuring health resources are carefully targeted to support the communities needing them most. This study aimed at reviewing various definitions and demonstrating how the application of different rural area definitions implies geographic doctor distribution to inform the development of a more fit-for-purpose rural area definition for health workforce research and policies.

Methods
We reviewed policy documents and literature to identify the rural area definitions in Indonesian health research and policies. First, we used the health policy triangle to critically summarize the contexts, contents, actors and process of developing the rural area definitions. Then, we compared each definition’s strengths and weaknesses according to the norms of appropriate rural area definitions (i.e. explicit, meaningful, replicable, quantifiable and objective, derived from high-quality data and not frequently changed; had on-the-ground validity and clear boundaries). Finally, we validated the application of each definition to describe geographic distribution of doctors by estimating doctor-to-population ratios and the Theil-L decomposition indices using each definition as the unit of analysis.

Results
Three definitions were identified, all applied at different levels of geographic areas: “urban/rural” villages (Central Bureau of Statistics [CBS] definition), “remote/non-remote” health facilities (Ministry of Health [MoH] definition) and “less/more developed” districts (presidential/regulated definition). The CBS and presidential definitions are objective and derived from nationwide standardized calculations on high-quality data, whereas the MoH definition is more subjective, as it allows local government to self-nominate the facilities to be classified as remote. The CBS and presidential definition criteria considered key population determinants for doctor availability, such as population density and economic capacity, as well as geographic accessibility. Analysis of national doctor data showed that remote, less developed and rural areas (according to the respective definitions) had lower doctor-to-population ratios than their counterparts. In all definitions, the Theil-L-within ranged from 76 to 98%, indicating that inequality of doctor density between these districts was attributed mainly to within-group rather than between-group differences. Between 2011 and 2018, Theil-L-within decreased when calculated using the MoH and presidential definitions, but increased when the CBS definition was used.

Conclusion
Comparing the content of off-the-shelf rural area definitions critically and how the distribution of health resource differs when analysed using different definitions is invaluable to inform the development of fit-for-purpose rural area definitions for future health policy.
Unusual presentation of primary ovarian diffuse large B-cell lymphoma: a case report
Authors: Luo Bin , He Rong-quan , Peng Zhi-gang , Ma Jie , Feng Zhen-bo , Chen Gang , Zeng Jing-jing 
Published: April 2022

Abstract
Background
Primary ovarian lymphoma has been difficult to diagnose clinically and pathologically due to its rare incidence and non-specific clinical symptoms.

Case presentation
A 75-year-old female patient was reported in this study. The patient had a six-month history of changes in bowel habits, with occasional black feces and paroxysmal pain in the abdomen. The computed tomography scan of the pelvic cavity illustrated that rectal cancer and sigmoid colon adenocarcinoma invaded the lower part of the right-side ureter. The patient was once treated with excision of part of small intestine, fallopian tube and ovary, and uterus. The pathological examination of these excised tissues, combined with the immunohistochemistry, confirmed that the female patient suffered from primary ovarian diffuse large B-cell lymphoma (DLBCL), and the lymphoma had invaded the entire right-side ovary tissues, serous membranes on the posterior surface of the uterus, and the wall of small intestine.

Conclusion
Few reports were available regarding the primary ovarian DLBCL. The initial symptom of the patient was the changes in bowel habits, which had not been reported beforehand. Hopefully, this case could helpfully render the early diagnosis possible, and increase clinical understanding of primary ovarian DLBCL, which would thereby reduce the chance of misdiagnosis.
Systemic sclerosis and pregnancy outcomes: a retrospective study from a single center
Authors: Barilaro Giuseppe , Castellanos Aleida , Gomez-Ferreira Inês , Lledó Gema Maria , Della Rocca Carlo , Fernandez-Blanco Lorena , Cervera Ricard , Baños Núria , Figueras Francesc , Espinosa Gerard 
Published: April 2022

Abstract
Background
Pregnancy in systemic sclerosis (SSc) patients is no more an infrequent event as it used to be, but literature data on pregnancy outcomes in women with SSc are scarce. The rate of preterm deliveries and intrauterine growth restriction (IUGR) seems to be increased, while the risk of miscarriages is controversial. Moreover, no study compared pregnancy outcomes in SSc with antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). We performed a retrospective study to compare the pregnancy and disease outcomes of women with SSc with a cohort of age-matched women with systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and healthy controls (HC).

Methods
A total of 154 pregnancies from SSc, SLE, APS patients, and HC were prospectively followed at the High-Risk Pregnancy Unit of our center from 2008 to 2019. The primary outcome was a composite endpoint of miscarriages, fetal deaths, intrauterine growth restriction (IUGR), preeclampsia, neonatal deaths, preterm birth, and small-for-gestational-age (SGA) newborns. Single adverse pregnancy outcomes (APO) represented secondary endpoints. SSc activity variations in relation to pregnancy were assessed.

