bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatitis B doubly spliced protein (HBDSP) promotes hepatocellular carcinoma cell apoptosis via ETS1/GATA2/YY1-mediated p53 transcription
Authors: Xu Xiazhen , Zhang Lu , Ye Guiying , Shi Jiajian , Peng Yibin , Xin Fan , Lin Yi , Wu Qiong , Lin Xu , Chen Wannan 
Published: November 2023

ABSTRACT

Chronic hepatitis B virus (HBV) infection represents an important global public health concern. The spliced variants generated by RNA splicing from 3.5-kb HBV pre-genomic RNA are involved in chronic hepatitis B pathogenicity and associated with hepatocellular carcinoma development. Although the HBV spliced variants with a length of 2.2 kb have been widely detected, their roles in the development of HBV-associated liver diseases remain unknown. In the present study, the pro-apoptotic effects of hepatitis B doubly spliced protein (HBDSP) encoded by 2.2-kb doubly spliced variants of HBV in wild-type
p53
(wt
-p53
) hepatocytes were determined. We primarily found that HBDSP promoted the apoptosis of HepG2 and SMMC-7721 cells with wt
-p53
. The role of wt-
p53
in HBDSP-induced apoptosis was further investigated. It was demonstrated that HBDSP upregulated p53 and phospho-p53 (Ser15) expression and herein stimulated the
p53
-dependent apoptotic signaling pathway. Mechanistically, HBDSP indirectly transactivated the
p53
promoter in an ETS1-, GATA2-, and YY1-dependent manner, in which HBDSP increased the nuclear translocation of ETS1, GATA2, and YY1. Besides, it was demonstrated that HBDSP could promote cellular apoptosis and activate
p53
-dependent apoptotic signaling pathway, resulting in increased secretion of HBV DNA, HBsAg, and HBeAg in HepG2.2.15 cells and HBV-infected HepG2-NTCP cells. Taken together, our results reveal a novel mechanism by which HBDSP promotes ETS1/GATA2/YY1-dependent
p53
gene transcription and induces apoptosis in wt-
p53
cells, and increases the production of HBV progeny and viral antigens. These findings may provide novel insight into the pathogenesis of HBDSP involved in HBV-associated liver diseases.

IMPORTANCE

Hepatitis B virus (HBV) spliced variants are associated with viral persistence or pathogenicity. Hepatitis B doubly spliced protein (HBDSP), which has been previously reported as a pleiotropic transactivator protein, can potentially serve as an HBV virulence factor. However, the underlying mechanisms of HBDSP in HBV-associated liver diseases remain to be elucidated. In this study, we revealed that HBDSP promotes cellular apoptosis and induces wt-
p53
-dependent apoptotic signaling pathway in wt-
p53
hepatocellular cells by transactivating p53 transcription, and increases the release of HBV progeny. Therefore, HBDSP may promote the HBV particles release through wt-
p53
-dependent hepatocellular apoptosis. Our findings suggest that blocking HBDSP-induced wt-
p53
-dependent apoptosis might have therapeutic values for chronic hepatitis B.
Genomic analysis of penicillin-binding proteins and recombination events in an emerging amoxicillin- and meropenem-resistant PMEN3 (Spain
9V
-3, ST156) variant in Taiwan and comparison with global descendants of this lineage
Authors: Chen Yi-Yin , Chi Hsin , Liao Wei-Chao , Li Shiao-Wen , Yang Yu-Ching , Lin Ho-Chen , Chang Hsiao-Pei , Pan Yi-Jiun , Chiang Ruei-Lin , Hsieh Yu-Chia 
Published: November 2023

ABSTRACT

From 2008 to 2020, the Taiwan National Notifiable Disease Surveillance System database demonstrated that the incidence of non-vaccine serotype 23A invasive pneumococcal disease (IPD) approximately doubled. In this study, 276 non-repetitive pneumococcal clinical isolates were collected from two medical centers in Taiwan between 2019 and 2021. Of these 267 pneumococci, 60 were serotype 23A. Among them, 50 (83%) of serotype 23A isolates belonged to the sequence type (ST) 166 variant of the Spain
9V
-3 clone. Pneumococcal 23A-ST166 isolates were collected to assess their evolutionary relationships using whole-genome sequencing. All 23A-ST166 isolates were resistant to amoxicillin and meropenem, and 96% harbored a novel combination of penicillin-binding proteins (PBPs) (1a:2b:2x):15:11:299, the newly identified PBP2x-299 in Taiwan. Transformation of the
pbp1a
,
pbp2b
, and
pbp2x
alleles into the β-lactam-susceptible R6 strain revealed that PBP2x-299 and PBP2b-11 increased the MIC of ceftriaxone and meropenem by 16-fold, respectively. Prediction analysis of recombination sites in PMEN3 descendants (23A-ST166 in Taiwan, 35B-ST156 in the United States, and 11A-ST838/ST6521 in Europe) showed that adaptive evolution involved repeated, selectively favored convergent recombination in the capsular polysaccharide synthesis region, PBPs,
murM
, and
folP
genome sites. In the late 13-valent pneumococcal conjugate vaccine era, PMEN3 continuously displayed an evolutionary capacity for global dissemination and persistence, increasing IPD incidence, leading to an offset in the decrease of pneumococcal conjugate vaccine serotype-related diseases, and contributing to high antibiotic resistance.

