bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ethanolaminephosphate cytidyltransferase is essential for survival, lipid homeostasis and stress tolerance inLeishmania major
Authors: Basu Somrita , Pawlowic Mattie , Hsu Fong-Fu , Thomas Geoff , Zhang Kai 
Published: January 2023

ABSTRACTGlycerophospholipids including phosphatidylethanolamine (PE) and phosphatidylcholine (PC) are vital components of biological membranes. Trypanosomatid parasites of the genusLeishmaniacan acquire PE and PC viade novosynthesis and the uptake/remodeling of host lipids. In this study, we investigated the ethanolaminephosphate cytidyltransferase (EPCT) inLeishmania major, which is the causative agent for cutaneous leishmaniasis. EPCT is a key enzyme in the ethanolamine branch of the Kennedy pathway which is responsible for thede novosynthesis of PE. Our results demonstrate thatL. majorEPCT is a cytosolic protein capable of catalyzing the formation of CDP-ethanolamine from ethanolamine-phosphate and cytidine triphosphate. Genetic manipulation experiments indicate that EPCT is essential in both the promastigote and amastigote stages ofL. majoras the chromosomal null mutants cannot survive without the episomal expression of EPCT. This differs from our previous findings on the choline branch of the Kennedy pathway (responsible for PC synthesis) which is required only in promastigotes but not amastigotes. While episomal EPCT expression does not affect promastigote proliferation under normal conditions, it leads to reduced production of ethanolamine plasmalogen or plasmenylethanolamine, the dominant PE subtype inLeishmania. In addition, parasites with epsiomal EPCT exhibit heightened sensitivity to acidic pH and starvation stress, and significant reduction in virulence. In summary, our investigation demonstrates that proper regulation of EPCT expression is crucial for PE synthesis, stress response, and survival ofLeishmaniaparasites throughout their life cycle.AUTHOR SUMMARYIn nature,Leishmaniaparasites alternate between fast replicating, extracellular promastigotes in sand fly gut and slow growing, intracellular amastigotes in macrophages. Previous studies suggest that promastigotes acquire most of their lipids viade novosynthesis whereas amastigotes rely on the uptake and remodeling of host lipids. Here we investigated the function of ethanolaminephosphate cytidyltransferase (EPCT) which catalyzes a key step in thede novosynthesis of phosphatidylethanolamine (PE) inLeishmania major. Results showed that EPCT is indispensable for both promastigotes and amastigotes, indicating thatde novoPE synthesis is still needed at certain capacity for the intracellular form ofLeishmaniaparasites. In addition, elevated EPCT expression alters overall PE synthesis and compromises parasite’s tolerance to adverse conditions and is deleterious to the growth of intracellular amastigotes. These findings provide new insight into howLeishmaniaacquire essential phospholipids and how disturbance of lipid metabolism can impact parasite fitness.
Gestational age-dependent decrease in fetal Hofbauer cells in placentas from pregnancies exposed to wildfire smoke in California
Authors: Basilio Emilia , Ozarslan Nida , Buarpung Sirirak , Benmarhnia Tarik , Padula Amy M. , Robinson Joshua F. , Gaw Stephanie L. 
Published: January 2023

