bluuebunny/crossref_metadata_2025_split huggingface dataset:
Horizontal gene transfer-mediated bacterial strain variation affects host fitness in Drosophila
Authors: Wang Yun , Baumdicker Franz , Schweiger Paul , Kuenzel Sven , Staubach Fabian 
Published: September 2021

AbstractBackgroundHow microbes affect host fitness and environmental adaptation has become a fundamental research question in evolutionary biology. To better understand the role of microbial genomic variation for host fitness, we tested for associations of bacterial genomic variation andDrosophila melanogasteroffspring number in a microbial Genome Wide Association Study (GWAS).ResultsWe performed a microbial GWAS, leveraging strain variation in the genusGluconobacter, a genus of bacteria that are commonly associated withDrosophilaunder natural conditions. We pinpoint the thiamine biosynthesis pathway (TBP) as contributing to differences in fitness conferred to the fly host. While an effect of thiamine on fly development has been described, we show that strain variation in TBP between bacterial isolates from wild-caughtD. melanogastercontributes to variation in offspring production by the host. By tracing the evolutionary history of TBP genes inGluconobacter, we find that TBP genes were most likely lost and reacquired by horizontal gene transfer (HGT).ConclusionOur study emphasizes the importance of strain variation and highlights that HGT can add to microbiome flexibility and potentially to host adaptation.
Clinical and functional characterization of a novel STUB1 frameshift mutation in autosomal dominant spinocerebellar ataxia type 48 (SCA48)
Authors: Chen Huan-Yun , Hsu Chia-Lang , Lin Han-Yi , Lin Yung-Feng , Tsai Shih-Feng , Ho Yu-Jung , Li Ye-Ru , Tsai Jin-Wu , Teng Shu-Chun , Lin Chin-Hsien 
Published: September 2021

Abstract
Background
Heterozygous pathogenic variants in STUB1 are implicated in autosomal dominant spinocerebellar ataxia type 48 (SCA48), which is a rare familial ataxia disorder. We investigated the clinical, genetic and functional characteristics of STUB1 mutations identified from a Taiwanese ataxia cohort.

Methods
We performed whole genome sequencing in a genetically undiagnosed family with an autosomal dominant ataxia syndrome. Further Sanger sequencing of all exons and intron–exon boundary junctions of STUB1 in 249 unrelated patients with cerebellar ataxia was performed. The pathogenicity of the identified novel STUB1 variant was investigated.

Results
We identified a novel heterozygous frameshift variant, c.832del (p.Glu278fs), in STUB1 in two patients from the same family. This rare mutation is located in the U-box of the carboxyl terminus of the Hsc70-interacting protein (CHIP) protein, which is encoded by STUB1. Further in vitro experiments demonstrated that this novel heterozygous STUB1 frameshift variant impairs the CHIP protein’s activity and its interaction with the E2 ubiquitin ligase, UbE2D1, leading to neuronal accumulation of tau and α-synuclein, caspase-3 activation, and promoting cellular apoptosis through a dominant-negative pathogenic effect. The in vivo study revealed the influence of the CHIP expression level on the differentiation and migration of cerebellar granule neuron progenitors during cerebellar development.

Conclusions
Our findings provide clinical, genetic, and a mechanistic insight linking the novel heterozygous STUB1 frameshift mutation at the highly conserved U-box domain of CHIP as the cause of autosomal dominant SCA48. Our results further stress the importance of CHIP activity in neuronal protein homeostasis and cerebellar functions.
Blood leukocyte count as a systemic inflammatory biomarker associated with a more rapid spirometric decline in a large cohort of iron and steel industry workers
Authors: Kong Nan , Chen Guoshun , Wang Haitao , Li Jianyu , Yin Shuzhen , Cao Xue , Wang Tao , Li Xin , Li Yanan , Zhang Huanling , Yu Shanfa , Tang Jinglong , Sood Akshay , Zheng Yuxin , Leng Shuguang 
Published: September 2021

Abstract
Objective
Iron and steel industry workers are exposed to high levels of inhalable dust particles that contain various elements, including metals, and cause occupational lung diseases. We aim to assess the relationship between occupational dust exposure, systemic inflammation, and spirometric decline in a cohort of Chinese iron and steel workers.

