bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study, and dosing regimen selection for a pivotal COVID-19 trial of GST-HG171
Authors: Zhang Hong , Zhou Jing , Chen Hong , Mao John , Tang Yanan , Yan Wenhao , Zhang Tianxiang , Li Chuanjing , Chen Shikui , Li Guoping , Zhang George , Ding Yanhua , Liu Li 
Published: December 2023

ABSTRACT

This study is aimed to evaluate the safety, tolerability, and pharmacokinetics (PK), as well as to select an appropriate dosing regimen for the pivotal clinical trial of GST-HG171, an orally bioavailable, potent, and selective 3CL protease inhibitor by a randomized, double-blind, and placebo-controlled phase I trial in healthy subjects. We conducted a Ph1 study involving 78 healthy subjects to assess the safety, tolerability, and PK of single ascending doses (150–900 mg) as well as multiple ascending doses (MADs) (150 and 300 mg) of GST-HG171. Additionally, we examined the food effect and drug–drug interaction of GST-HG171 in combination with ritonavir through a MAD regimen of GST-HG171/ritonavir (BID or TID) for 5 days. Throughout the course of these studies, no serious AEs or deaths occurred, and no AEs necessitated study discontinuation. We observed that food had no significant impact on the exposure of GST-HG171. However, the presence of ritonavir substantially increased the exposure of GST-HG171, which facilitated the selection of the GST-HG171/ritonavir dose and regimen (150/100 mg BID) for subsequent phase II/III trials. The selected dose regimen was achieved through concentrations continuously at 6.2–9.9-fold above the levels required for protein-binding adjusted 50% inhibition (IC50) of viral replication
in vitro
. The combination of 150 mg GST-HG171/100 mg ritonavir demonstrated favorable safety and tolerability profiles. The PK data obtained from GST-HG171/ritonavir administration guided the selection of appropriate dose for a pivotal phase II/III trial currently in progress. (This study has been registered at ClinicalTrials.gov under identifier NCT05668897).
Wastewater surveillance for bacterial targets: current challenges and future goals
Authors: Philo Sarah E. , De León Kara B. , Noble Rachel T. , Zhou Nicolette A. , Alghafri Rashed , Bar-Or Itay , Darling Amanda , D'Souza Nishita , Hachimi Oumaima , Kaya Devrim , Kim Sooyeol , Gaardbo Kuhn Katrin , Layton Blythe A. , Mansfeldt Cresten , Oceguera Bethany , Radniecki Tyler S. , Ram Jeffrey L. , Saunders Lauren P. , Shrestha Abhilasha , Stadler Lauren B. , Steele Joshua A. , Stevenson Bradley S. , Vogel Jason R. , Bibby Kyle , Boehm Alexandria B. , Halden Rolf U. , Delgado Vela Jeseth 
Published: December 2023

ABSTRACT
Wastewater-based epidemiology (WBE) expanded rapidly in response to the COVID-19 pandemic. As the public health emergency has ended, researchers and practitioners are looking to shift the focus of existing wastewater surveillance programs to other targets, including bacteria. Bacterial targets may pose some unique challenges for WBE applications. To explore the current state of the field, the National Science Foundation-funded Research Coordination Network (RCN) on Wastewater Based Epidemiology for SARS-CoV-2 and Emerging Public Health Threats held a workshop in April 2023 to discuss the challenges and needs for wastewater bacterial surveillance. The targets and methods used in existing programs were diverse, with twelve different targets and nine different methods listed. Discussions during the workshop highlighted the challenges in adapting existing programs and identified research gaps in four key areas: choosing new targets, relating bacterial wastewater data to human disease incidence and prevalence, developing methods, and normalizing results. To help with these challenges and research gaps, the authors identified steps the larger community can take to improve bacteria wastewater surveillance. This includes developing data reporting standards and method optimization and validation for bacterial programs. Additionally, more work is needed to understand shedding patterns for potential bacterial targets to better relate wastewater data to human infections. Wastewater surveillance for bacteria can help provide insight into the underlying prevalence in communities, but much work is needed to establish these methods.