A clonal shift with a highly β-lactam-resistant non-vaccine serotype 23A, from ST338 to ST166, increased in Taiwan. ST166 is a single-locus variant of the Spain
9V
-3 clone, which is also called the PMEN3 lineage. All 23A-ST166 isolates, in this study, were resistant to amoxicillin and meropenem, and 96% harbored a novel combination of penicillin-binding proteins (PBPs) (1a:2b:2x):15:11:299. PBP2x-299 and PBP2b-11 contributed to the increasing MIC of ceftriaxone and meropenem, respectively. Prediction analysis of recombination sites in PMEN3 descendants showed that adaptive evolution involved repeated, selectively favored convergent recombination in the capsular polysaccharide synthesis region, PBPs,
murM
, and
folP
genome sites. In the late 13-valent pneumococcal conjugate vaccine era, PMEN3 continuously displays the evolutionary capacity for dissemination, leading to an offset in the decrease of pneumococcal conjugate vaccine serotype-related diseases and contributing to high antibiotic resistance.
Alternative oxidase promotes high iron tolerance in
Candida albicans
Authors: Sharma Rishabh , Gibb Andrew A. , Barnts Kelcie , Elrod John W. , Puri Sumant 
Published: November 2023

ABSTRACT

Although crucial for cellular functioning, iron is toxic when present in excess. Iron overload can create a labile iron pool (LIP) that harms the mitochondrion, resulting in disruption of oxidative respiration. Fungal pathogen
C. albicans
possesses an unconventional terminal oxidase [alternative oxidase (AOX)] that can disrupt the electron transport chain to remove excess electrons, generated from various stressors, to shield the respiratory apparatus. Here, we identify a novel role for AOX under high iron, whereby it works as “safety valve” to protect the mitochondrion from high iron-induced reactive oxygen species (ROS).
C. albicans
showed pronounced metabolic flexibility to environmental iron, ranging from 1 to 500 µM. High iron significantly increased intracellular iron, LIP, and levels of cellular ROS. Expression of both
AOX1/2
was induced by iron, and cells lacking Aox1/2 showed high levels of mitochondrial ROS as well as significant growth defect under high iron. Thus, Aox1/2 helps mitigate the negative effects of iron. Furthermore, iron-induced expression of
AOX1/2
was intermittent, thus preventing ATP loss despite AOX being non-proton motive. Mitochondrial oxygen consumption rate (OCR) was significantly higher (62.8%) under high iron conditions. Contribution of Aox1/2 was greater toward this high OCR, compared to their contribution in low iron conditions. Lastly, enhanced virulence of
C. albicans
that is observed for wild-type cells under high iron was lost when fungal cells lacking
AOX1/2
were used for murine infection. Thus, AOX is crucial for preserving mitochondrial function for survival in a high iron host.

IMPORTANCE

The yeast
C. albicans
exhibits metabolic flexibility for adaptability to host niches with varying availability of nutrients including essential metals like iron. For example, blood is iron deplete, while the oral cavity and the intestinal lumen are considered iron replete. We show here that
C. albicans
can tolerate very high levels of environmental iron, despite an increase in high iron-induced reactive oxygen species (ROS) that it mitigates with the help of a unique oxidase, known as alternative oxidase (AOX). High iron induces
AOX1/2
that limits mitochondrial accumulation of ROS. Genetic elimination of
AOX1/2
resulted in diminished virulence during oropharyngeal candidiasis in high iron mice. Since human mitochondria lack AOX protein, it represents a unique target for treatment of fungal infections.
The neutrophil oxidant hypothiocyanous acid causes a thiol-specific stress response and an oxidative shift of the bacillithiol redox potential in
Staphylococcus aureus
Authors: Loi Vu Van , Busche Tobias , Schnaufer Franziska , Kalinowski Jörn , Antelmann Haike 
Published: November 2023