Methods
We studied 7513 workers who participated in a Health Surveillance program at Wugang Institute for Occupational Health between 2008 and 2017. Time-weighted exposure intensity (TWEI) of dust was quantified based on self-reported dust exposure history, the experience of occupational hygienists, and historical data of dust exposure for workers with certain job titles. A linear mixed-effects model was used for association analyses.

Results
The average annual change of lung function was − 50.78 ml/year in forced expiratory volume in 1 s (FEV1) and − 34.36 ml/year in forced vital capacity (FVC) in males, and − 39.06 ml/year in FEV1 and − 26.66 ml/year in FVC in females. Higher TWEI prior to baseline was associated with lower longitudinal measurements of FEV1 and FVC but not with their decline rates. Higher WBC and its differential at baseline were associated with lower longitudinal measurements and a more rapid decline of FEV1 and FVC in a dose-dependent monotonically increasing manner. Moreover, the increase of WBC and its differential post-baseline was also associated with a more rapid decline of FEV1 and FVC.

Conclusions
Our findings support the important role of systemic inflammation in affecting the temporal change of lung function in iron and steel industry workers.
Metabolic engineering of Deinococcus radiodurans for pinene production from glycerol
Authors: Helalat Seyed Hossein , Jers Carsten , Bebahani Mandana , Mohabatkar Hassan , Mijakovic Ivan 
Published: September 2021

Abstract
Background
The objective of this work was to engineer Deinococcus radiodurans R1 as a microbial cell factory for the production of pinene, a monoterpene molecule prominently used for the production of fragrances, pharmaceutical products, and jet engine biofuels. Our objective was to produce pinene from glycerol, an abundant by-product of various industries.

Results
To enable pinene production in D. radiodurans, we expressed the pinene synthase from Abies grandis, the geranyl pyrophosphate (GPP) synthase from Escherichia coli, and overexpressed the native 1-deoxy-d-xylulose 5-phosphate synthase. Further, we disrupted the deinoxanthin pathway competing for the substrate GPP by either inactivating the gene dr0862, encoding phytoene synthase, or substituting the native GPP synthase with that of E. coli. These manipulations resulted in a D. radiodurans strain capable of producing 3.2 ± 0.2 mg/L pinene in a minimal medium supplemented with glycerol, with a yield of 0.13 ± 0.04 mg/g glycerol in shake flask cultures. Additionally, our results indicated a higher tolerance of D. radiodurans towards pinene as compared to E. coli.

Conclusions
In this study, we successfully engineered the extremophile bacterium D. radiodurans to produce pinene. This is the first study demonstrating the use of D. radiodurans as a cell factory for the production of terpenoid molecules. Besides, its high resistance to pinene makes D. radiodurans a suitable host for further engineering efforts to increase pinene titer as well as a candidate for the production of the other terpenoid molecules.
Influence of B. subtilis 3NA mutations in spo0A and abrB on surfactin production in B. subtilis 168
Authors: Klausmann Peter , Lilge Lars , Aschern Moritz , Hennemann Katja , Henkel Marius , Hausmann Rudolf , Morabbi Heravi Kambiz 
Published: September 2021

Abstract
Background
Bacillus subtilis is a well-established host for a variety of bioproduction processes, with much interest focused on the production of biosurfactants such as the cyclic lipopeptide surfactin. Surfactin production is tightly intertwined with quorum sensing and regulatory cell differentiation processes. As previous studies have shown, a non-sporulating B. subtilis strain 3NA encoding a functional sfp locus but mutations in the spo0A and abrB loci, called JABs32, exhibits noticeably increased surfactin production capabilities. In this work, the impacts of introducing JABs32 mutations in the genes spo0A, abrB and abh from 3NA into strain KM1016, a surfactin-forming derivative of B. subtilis 168, was investigated. This study aims to show these mutations are responsible for the surfactin producing performance of strain JABs32 in fed-batch bioreactor cultivations.