AbstractOBJECTIVEWildfires are more common over the last decade and the frequency of wildfire events has been accelerated by climate change. The existing body of literature suggests that exposure to wildfire smoke during pregnancy contributes to adverse perinatal outcomes such as preterm birth and fetal growth restriction. We hypothesize that exposures to wildfire smoke and its constituents triggers a fetal inflammatory response which contributes to pathological changes that underlie these adverse pregnancy outcomes. In this study, we quantified the presence of fetal macrophages (i.e., Hofbauer cells) in human placentas obtained between 2018 and 2020 to assess the relationship between fetal immune status and wildfire exposure.STUDY DESIGNWe collected placentas from pregnancies from two hospitals in San Francisco over a two-year period that included two severe major wildfires. The average particulate matter < 2.5 μm (PM2.5) or wildfire specific PM2.5levels were estimated over the gestational duration of each sample. Immunostaining against CK7 and CD68 was performed to identify intravillous fetal Hofbauer cells. We assessed the gestational-age dependent relationship between placental CD68+ cell density and mean daily PM2.5or wildfire-specific PM2.5via linear regression and Welch’s t-test. Additionally, we compared placental CD68+ cell density with estimated peak wildfire exposures during the gestation to determine if timing of exposure during pregnancy may influence the occurrence of Hofbauer cells in the placenta.RESULTSThe gestational ages ranged from 7-41 weeks (n = 67). The majority of samples were collected during one of two major wildfire events in Northern California (70%; n = 47). In general, we observed a significant inverse relationship between placental CD68 density and PM2.5 or wildfire specific PM2.5, however, these associations were only observed in first or second trimester samples, and not in term samples. For example, among first trimester samples (n=22), we observed lower mean CD68 density among samples likely to be exposed to wildfire events (mean= 1.42,SD= 0.8) as compared to those not exposed (mean= 3.73,SD= 1.983) (p= 0.0015). Based on our linear regression model results, we predicted that a one μg/m3increase in daily mean wildfire PM2.5was associated with a 0.457 decrease in CD68 density (ß =-0.457; 95% CI: -0.722, -0.193). This association was also significant for daily mean overall PM2.5, though smaller in magnitude (ß = -0.139; 95% CI: -0.218, -0.059).CONCLUSIONSOur results suggest that wildfire smoke exposures are associated with decreased presence of fetal Hofbauer cells in first and second trimester placentas, suggesting exposure may lead to impaired placental function via altered presence of fetal Hofbauer cells and changes in immune status.
Bacterial community modifies host genetics effect on early childhood caries
Authors: Blostein Freida , Zou Tianyu , Bhaumik Deesha , Salzman Elizabeth , Bakulski Kelly M. , Shaffer John R. , Marazita Mary L. , Foxman Betsy 
Published: January 2023

AbstractBackgroundBy age five approximately one-fifth of children have early childhood caries (ECC). Both the oral microbiome and host genetics are thought to influence susceptibility. Whether the oral microbiome modifies genetic susceptibility to ECC has not been tested. We test whether the salivary bacteriome modifies the association of a polygenic score (PGS, a score derived from genomic data that summarizes genetic susceptibility to disease) for primary tooth decay on ECC in the Center for Oral Health Research in Appalachia 2 longitudinal birth cohort.MethodsChildren were genotyped using the Illumina Multi-Ethnic Genotyping Array and underwent annual dental examinations. We constructed a PGS for primary tooth decay using weights from an independent, genome-wide association meta-analysis. Using Poisson regression, we tested for associations between the PGS (high versus low) and ECC incidence, adjusting for demographic characteristics (n=783). An incidence-density sampled subset of the cohort (n=138) had salivary bacteriome data at 24- months of age. We tested for effect modification of the PGS on ECC case status by salivary bacterial community state type (CST).ResultsBy 60-months, 20.69% of children had ECC. High PGS was not associated with an increased rate of ECC (incidence-rate ratio:1.09 (95% confidence interval (CI): 0.83, 1.42)). However, having a cariogenic salivary bacterial CST at 24-months was associated with ECC (odds ratio (OR): 7.48 (95%CI: 3.06, 18.26)), which was robust to PGS adjustment. An interaction existed between the salivary bacterial CST and the PGS on the multiplicative scale (P= 0.04). The PGS was associated with ECC (OR: 4.83 (95% CI: 1.29, 18.17)) only among individuals with a noncariogenic salivary bacterial CST (n=70).ConclusionsGenetic causes of caries may be harder to detect when not accounting for cariogenic oral microbiomes. As certain salivary bacterial CSTs increased ECC-risk across genetic-risk strata, preventing colonization of cariogenic microbiomes would be universally beneficial.
The correlation between small papillary thyroid cancers and gamma radionuclides Cs-137, Th-232, U-238 and K-40 using spatially-explicit, register-based methods
Authors: Bayadsi Haytham , Van Den Brink Paul , Erlandsson Mårten , Gudbjornsdottir Soffia , Sebraoui Samy , Koorem Sofi , Nordin Pär , Hennings Joakim , Englund Oskar 
Published: January 2023