Results
The risk of APO was significantly higher in SSc patients compared to HC (60.6% vs 10.0%; OR = 14.42; 95% CI 3.70–56.18, p = 0.001) and SLE patients (60.6% vs 37.5%; OR = 3.56; 95% CI 1.29–9.83, p = 0.014). Compared to HC, women with SSc had an increased frequency of first trimester miscarriage (15% vs 0 %; p = 0.016), preeclampsia (12% vs 0%, p = 0.038), and SGA newborns (21.2% vs 0%; p = 0.003). Preterm deliveries were more frequent in SSc pregnancies in comparison with HC (24.2% vs 5%; OR = 6.08; 95% CI 1.19–31.02, p = 0.036) and SLE patients (24.2% vs 7.5%, OR = 5.68; 95% CI 1.1–29.38, p = 0.038). Disease remained stable in all SSc patients during pregnancy and up to 1 year after delivery.

Conclusions
We found an increased risk of APO in our SSc cohort in comparison with HC (with higher rates of miscarriages, preeclampsia, SGA newborns, and preterm deliveries) and SLE patients (presenting a higher rate of preterm deliveries). High-risk multidisciplinary management of SSc pregnant women is highly recommended.
Software evaluation for de novo detection of transposons
Authors: Rodriguez Matias , Makałowski Wojciech 
Published: April 2022

AbstractTransposable elements (TEs) are major genomic components in most eukaryotic genomes and play an important role in genome evolution. However, despite their relevance the identification of TEs is not an easy task and a number of tools were developed to tackle this problem. To better understand how they perform, we tested several widely used tools for de novo TE detection and compared their performance on both simulated data and well curated genomic sequences. As expected, tools that build TE-models performed better than k-mer counting ones, with RepeatModeler beating competitors in most datasets. However, there is a tendency for most tools to identify TE-regions in a fragmented manner and it is also frequent that small TEs or fragmented TEs are not detected. Consequently, the identification of TEs is still a challenging endeavor and it requires a significant manual curation by an experienced expert. The results will be helpful for identifying common issues associated with TE-annotation and for evaluating how comparable are the results obtained with different tools.
Technical considerations in PCR-based assay design for diagnostic DNA methylation cancer biomarkers
Authors: Massen Maartje , Lommen Kim , Wouters Kim A. D. , Vandersmissen Johan , van Criekinge Wim , Herman James G. , Melotte Veerle , Schouten Leo J. , van Engeland Manon , Smits Kim M. 
Published: April 2022

AbstractBackgroundDNA methylation biomarkers for early detection, risk stratification and treatment response in cancer have been of great interest over the past decades. Nevertheless, clinical implementation of these biomarkers is limited, as only < 1% of the identified biomarkers is translated into a clinical or commercial setting. Technical factors such as a suboptimal genomic location of the assay and inefficient primer or probe design have been emphasized as important pitfalls in biomarker research. Here, we use eleven diagnostic DNA methylation biomarkers for colorectal cancer (ALX4,APC,CDKN2A,MGMT,MLH1,NDRG4,SDC2,SFRP1,SFRP2,TFPI1andVIM), previously described in a systematic literature search, to evaluate these pitfalls.ResultsTo assess the genomic assay location, the optimal genomic locations according to TCGA data were extracted and compared to the genomic locations used in the published assays for all eleven biomarkers. In addition, all primers and probes were technically evaluated according to several criteria, based on literature and expert opinion. Both assay location and assay design quality varied widely among studies.ConclusionsLarge variation in both assay location and design hinders the development of future DNA methylation biomarkers as well as inter-study comparability.
Effects of stressful life-events on DNA methylation in panic disorder and major depressive disorder
Authors: Czamara Darina , Neufang Alexa , Dieterle Roman , Iurato Stella , Arloth Janine , Martins Jade , Ising Marcus , Binder Elisabeth E. , Erhardt Angelika 
Published: April 2022

Abstract
Background
Panic disorder (PD) is characterized by recurrent panic attacks and higher affection of women as compared to men. The lifetime prevalence of PD is about 2–3% in the general population leading to tremendous distress and disability. Etiologically, genetic and environmental factors, such as stress, contribute to the onset and relapse of PD. In the present study, we investigated epigenome-wide DNA methylation (DNAm) in respond to a cumulative, stress-weighted life events score (wLE) in patients with PD and its boundary to major depressive disorder (MDD), frequently co-occurring with symptoms of PD.