Results
Single and double mutant strains of B. subtilis KM1016 were constructed encoding gene deletions of spo0A, abrB and homologous abh. Furthermore, an elongated abrB version, called abrB*, as described for JABs32 was integrated. Single and combinatory mutant strains were analysed in respect of growth behaviour, native PsrfA promoter expression and surfactin production. Deletion of spo0A led to increased growth rates with lowered surfactin titers, while deletion or elongation of abrB resulted in lowered growth rates and high surfactin yields, compared to KM1016. The double mutant strains B. subtilis KM1036 and KM1020 encoding Δspo0A abrB* and Δspo0A ΔabrB were compared to reference strain JABs32, with KM1036 exhibiting similar production parameters and impeded cell growth and surfactin production for KM1020. Bioreactor fed-batch cultivations comparing a Δspo0A abrB* mutant of KM1016, KM681, with JABs32 showed a decrease of 32% in surfactin concentration.

Conclusions
The genetic differences of B. subtilis KM1016 and JABs32 give rise to new and improved fermentation methods through high cell density processes. Deletion of the spo0A locus was shown to be the reason for higher biomass concentrations. Only in combination with an elongation of abrB was this strain able to reach high surfactin titers of 18.27 g L−1 in fed-batch cultivations. This work shows, that a B. subtilis strain can be turned into a high cell density surfactin production strain by introduction of two mutations.
Regulating the T7 RNA polymerase expression in E. coli BL21 (DE3) to provide more host options for recombinant protein production
Authors: Du Fei , Liu Yun-Qi , Xu Ying-Shuang , Li Zi-Jia , Wang Yu-Zhou , Zhang Zi-Xu , Sun Xiao-Man 
Published: September 2021

AbstractEscherichia coli is the most widely used bacterium in prokaryotic expression system for the production of recombinant proteins. In BL21 (DE3), the gene encoding the T7 RNA polymerase (T7 RNAP) is under control of the strong lacUV5 promoter (PlacUV5), which is leakier and more active than wild-type lac promoter (PlacWT) under certain growth conditions. These characteristics are not advantageous for the production of those recombinant proteins with toxic or growth-burdened. On the one hand, leakage expression of T7 RNAP leads to rapid production of target proteins under non-inducing period, which sucks resources away from cellular growth. Moreover, in non-inducing or inducing period, high expression of T7 RNAP production leads to the high-production of hard-to-express proteins, which may all lead to loss of the expression plasmid or the occurrence of mutations in the expressed gene. Therefore, more BL21 (DE3)-derived variant strains with rigorous expression and different expression level of T7 RNAP should be developed. Hence, we replaced PlacUV5 with other inducible promoters respectively, including arabinose promoter (ParaBAD), rhamnose promoter (PrhaBAD), tetracycline promoter (Ptet), in order to optimize the production of recombinant protein by regulating the transcription level and the leakage level of T7 RNAP. Compared with BL21 (DE3), the constructed engineered strains had higher sensitivity to inducers, among which rhamnose and tetracycline promoters had the lowest leakage ability. In the production of glucose dehydrogenase (GDH), a protein that causes host autolysis, the engineered strain BL21 (DE3::ara) exhibited higher biomass, cell survival rate and foreign protein expression level than that of BL21 (DE3). In addition, these engineered strains had been successfully applied to improve the production of membrane proteins, including E. coli cytosine transporter protein (CodB), the E. coli membrane protein insertase/foldase (YidC), and the E. coli F-ATPase subunit b (Ecb). The engineered strains constructed in this paper provided more host choices for the production of recombinant proteins.
Transcriptional alterations of protein coding and noncoding RNAs in triple negative breast cancer in response to DNA methyltransferases inhibition
Authors: Elango Ramesh , Vishnubalaji Radhakrishnan , Shaath Hibah , Alajez Nehad M. 
Published: September 2021

Abstract
Background
DNA methylation plays a crucial role in multiple cellular processes such as gene regulation, chromatin stability, and genetic imprinting. In mammals, DNA methylation is achieved by DNA methyltransferases (DNMTs). A number of studies have associated alterations in DNMT activity to tumorigenesis; however, the exact role of DNMTs in shaping the genome in triple negative breast cancer (TNBC) is still being unraveled.

Methods
In the current study, we employed two DNMT inhibitors (Decitabine and 5-Azacytidine), two TNBC models (MDA-MB-231 and BT-549) and whole transcriptome RNA-Seq and characterized the transcriptional alterations associated with DNMT inhibition. Colony forming unit (CFU), flow cytometry, and fluorescent microscopy were used to assess cell proliferation, cell cycle distribution, and cell death, respectively. Ingenuity pathway analysis (IPA) was used for network and pathway analyses.