ABSTRACT

During infections,
Staphylococcus aureus
is exposed to hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN), which are produced by the neutrophil myeloperoxidase as potent antimicrobial killing agents. In this work, we applied RNAseq transcriptomics, Brx-roGFP2 biosensor measurements, and phenotype analyses to investigate the stress responses and defense mechanisms of
S. aureus
COL toward HOSCN stress. Based on the RNAseq transcriptome profile, HOSCN exerts strong thiol-specific oxidative, electrophile, and metal stress responses as well as protein damage in
S. aureus
, which is indicated by the strong induction of the HypR, TetR1, PerR, QsrR, MhqR, CstR, CsoR, CzrA, AgrA, HrcA, and CtsR regulons. Phenotype analyses of various mutants in HOSCN-responsive genes revealed that the HOSCN reductase MerA conferred the highest resistance toward HOSCN stress in
S. aureus
COL, whereas the QsrR and MhqR electrophile stress regulons do not contribute to protection. Brx-roGFP2 biosensor measurements and bacillithiol (BSH)-specific Western blot analyses revealed a strong oxidative shift of the bacillithiol redox potential (
E
BSH
) and increased
S
-bacillithiolations in
S. aureus
, indicating that BSH is oxidized to bacillithiol disulfide (BSSB) under HOSCN stress. While the Δ
merA
mutant was delayed in recovery of the reduced
E
BSH
, overproduction of MerA in the Δ
hypR
mutant enabled faster recovery of
E
BSH
due to efficient HOSCN detoxification. Moreover, both MerA and BSH were shown to contribute to HOSCN resistance in growth assays. In summary, HOSCN provokes a thiol-specific oxidative, electrophile, and metal stress response, an oxidative shift in
E
BSH
and increased
S
-bacillithiolation in
S. aureus
.

IMPORTANCE

Staphylococcus aureus
colonizes the skin and the airways but can also lead to life-threatening systemic and chronic infections. During colonization and phagocytosis by immune cells,
S. aureus
encounters the thiol-reactive oxidant HOSCN. The understanding of the adaptation mechanisms of
S. aureus
toward HOSCN stress is important to identify novel drug targets to combat multi-resistant
S. aureus
isolates. As a defense mechanism,
S. aureus
uses the flavin disulfide reductase MerA, which functions as HOSCN reductase and protects against HOSCN stress. Moreover, MerA homologs have conserved functions in HOSCN detoxification in other bacteria, including intestinal and respiratory pathogens. In this work, we studied the comprehensive thiol-reactive mode of action of HOSCN and its effect on the reversible shift of the
E
BSH
to discover new defense mechanisms against the neutrophil oxidant. These findings provide new leads for future drug design to fight the pathogen at the sites of colonization and infections.
Performance of ChatGPT and Bard on the official part 1 FRCOphth practice questions
Authors: Fowler Thomas , Pullen Simon , Birkett Liam 
Published: November 2023

BackgroundChat Generative Pre-trained Transformer (ChatGPT), a large language model by OpenAI, and Bard, Google’s artificial intelligence (AI) chatbot, have been evaluated in various contexts. This study aims to assess these models’ proficiency in the part 1 Fellowship of the Royal College of Ophthalmologists (FRCOphth) Multiple Choice Question (MCQ) examination, highlighting their potential in medical education.MethodsBoth models were tested on a sample question bank for the part 1 FRCOphth MCQ exam. Their performances were compared with historical human performance on the exam, focusing on the ability to comprehend, retain and apply information related to ophthalmology. We also tested it on the book ‘MCQs for FRCOpth part 1’, and assessed its performance across subjects.ResultsChatGPT demonstrated a strong performance, surpassing historical human pass marks and examination performance, while Bard underperformed. The comparison indicates the potential of certain AI models to match, and even exceed, human standards in such tasks.ConclusionThe results demonstrate the potential of AI models, such as ChatGPT, in processing and applying medical knowledge at a postgraduate level. However, performance varied among different models, highlighting the importance of appropriate AI selection. The study underlines the potential for AI applications in medical education and the necessity for further investigation into their strengths and limitations.
Cohort profile: the longitudinal National Growth and Health Study (NGHS) of black and white girls from Northern California tracking how behavioural and psychosocial risk factors predict cardiovascular risk and biological ageing in midlife and in offspring
Authors: Laraia Barbara , Brownell Kristy , Friebur Robin , Perera Rachel , Brown Erika , Mayer Stefanie E , Feng Ingrid , Clermont Sabrina , Ritchie Lorrene D , Epel Elissa 
Published: November 2023