AbstractA steep increase of small papillary thyroid cancers (sPTCs) has been observed globally. A major risk factor for developing PTC is ionizing radiation. The aim of this study is to investigate whether geological differences in the prevalence of sPTCs in Sweden are correlated to the deposit of Caecium-137, Thorium-232 (Th-232), Uranium-238 (U-238) or Potassium-40 (K-40) using different Geographical Information System (GIS) methods. Datasets of 812 sPTC patients were combined with the datasets of the total population in Sweden and were layered with the gamma radionuclide deposits. The prevalence of metastatic sPTC was associated with significantly higher levels of Gamma radiation from Th-232, U-238 and K-40. The observed results clearly indicate that sPTC has causative factors that are neither evenly distributed among the population, nor geographically, calling for further studies with bigger cohorts where environmental factors are believed to play a major role in the pathogenesis of the disease.
Depression screening in chronic hemodialysis patients
Authors: Alicja Kubanek , Mateusz Przybylak , Przemysław Paul , Sylwia Kowalska Anna , Michał Błaszczyk , Aleksandra Macul-Sanewska , Kamila Czarnacka , Krzysztof Bednarski , Katarzyna Kanclerz , Aleksandra Szydłowska , Dariusz Świetlik , Przemysław Rutkowski , Leszek Bidzan , Marcin Renke , Jakub Grabowski 
Published: January 2023

AbstractPurposeDepressive disorder is common among hemodialysis (HD) patients and is associated with higher mortality rate. However, depression screening and treatment in dialysis population remains insufficient. The aim of the study was to show the prevalence of depression in patients on maintenance HD and to discuss the proper diagnostic approach, including dementia screening.Patients and methodsWe conducted a cross-sectional study that included 103 HD patients from one Dialysis Centre in Gdańsk (Poland). Cognitive functions were evaluated using Mini–Mental State Examination (MMSE). The screening for depression was assessed using Beck Depression Inventory (BDI-II). The diagnosis of depressive disorder was confirmed and its severity evaluated by psychiatrists based upon clinical assessment and scales. Sociodemographic, laboratory and dialysis data were also collected.ResultsAccording to BDI-II depressive symptoms were present in 43% of patients while the diagnosis of clinical Major Depressive Disorder (MDD) was confirmed by the psychiatrists in 13% of all subjects. In the depressive disorder group there was a prevalence of female and patients suffering from diabetes mellitus, levels of calcium phosphate index (CaxPi) were higher and Kt/V was lower. The optimal cut- off score for diagnosing major depressive disorder using BDI-II was ≥ 20 points. Cognitive impairment on the level of major neurocognitive disorder (dementia) was found in 18 % of the study group.ConclusionsThe prevalence of depression assessed using self- or clinician-administered questionnaires was higher than reported by clinical interview performed by the psychiatrist. Higher scores of CaxPi and lower Kt/V in depressive patients may suggest worse compliance in this group. The psychiatrist’s examination as a part of care at the Dialysis Centre could improve diagnosis of depression and its treatment with the goal to improve quality of life and lower the mortality rate in this population.
Prevalence of substance use and associated factors among patients with mental illness at Muhimbili National Hospital, Dar es Salaam, Tanzania
Authors: Karino Kilaye , Ambikile Joel S. , Iseselo Masunga K. 
Published: January 2023

AbstractThe burden of substance use among patients with mental illness is prevalent in developing countries including Tanzania with negative consequences on treatment outcomes. However, the current prevalence of substance use and its associated factors in this population remains unclear in Tanzania. This study aimed at determining the prevalence of substance use and associated factors among patients with mental illness at Muhimbili National Hospital, Dar es Salaam Tanzania.We conducted a descriptive cross-sectional study between March and May 2022. Data were collected during a face-to-face interview with patients attending the outpatient clinic at the Psychiatric Unit at MNH. We used a structured social demographic questionnaire and WHO ASSIST V3.0 tool was used to collect the data. Bivariate and multivariate regression analyses were performed using SPSS version 26 to determine the association between patient characteristics and substance use. A p-value of less than 0.05 was considered statistically significant. A total of 364 patients were enrolled. Among these, 215 (59.1%) were males and the mean (SD) age was 35.57 (±9.01) years. We found the prevalence of substance use to be 32.7%, and the most commonly used substance was alcohol (21.7%), followed by tobacco (19.8%) and cannabis (12.7%). Being a male [Adjusted Odds Ratio (AOR): 2.133; 95% Confidence Interval (CI): 1.258-3.619; P=0.005], younger age [AOR:3.301; 95% CI: 1.152-9.453; P=0.026], positive family history of mental illness [AOR:2.423; 95% CI: 1.448-4.056; P=0.001], and having a family history of substance use [AOR:3.721; 95% CI: 2.215-6.252; P=0.001], were significantly associated with substances use.In conclusion, substance use among patients with mental illness is prevalent. Establishing a routine screening program at the psychiatric clinics is essential in identifying substance use among these risk groups and providing appropriate treatment will improve treatment outcomes. Future research should explore help-seeking behaviors and the accessibility of substance use treatment in patients with mental illness.
Understanding the Biering-Sørensen test: contributors to extensor endurance in young adults with and without low back pain
Authors: Shaw Jonathan , Jacobs Jesse V. , Van Dillen Linda R. , Beneck George J. , Smith Jo Armour 
Published: January 2023