Results
Remarkably, DNMT inhibition induced the expression of genes involved in endoplasmic reticulum response to stress, response to unfolder protein, as well as cobalamin metabolic processes. In contrast, suppression of cellular processes related to cell cycle and mitosis were hallmarks of DNMT inhibition. Concordantly, DNMT inhibition led to significant inhibition of TNBC cell proliferation, G2-M cell cycle arrest and induction of cell death. Mechanistically, DNMT inhibition activated TP53, NUPR1, and NFkB (complex) networks, while RARA, RABL6, ESR1, FOXM1, and ERBB2 networks were suppressed. Our data also identified the long noncoding RNA (lncRNA) transcriptional portrait associated with DNMT inhibition and identified 25 commonly upregulated and 60 commonly downregulated lncRNAs in response to Decitabine and 5-Azacytidinec treatment in both TNBC models. TPT1-AS1 was the most highly induced (6.3 FC), while MALAT1 was the most highly suppressed (− 7.0 FC) lncRNA in response to DNMT inhibition.

Conclusions
Taken together, our data provides a comprehensive view of transcriptome alterations in the coding and noncoding transcriptome in TNBC in response to DNMT inhibition.
Asymptomatic and sub-microscopic Plasmodium falciparum infection in children in the Mount Cameroon area: a cross-sectional study on altitudinal influence, haematological parameters and risk factors
Authors: Sumbele Irene Ule Ngole , Teh Rene Ning , Nkeudem Gillian Asoba , Sandie Sorelle Mekachie , Moyeh Marcel Nyuylam , Shey Robert Adamu , Shintouo Cabirou Mounchili , Ghogomu Stephen Mbigha , Batiha Gaber El-Saber , Alkazmi Luay , Kimbi Helen Kuokuo 
Published: September 2021

Abstract
Background
The Mount Cameroon area has experienced a 57.2% decline in confirmed malaria cases between 2006 and 2013 with the implementation of different control measures but, the disease is still of public health concern. The objective of the study was to assess the burden of asymptomatic and sub-microscopic Plasmodium infection, altitudinal influence on it, their effect on haematological parameters as well as identify the risk factors of infection.

Methodology
A cross-sectional community-based survey involving 1319 children of both sexes aged 6 months to 14 years was conducted between July 2017 and May 2018. Malaria parasitaemia was confirmed by Giemsa-stained microscopy, sub-microscopic Plasmodium infection by 18S mRNA using nested PCR and full blood count analysis was done using an auto haematology analyser.

Results
Malaria parasite, asymptomatic malaria parasitaemia and sub-microscopic Plasmodium infection and anaemia were prevalent in 36.4%, 34.0%, 43.8% and 62.3% of the children, respectively. The risk of having sub-microscopic Plasmodium infection was highest in children 5‒9 (OR = 3.13, P < 0.001) and 10‒14 years of age (OR = 8.18, P < 0.001), non-insecticide treated net users (OR = 1.69, P < 0.04) and those anaemic (OR = 9.01, P < 0.001). Children with sub-microscopic infection had a significantly lower mean haemoglobin (9.86 ± 1.7 g/dL, P < 0.001), red blood cell counts (4.48 ± 1.1 × 1012/L, P < 0.001), haematocrit (31.92%, P < 0.001), mean corpuscular haemoglobin concentration (313.25 ± 47.36, P = 0.035) and platelet counts (280.83 ± 112.62, P < 0.001) than their negative counterparts. Children < 5 years old (73.8%), having asymptomatic (69.8%) and sub-microscopic Plasmodium infection (78.3%) as well as resident in the middle belt (72.7%) had a higher prevalence of anaemia than their peers.