PurposeThe National Heart, Lung and Blood Institute Growth and Health Study (NGHS) prospectively collected anthropometric, biospecimens, clinical, health behaviour and psychosocial measures associated with cardiovascular disease from childhood to young adulthood. The aim of the current study was to assess the impact of stress, dysregulated eating and social genomic biomarkers on cardiometabolic risk factors among the original participants now in midlife and their children.ParticipantsBeginning in 1987–1988, NGHS recruited black and white girls (age 9–10 years) from socioeconomically diverse backgrounds from from three sites: Cincinnati, Ohio; Washington, DC; and Western Contra Costa County, California (N=2379) and followed them for 10 years. The study maintained an 89% retention rate. The current study is 30 years after the start of the original study and focused on the participants of California (n=887) and their children aged 2–17 years. We re-enrolled 624 of 852 eligible participants (73%): 49.2% black and 50.8% white. The mean age was 39.5 years. Among the 645 eligible biological children, 553 were enrolled; 49% black and 51% white, with 51.5% girls and 48.5% boys. The mean age was 9.3 years.Findings to dateLongitudinal analysis of adolescent drive for thinness predicted higher scores for drive for thinness during midlife, which was indirectly associated with greater adult body mass index through adult drive for thinness. Latent trajectory modelling of adolescent growth over 10 years found that women with persistently high weight trajectory had twice the odds of having children who met the definition for obesity compared with the persistently normal group, adjusting for adult weight.Future plansNew studies on neighbourhood socioeconomic status, food insecurity and additional biomarkers of chronic stress, microbiome and accelerated ageing (ie, telomere length and epigenetic clock) are underway. We are developing a 10-year follow-up to understand changes in ageing biomarkers of the participants and their children.Trial registration numberNCT00005132.
Supporting and retaining competent primary care workforce in low-resource settings: lessons learned from a prospective cohort study
Authors: Li Mingyue , Tang Haoqing , Zheng Huixian , Tian Yiran , Cheng Xiaoran , Cheng Haozhe , Zhang Xiaotian , Hu Dan , Liu Xiaoyun 
Published: November 2023

ObjectiveAssess whether local health facilities can adequately support the performance of general practitioners (GPs) trained by China’s national compulsory services programme (CSP).DesignProspective cohort study.SettingHealth facilities in middle and western rural areas in China, 2015–2022.ParticipantsCohorts of CSP graduates from 2015 to 2019 in four major medical universities.Main outcomesJob performance measured by a 12-item Job Performance Scale; productivity measured by outpatient volume per day; turnover measured by ever changing jobs within the past year.Results91.2%, 92.0% and 90.5% GPs working in township health centres reported inadequate medication, equipment and external assistance from higher level hospitals, while CSP graduates working in secondary or tertiary hospitals reported a lower rate of less than 60%. The top three tests reported as lacking were blood gases (67.7%), microbiology (61.6%) and cancer biomarkers (49.7%); the top three lacked procedures were CT scan (64.8%), MRI scan (58.1%) and ambulatory BP monitoring (55.8%); and the top three lacked drugs were drugs for cardiovascular diseases (23.3%), systematic hormonal preparations (17.7%) and traditional Chinese medicines (13.0%). Multivariable analysis showed that facility support was positively associated with job performance—adequate medication increased job performance by 2.2 points (95% CI 0.7 to 3.8), and adequate external assistance increased job performance by 3.3 points (95% CI 1.8 to 4.8). Facility support was also positively associated with productivity—adequate medication increased outpatients seen per day by 20% (95% CI 0.1 to 0.3), and adequate equipment increased outpatients seen per day by 12% (95% CI 0.0 to 0.2). Facility support did not have significant impact on turnover, but GPs who changed jobs in the past year were 1.9–2.3 times more likely to report adequate facility support.ConclusionGPs in township health centres experienced a high prevalence of shortage in facility support. The identification of a positive association between facility support and performance and productivity has implications for future research and resources deployment in primary healthcare.
An evaluation of the effects of dietary mixed-species direct-fed microbial (probiotic) on growth performance, gas emissions, meat quality, nutrient digestibility, and fecal score in finishing pigs
Authors: Wahid Sumaya Tanzin , Kim In Ho 
Published: November 2023