AbstractImpaired paraspinal muscle endurance may contribute to persistent low back pain (LBP) and is frequently assessed using a single repetition of the Biering-Sørensen test. This study investigated how Sørensen test duration, muscle activation, and muscle fatigability are affected by multiple repetitions of the test, and determined predictors of Sørensen test duration in young, active adults with and without a history of LBP. Sixty-four individuals with and without persistent LBP performed 3 repetitions of the Sørensen test. Amplitude of activation and median frequency slope (fatigability) were calculated for the lumbar and thoracic paraspinals and the hamstrings. Duration of the test was significantly less for the 2ndand 3rdrepetitions in individuals with LBP. In individuals without LBP, fatigability of the lumbar paraspinals was the best predictor of test duration. In individuals with LBP, Sørensen test duration was predicted by fatigability of the hamstrings and amplitude of activation of the thoracic and lumbar paraspinals. Our findings demonstrate that it is necessary to amplify the difficulty of the Sørensen test to elucidate impairments in young, active adults with LBP. Training programs aiming to improve lumbar paraspinal performance in individuals with LBP should monitor performance of other synergist muscles during endurance exercise.
Dynamic DNA methylation turnover at the exit of pluripotency epigenetically primes gene regulatory elements for hematopoietic lineage specification
Authors: Parry Aled , Krueger Christel , Lohoff Tim , Wingett Steven , Schoenfelder Stefan , Reik Wolf 
Published: January 2023

AbstractEpigenetic mechanisms govern developmental cell fate decisions, but how DNA methylation coordinates with chromatin structure and three-dimensional DNA folding to enact cell-type specific gene expression programmes remains poorly understood. Here, we use mouse embryonic stem and epiblast-like cells deficient for 5-methyl cytosine or its oxidative derivatives (5-hydroxy-, 5-formyl- and 5-carboxy-cytosine) to dissect the gene regulatory mechanisms that control cell lineage specification at the exit of pluripotency. Genetic ablation of either DNA methyltransferase (Dnmt) or Ten-eleven-translocation (Tet) activity yielded largely distinct sets of dysregulated genes, revealing divergent transcriptional defects upon perturbation of individual branches of the DNA cytosine methylation cycle. Unexpectedly, we found that disrupting DNA methylation or oxidation interferes with key enhancer features, including chromatin accessibility, enhancer-characteristic histone modifications, and long-range chromatin interactions with putative target genes. In addition to affecting transcription of select genes in pluripotent stem cells, we observe impaired enhancer priming, including a loss of three-dimensional interactions, at regulatory elements associated with key lineage-specifying genes that are required later in development, as we demonstrate for the key hematopoietic genesKlf1andLyl1. Consistently, we observe impaired transcriptional activation of blood genes during embryoid body differentiation of knockout cells. Our findings identify a novel role for the dynamic turnover of DNA methylation at the exit of pluripotency to establish and maintain chromatin states that epigenetically prime enhancers for later activation during developmental cell diversification.HighlightsWe perform a detailed epigenetic characterisation of the mouse embryonic stem cell (ESC) to epiblast-like cell (EpiLC) transition in wild type,Tettriple-knockout (TKO) andDnmtTKO lines and develop a novel clustering approach to interrogate the data.TetTKO reduces H3K4me1 and H3K27ac levels across enhancer elements upon pluripotency exit whilstDnmtTKO affects only H3K4me1 levels, suggesting a novel role for oxidative derivatives in H3K4me1 deposition.TetTKO andDnmtTKO affect enhancer priming in EpiLCs which is associated with failure to upregulate hematopoietic genes upon differentiation.Long-range chromosomal interactions between primed enhancers and their target genes are weakened in bothDnmtandTetTKO.
Online abstraction during statistical learning revealed by neural entrainment from intracranial recordings
Authors: Sherman Brynn E. , Aljishi Ayman , Graves Kathryn N. , Quraishi Imran H. , Sivaraju Adithya , Damisah Eyiyemisi C. , Turk-Browne Nicholas B. 
Published: January 2023