Conclusion
The meaningful individual-level heterogeneity in the burden of asymptomatic and sub-microscopic Plasmodium infection in addition to its corollary on haematological variables among children in the different attitudinal sites of the Mount Cameroon Region accentuate the need for strategic context specific planning of malaria control and preventative measures.
Inequalities in population health loss by multiple deprivation: COVID-19 and pre-pandemic all-cause disability-adjusted life years (DALYs) in Scotland
Authors: Wyper Grant M. A. , Fletcher Eilidh , Grant Ian , Harding Oliver , de Haro Moro Maria Teresa , Stockton Diane L. , McCartney Gerry 
Published: September 2021

AbstractBackgroundCOVID-19 has caused almost unprecedented change across health, education, the economy and social interaction. It is widely understood that the existing mechanisms which shape health inequalities have resulted in COVID-19 outcomes following this same, familiar, pattern. Our aim was to estimate inequalities in the population health impact of COVID-19 in Scotland, measured by disability-adjusted life years (DALYs) in 2020. Our secondary aim was to scale overall, and inequalities in, COVID-19 DALYs against the level of pre-pandemic inequalities in all-cause DALYs, derived from the Scottish Burden of Disease (SBoD) study.MethodsNational deaths and daily case data were input into the European Burden of Disease Network consensus model to estimate DALYs. Total Years of Life Lost (YLL) were estimated for each area-based deprivation quintile of the Scottish population. Years Lived with Disability were proportionately distributed to deprivation quintiles, based on YLL estimates. Inequalities were measured by: the range, Relative Index of Inequality (RII), Slope Index of Inequality (SII), and attributable DALYs were estimated by using the least deprived quintile as a reference.ResultsMarked inequalities were observed across several measures. The SII range was 2048 to 2289 COVID-19 DALYs per 100,000 population. The rate in the most deprived areas was around 58% higher than the mean population rate (RII = 1.16), with 40% of COVID-19 DALYs attributed to differences in area-based deprivation. Overall DALYs due to COVID-19 ranged from 7 to 20% of the annual pre-pandemic impact of inequalities in health loss combined across all causes.ConclusionThe substantial population health impact of COVID-19 in Scotland was not shared equally across areas experiencing different levels of deprivation. The extent of inequality due to COVID-19 was similar to averting all annual DALYs due to diabetes. In the wider context of population health loss, overall ill-health and mortality due to COVID-19 was, at most, a fifth of the annual population health loss due to inequalities in multiple deprivation. Implementing effective policy interventions to reduce health inequalities must be at the forefront of plans to recover and improve population health.
Differences in depressive symptoms by rurality in Japan: a cross-sectional multilevel study using different aggregation units of municipalities and neighborhoods (JAGES)
Authors: Kanamori Mariko , Hanazato Masamichi , Takagi Daisuke , Kondo Katsunori , Ojima Toshiyuki , Amemiya Airi , Kondo Naoki 
Published: September 2021

Abstract
Background
Rurality can reflect many aspects of the community, including community characteristics that may be associated with mental health. In this study, we focused on geographical units to address multiple layers of a rural environment. By evaluating rurality at both the municipality and neighborhood (i.e., a smaller unit within a municipality) levels in Japan, we aimed to elucidate the relationship between depression and rurality. To explore the mechanisms linking rurality and depression, we examined how the association between rurality and depression can be explained by community social capital according to geographical units.

Methods
We used cross-sectional data from the 2016 wave of the Japan Gerontological Evaluation Study involving 144,822 respondents aged 65 years or older residing in 937 neighborhoods across 39 municipalities. The population density quintile for municipality-level rurality and the quintile for the time required to reach densely inhabited districts for neighborhood-level rurality were used. We calculated the prevalence ratios of depressive symptoms by gender using a three-level (individual, neighborhood, and municipality) Poisson regression. Community social capital was assessed using three components: civic participation, social cohesion, and reciprocity.

Results
The prevalence of depressive symptoms was higher in municipalities with lower population density than those with the highest population density; the ratios were 1.22 (95% confidence intervals: 1.15, 1.30) for men and 1.22 (1.13, 1.31) for women. In contrast, when evaluating rurality at the neighborhood level, the prevalence of depressive symptoms was 0.9 times lower for men in rural areas; no such association was observed for women. In rural municipalities, community civic participation was associated with an increased risk of depressive symptoms. In rural neighborhoods, community social cohesion and reciprocity were linked to a lower risk of depressive symptoms.

Conclusions
The association between rurality and depression varied according to geographical unit. In rural municipalities, the risk of depression may be higher for both men and women, and the presence of an environment conducive to civic participation may contribute to a higher risk of depression, as observed in this study. The risk of depression in men may be lower in rural neighborhoods in Japan, which may be related to high social cohesion and reciprocity.