This study examined the effects of mixed-species direct-fed microbial (DFM) on growth performance, gas emissions, meat quality, nutrient digestibility, and the fecal score of finishing pigs. A total of 100 crossbred finishing pigs ((Yorkshire × Landrace) × Duroc) weighing 58.97 ± 3.12 kg were randomly assigned to one of two diets (5 pigs per pen (2 barrows and 3 gilts); 50 pigs per treatment) in an 8-week trial. Dietary treatments comprised of the basal diet without probiotics control or basal diet + (0.1%) mixed probiotics (DFM). Mixed DFM supplementation showed a tendency to increase ( P = 0.093) the body weight of finishing pigs during day 56. Comparing mixed DFM with the control diet, mixed probiotics significantly improved average daily gain (ADG) during weeks 5–8 ( P = 0.024) and overall ( P = 0.013). DFM-supplemented diets reduced the emission of CH4 and NH3 significantly at weeks 4 and 8 compared with control. DFM supplementation did not affect H2S, methyl mercaptans, acetic acid, or CO2 emissions. Mixed DFM supplementation showed a tendency to increase ( P = 0.07) nitrogen digestibility. Pigs receiving mixed DFM had improved ADG and reduced NH3 and CH4 emissions without affecting meat quality, nutrient digestibility, intestinal microbes, and fecal score.
Production of antihydrogen atoms by 6 keV antiprotons through a positronium cloud
Authors: Adrich P. , Blumer P. , Caratsch G. , Chung M. , Cladé P. , Comini P. , Crivelli P. , Dalkarov O. , Debu P. , Douillet A. , Drapier D. , Froelich P. , Garroum N. , Guellati-Khelifa S. , Guyomard J. , Hervieux P.-A. , Hilico L. , Indelicato P. , Jonsell S. , Karr J.-P. , Kim B. , Kim S. , Kim E.-S. , Ko Y. J. , Kosinski T. , Kuroda N. , Latacz B. M. , Lee B. , Lee H. , Lee J. , Lim E. , Liszkay L. , Lunney D. , Manfredi G. , Mansoulié B. , Matusiak M. , Nesvizhevsky V. , Nez F. , Niang S. , Ohayon B. , Park K. , Paul N. , Pérez P. , Regenfus C. , Reynaud S. , Roumegou C. , Roussé J.-Y. , Sacquin Y. , Sadowski G. , Sarkisyan J. , Sato M. , Schmidt-Kaler F. , Staszczak M. , Szymczyk K. , Tanaka T. A. , Tuchming B. , Vallage B. , Voronin A. , van der Werf D. P. , Welker A. , Won D. , Wronka S. , Yamazaki Y. , Yoo K.-H. , Yzombard P. 
Published: November 2023

AbstractWe report on the first production of an antihydrogen beam by charge exchange of 6.1 keV antiprotons with a cloud of positronium in the GBAR experiment at CERN. The 100 keV antiproton beam delivered by the AD/ELENA facility was further decelerated with a pulsed drift tube. A 9 MeV electron beam from a linear accelerator produced a low energy positron beam. The positrons were accumulated in a set of two Penning–Malmberg traps. The positronium target cloud resulted from the conversion of the positrons extracted from the traps. The antiproton beam was steered onto this positronium cloud to produce the antiatoms. We observe an excess over background indicating antihydrogen production with a significance of 3–4 standard deviations.
Reconstructing an early Albian (Cretaceous) marine food web by employing macrofossil δ
13
C
carb
data
Authors: Mutterlose Jörg , Ohnemus Bernhard 
Published: November 2023

Abstract

Stable isotope data (δ
13
C, δ
18
O,
87
Sr/
86
Sr) from fossil carbonate shells are widely used throughout the Phanerozoic for stratigraphic dating and palaeoenvironmental reconstructions. The incorporation of δ
13
C carbonate (δ
13
C
carb
) is controlled by various factors, making its interpretation ambiguous. The analysis of co-occurring pristine carbonate-shelled organisms, which occupied different ecological niches during their lifetimes, will help to better understand the effect of biological parameters (food sources, biofractionation) on the carbonate composition.

We have studied the geochemistry (elements, δ
13
C
carb
, δ
18
O
carb
,
87
Sr/
86
Sr) of eight well-preserved macrofossils (corals, oysters, gastropod, ammonite, belemnites) of earliest Albian age (112 Ma). The up to 5‰ variation in δ
13
C
carb
values from the aragonitic and calcitic skeletons of these organisms with different feeding strategies (primary, secondary, tertiary consumers) was used to reconstruct a food-chain. The exceptional low δ
13
C
carb
values of belemnites are explained by the incorporation of larger amounts of metabolic carbon into the skeletons of these active predators. The findings suggest that the δ
13
C
carb
signal of the different organisms is controlled by (1) their food source and (2) subsequent biofractionation. The here discussed approach to interpreting δ
13
C
carb
data may help in the future to reconstruct past food-webs.