Methods
DNAm was assessed by the Illumina HumanMethylation450 BeadChip. In a meta-analytic approach, epigenome-wide DNAm changes in association with wLE were first analyzed in two PD cohorts (with a total sample size of 183 PD patients and 85 healthy controls) and lastly in 102 patients with MDD to identify possible overlapping and opposing effects of wLE on DNAm. Additionally, analysis of differentially methylated regions (DMRs) was conducted to identify regional clusters of association.

Results
Two CpG-sites presented with p-values below 1 × 10−05 in PD: cg09738429 (p = 6.40 × 10−06, located in an intergenic shore region in next proximity of PYROXD1) and cg03341655 (p = 8.14 × 10−06, located in the exonic region of GFOD2). The association of DNAm at cg03341655 and wLE could be replicated in the independent MDD case sample indicating a diagnosis independent effect. Genes mapping to the top hits were significantly upregulated in brain and top hits have been implicated in the metabolic system. Additionally, two significant DMRs were identified for PD only on chromosome 10 and 18, including CpG-sites which have been reported to be associated with anxiety and other psychiatric phenotypes.

Conclusion
This first DNAm analysis in PD reveals first evidence of small but significant DNAm changes in PD in association with cumulative stress-weighted life events. Most of the top associated CpG-sites are located in genes implicated in metabolic processes supporting the hypothesis that environmental stress contributes to health damaging changes by affecting a broad spectrum of systems in the body.
Predicting male fertility from the sperm methylome: application to 120 bulls with hundreds of artificial insemination records
Authors: Costes Valentin , Chaulot-Talmon Aurélie , Sellem Eli , Perrier Jean-Philippe , Aubert-Frambourg Anne , Jouneau Luc , Pontlevoy Charline , Hozé Chris , Fritz Sébastien , Boussaha Mekki , Le Danvic Chrystelle , Sanchez Marie-Pierre , Boichard Didier , Schibler Laurent , Jammes Hélène , Jaffrézic Florence , Kiefer Hélène 
Published: April 2022

Abstract
Background
Conflicting results regarding alterations to sperm DNA methylation in cases of spermatogenesis defects, male infertility and poor developmental outcomes have been reported in humans. Bulls used for artificial insemination represent a relevant model in this field, as the broad dissemination of bull semen considerably alleviates confounding factors and enables the precise assessment of male fertility. This study was therefore designed to assess the potential for sperm DNA methylation to predict bull fertility.

Results
A unique collection of 100 sperm samples was constituted by pooling 2–5 ejaculates per bull from 100 Montbéliarde bulls of comparable ages, assessed as fertile (n = 57) or subfertile (n = 43) based on non-return rates 56 days after insemination. The DNA methylation profiles of these samples were obtained using reduced representation bisulfite sequencing. After excluding putative sequence polymorphisms, 490 fertility-related differentially methylated cytosines (DMCs) were identified, most of which were hypermethylated in subfertile bulls. Interestingly, 46 genes targeted by DMCs are involved in embryonic and fetal development, sperm function and maturation, or have been related to fertility in genome-wide association studies; five of these were further analyzed by pyrosequencing. In order to evaluate the prognostic value of fertility-related DMCs, the sperm samples were split between training (n = 67) and testing (n = 33) sets. Using a Random Forest approach, a predictive model was built from the methylation values obtained on the training set. The predictive accuracy of this model was 72% on the testing set and 72% on individual ejaculates collected from an independent cohort of 20 bulls.

Conclusion
This study, conducted on the largest set of bull sperm samples so far examined in epigenetic analyses, demonstrated that the sperm methylome is a valuable source of male fertility biomarkers. The next challenge is to combine these results with other data on the same sperm samples in order to improve the quality of the model and better understand the interplay between DNA methylation and other molecular features in the regulation of fertility. This research may have potential applications in human medicine, where infertility affects the interaction between a male and a female, thus making it difficult to isolate the male factor.
Peptide hydrogel with self-healing and redox-responsive properties
Authors: D’Souza Areetha , Marshall Liam R. , Yoon Jennifer , Kulesha Alona , Edirisinghe Dona I. U. , Chandrasekaran Siddarth , Rathee Parth , Prabhakar Rajeev , Makhlynets Olga V. 
Published: April 2022

AbstractWe have rationally designed a peptide that assembles into a redox-responsive, antimicrobial metallohydrogel. The resulting self-healing material can be rapidly reduced by ascorbate under physiological conditions and demonstrates a remarkable 160-fold change in hydrogel stiffness upon reduction. We provide a computational model of the hydrogel, explaining why position of nitrogen in non-natural amino acid pyridyl-alanine results in drastically different gelation properties of peptides with metal ions. Given its antimicrobial and rheological properties, the newly designed hydrogel can be used for removable wound dressing application, addressing a major unmet need in clinical care.