AbstractWe encounter the same people, places, and objects in predictable sequences and configurations. These regularities are learned efficiently by humans via statistical learning. Importantly, statistical learning creates knowledge not only of specific regularities, but also of more abstract, generalizable regularities. However, prior evidence of such abstract learning comes from post-learning behavioral tests, leaving open the question of whether abstraction occurs online during initial exposure. We address this question by measuring neural entrainment during statistical learning with intracranial recordings. Neurosurgical patients viewed a stream of scene photographs with regularities at one of two levels: In the Exemplar-level Structured condition, the same photographs appeared repeatedly in pairs. In the Category-level Structured condition, the photographs were trial-unique but their categories were paired across repetitions. In a baseline Random condition, the same photographs repeated but in a scrambled order. We measured entrainment at the frequency of individual photographs, which was expected in all conditions, but critically also at half of that frequency — the rate at which to-be-learned pairs appeared in the two structured conditions (but not the random condition). Neural entrainment to both exemplar and category pairs emerged within minutes throughout visual cortex and in frontal and temporal brain regions. Many electrode contacts were sensitive to only one level of structure, but a significant number encoded both exemplar and category regularities. These findings suggest that abstraction occurs spontaneously during statistical learning, providing insight into the brain’s unsupervised mechanisms for building flexible and robust knowledge that generalizes across input variation and conceptual hierarchies.
Characterization of the REC114-MEI4-IHO1 complex regulating meiotic DNA double-strand break formation
Authors: Laroussi Hamida , Juarez-Martinez Ariadna B. , Roy Aline Le , Erba Elisabetta Boeri , de Massy Bernard , Kadlec Jan 
Published: January 2023

AbstractMeiotic recombination is initiated by the formation of DNA double-strand breaks (DSBs), essential for fertility and genetic diversity. In the mouse, DSBs are formed by the catalytic TOPOVIL complex consisting of SPO11 and TOPOVIBL. To preserve genome integrity, the activity of the TOPOVIL complex is finely controlled by several meiotic factors including REC114, MEI4 and IHO1, but the underlying mechanism is poorly understood. Here, we report that mouse REC114 forms homodimers, that it associates with MEI4 as a 2:1 heterotrimer that further dimerizes, and that IHO1 forms coiled-coil based tetramers. Using AlphaFold2 modelling combined with biochemical characterization we uncovered the molecular details of these assemblies. Finally, we show that IHO1 directly interacts with the PH domain of REC114 by recognizing the same surface as TOPOVIBL and another meiotic factor ANKRD31. These results provide strong evidence for the existence of a ternary IHO1-REC114-MEI4 complex and show that REC114 is a potential regulatory platform mediating mutually exclusive interactions with several partners.
A role for the proteasome alpha2 subunit N-tail in substrate processing
Authors: Sahu Indrajit , Bajorek Monika , Xiaolin Tan , Srividya Madabhushi , Krutauz Daria , Reis Noa , Osmulski Pawel A , Gaczynska Maria E , Glickman Michael H 
Published: January 2023

AbstractThe proteolytic active sites of the 26S proteasome are sequestered within the catalytic chamber of its 20S core particle (CP). Access to this chamber is through a narrow channel defined by the outer α subunits. Free 20S CP is found in a latent state in which the N-termini of neighboring α subunits form a gate blocking access to the channel. Entry of substrates can be facilitated by the attachment of the activators or regulatory particles, which can rearrange the blocking α subunit N-terminal residues. In order to determine the specific physiological role of individual elements working in concert within the gate, we constructed a set of truncations or single-site mutations in each of the participating α N-terminal tails. We report herein that whereas only a few N-termini are important for maintaining a closed gate, all seven N-termini participate in the open gate. Specifically, an invariant tyrosine (Y) in each subunit forms a hydrogen bond with a conserved aspartate (D) in the N-terminal tail of its counterclockwise neighbor, with the exception of the α1-α2 pair leaving a gap in the ring circumference. A third residue (X) of this YD(X) motif aligns the open channel; specifically, the phenylalanine (F) at this position of the α2 subunit comes in direct contact with the translocating substrate. Consequently, deletion of this α2 N-terminal tail slows down proteolysis despite the appearance of an open gate state. We conclude that the YD(X) motif in N-terminal tail of α subunits plays an important role in gating the proteasome and in processing the substrate.