IMPORTANCE
Wastewater surveillance was a useful tool to elucidate the burden and spread of SARS-CoV-2 during the pandemic. Public health officials and researchers are interested in expanding these surveillance programs to include bacterial targets, but many questions remain. The NSF-funded Research Coordination Network for Wastewater Surveillance of SARS-CoV-2 and Emerging Public Health Threats held a workshop to identify barriers and research gaps to implementing bacterial wastewater surveillance programs.
Diversity and host specificity of
Borrelia burgdorferi
’s outer surface protein C (
ospC
) alleles in synanthropic mammals, with a notable
ospC
allele U absence from mixed infections
Authors: Shifflett Scarlet A. , Ferreira Francisco C. , González Julia , Toledo Alvaro , Fonseca Dina M. , Ellis Vincenzo A. 
Published: December 2023

ABSTRACT

Interactions among pathogen genotypes that vary in host specificity may affect overall transmission dynamics in multi-host systems.
Borrelia burgdorferi
, a bacterium that causes Lyme disease, is typically transmitted among wildlife by
Ixodes
ticks. Despite the existence of many alleles of
B. burgdorferi
’s
sensu stricto
outer surface protein C (
ospC
) gene, most human infections are caused by a small number of
ospC
alleles [“human infectious alleles” (HIAs)], suggesting variation in host specificity associated with
ospC
. To characterize the wildlife host association of
B. burgdorferi
’s
ospC
alleles, we used metagenomics to sequence
ospC
alleles from 68 infected individuals belonging to eight mammalian species trapped at three sites in suburban New Brunswick, New Jersey (USA). We found that multiple allele (“mixed”) infections were common. HIAs were most common in mice (
Peromyscus
spp.) and only one HIA was detected at a site where mice were rarely captured.
ospC
allele U was exclusively found in chipmunks (
Tamias striatus
), and although a significant number of different alleles were observed in chipmunks, including HIAs, allele U never co-occurred with other alleles in mixed infections. Our results suggest that allele U may be excluding other alleles, thereby reducing the capacity of chipmunks to act as reservoirs for HIAs.
IgA coating of vaginal bacteria is reduced in the setting of bacterial vaginosis (BV) and preferentially targets BV-associated species
Authors: Murphy Kerry , Gromisch Matthew , Srinivasan Sujatha , Wang Tao , Wood Lianna , Proll Sean , Liu Congzhou , Fiedler Tina , Valint D. J. , Fredricks David N. , Keller Marla J. , Herold Betsy C. 
Published: December 2023

ABSTRACT

Immunoglobulin (Ig) bacterial coating has been described in the gastrointestinal tract and linked to inflammatory bowel disease; however, little is known about Ig coating of vaginal bacteria and whether it plays a role in vaginal health including bacterial vaginosis (BV). We examined Ig coating in 18 women with symptomatic BV followed longitudinally before, 1 week, and 1 month after oral metronidazole treatment. Immunoglobulin A (IgA) and/or immunoglobulin G (IgG) coating of vaginal bacteria was assessed by flow cytometry, and Ig coated and uncoated bacteria were sorted and characterized using 16S rRNA sequencing. Despite higher levels of IgG compared to IgA in cervicovaginal fluid, the predominant Ig coating the bacteria was IgA. The majority of bacteria were uncoated at all visits, but IgA coating significantly increased after treatment for BV. Despite similar amounts of uncoated and IgA coated majority taxa ( >1% total) across all visits, there was preferential IgA coating of minority taxa (0.2%–1% total) associated with BV including
Sneathia
, several
Prevotella
species, and others. At the time of BV, we identified a principal component (PC) driven by proinflammatory mediators that correlated positively with an uncoated BV-associated bacterial community and negatively with an IgA coated protective
Lactobacillus
bacterial community. The preferential coating of BV-associated species, increase in coating following metronidazole treatment, and positive correlation between uncoated BV-associated species and inflammation suggest that coating may represent a host mechanism designed to limit bacterial diversity and reduce inflammatory responses. Elucidating the role of Ig coating in vaginal mucosal immunity may promote new strategies to prevent recurrent BV.
Draft genome sequence of
Monascus ruber
strain FM39-7
Authors: Yang Lei , Jing Yongfeng , Cheng Zhijun , Huang Ke , Yang Xianhai , Xiang Dong , Hilde LudwigSimaneka Omuwa , Zhang Huilin , Liu Yong 
Published: December 2023

ABSTRACT

In China, certain
Monascus ruber
strains are traditionally used as edible fungi. We sequenced the genome of
M. ruber
FM39-7 strain, an isolate from fermented rice. The genome is 25.89 Mb with a G + C content of 48.86%, containing 8485 annotated genes.
Dissecting components of the
Campylobacter jejuni fetMP-fetABCDEF
gene cluster under iron limitation
Authors: Richardson-Sanchez Tomas , Chan Anson C. K. , Sabatino Brendil , Lin Helen , Gaynor Erin C. , Murphy Michael E. P. 
Published: December 2023

ABSTRACT

Campylobacter jejuni
is a leading cause of bacterial gastroenteritis worldwide. Acute infection can be an antecedent to highly debilitating long-term sequelae. The expression of iron acquisition systems is vital for
C. jejuni
to survive the low iron availability within the human gut. The
C. jejuni fetMP-fetABCDEF
gene cluster is known to be upregulated during human infection and under iron limitation. While FetM and FetP have been functionally linked to iron transport in prior work, here we assess the contribution of each of the downstream genes (
fetABCDEF
) to
C. jejuni
growth during both iron-depleted and iron-replete conditions. Significant growth impairment was observed upon disruption of
fetA
,
fetB, fetC
, and
fetD
, suggesting a role in FetMP-mediated iron acquisition for each encoded protein. FetA expression was not dependent on the presence of FetB, FetC, FetD, FetE, or FetF. The functions of the putative thioredoxins FetE and FetF were redundant under iron-limited growth, requiring a double deletion (Δ
fetEF
) to exhibit a growth defect.
C. jejuni
FetE was expressed, and the structure was solved to 1.50 Å, revealing structural similarity to thiol-disulfide oxidases. Functional characterization in biochemical assays showed that FetE reduced insulin at a slower rate than
Escherichia coli
Trx and that together, FetEF promoted substrate oxidation in cell extracts, suggesting that FetE (and presumably FetF) are oxidoreductases that can mediate oxidation
in vivo
. This study advances our understanding of the contributions of the
fetMP-fetABCDEF
gene cluster to virulence at a genetic and functional level, providing foundational knowledge toward mitigating
C. jejuni
-related morbidity and mortality.

IMPORTANCE

Campylobacter jejuni
is a bacterium that is prevalent in the ceca of farmed poultry such as chickens. Consumption of ill-prepared poultry is thus the most common route by which
C. jejuni
infects the human gut to cause a typically self-limiting but severe gastrointestinal illness that can be fatal to very young, old, or immunocompromised people. The lack of a vaccine and an increasing resistance to current antibiotics highlight a need to better understand the mechanisms that make
C. jejuni
a successful human pathogen. This study focused on the functional components of one such mechanism—a molecular system that helps
C. jejuni
thrive despite the restriction on growth-available iron by the human body, which typically defends against pathogens. In providing a deeper understanding of how this system functions, this study contributes toward the goal of reducing the enormous global socioeconomic burden caused by
C. jejuni
.
Associations of diabetes, hypertension and obesity with COVID-19 mortality: a systematic review and meta-analysis
Authors: Li Chaoyang , Islam Nazrul , Gutierrez Juan Pablo , Gutiérrez-Barreto Samuel Eloy , Castañeda Prado Andrés , Moolenaar Ronald L , Lacey Ben , Richter Patricia 
Published: December 2023

IntroductionDespite a growing body of scholarly research on the risks of severe COVID-19 associated with diabetes, hypertension and obesity, there is a need for estimating pooled risk estimates with adjustment for confounding effects. We conducted a systematic review and meta-analysis to estimate the pooled adjusted risk ratios of diabetes, hypertension and obesity on COVID-19 mortality.MethodsWe searched 16 literature databases for original studies published between 1 December 2019 and 31 December 2020. We used the adapted Newcastle-Ottawa Scale to assess the risk of bias. Pooled risk ratios were estimated based on the adjusted effect sizes. We applied random-effects meta-analysis to account for the uncertainty in residual heterogeneity. We used contour-funnel plots and Egger’s test to assess possible publication bias.ResultsWe reviewed 34 830 records identified in literature search, of which 145 original studies were included in the meta-analysis. Pooled adjusted risk ratios were 1.43 (95% CI 1.32 to 1.54), 1.19 (95% CI 1.09 to 1.30) and 1.39 (95% CI 1.27 to 1.52) for diabetes, hypertension and obesity (body mass index ≥30 kg/m2) on COVID-19 mortality, respectively. The pooled adjusted risk ratios appeared to be stronger in studies conducted before April 2020, Western Pacific Region, low- and middle-income countries, and countries with low Global Health Security Index scores, when compared with their counterparts.ConclusionsDiabetes, hypertension and obesity were associated with an increased risk of COVID-19 mortality independent of other known risk factors, particularly in low-resource settings. Addressing these chronic diseases could be important for global pandemic preparedness and mortality prevention.PROSPERO registration numberCRD42021204371.
Association between alcohol consumption and risk of hyperuricaemia among adults: a large cross-sectional study in Chongqing, China
Authors: Chen Siyu , Ding Rui , Tang Xiaojun , Chen Liling , Luo Qinwen , Xiao Meng , Ding Xianbin , Peng Bin 
Published: December 2023

ObjectiveTo investigate the relationship between alcohol consumption and hyperuricaemia (HUA), we conducted a study based on a large population.SettingCross-sectional study.ParticipantsA total of 20 833 participants aged 30–79 years were enrolled in the China Multi-Ethnic Cohort, Chongqing region.OutcomesThe serum level of uric acid, fasting blood glucose and blood lipids were tested. Basic demographic statistics such as age, gender, marital status, education level, family annual income and the detail information of alcohol consumption were collected using a standardised questionnaire.ResultsAfter controlling for potential confounders, compared with participants who never consumed alcohol, participants who drank 3–5 days per week had the highest risk of HUA (OR: 1.51, 95% CI: 1.25 to 1.82) and those who drank alcohol harmfully had the highest risk of HUA (OR: 1.81, 95% CI: 1.41 to 2.32). In addition, we found that those who drank moderately had no significant association with risk of HUA. However, among men, compared with participants who never consumed alcohol, those who drank moderately was also a risk factor of HUA (OR: 1.23, 95% CI: 1.03 to 1.46) and those who drank alcohol harmfully had the highest risk of HUA (OR: 2.13, 95% CI: 1.64 to 2.78). Compared with participants who drank alcohol moderately, the OR (95% CI) for those who drank alcohol harmfully had the highest risk of HUA was 1.88 (1.42 to 2.48), and the corresponding OR (95% CI) for each level increment in the degree of alcohol consumption was 1.22 (1.12 to 1.33). Among men, compared with participants who drank alcohol moderately, those who drank alcohol harmfully had the highest risk of HUA (OR: 1.93, 95% CI: 1.45 to 2.57), as well as the corresponding OR (95% CI) for each level increment in the degree of alcohol consumption was 1.24 (1.13 to 1.35).ConclusionThis study suggested that the frequency and degree of alcohol consumption may be the risk factors for HUA, especially in males.
Strong and graded associations between level of asthma severity and all-cause hospital care use and costs in the UK
Authors: Jacobs Anya , Wu Runguo , Tomini Florian , De Simoni Anna , Mihaylova Borislava 
Published: December 2023

BackgroundHospital admissions account for a large share of the healthcare costs incurred by people with asthma. We assessed the hospital care use and costs associated with asthma severity using the UK Biobank cohort and linked healthcare data.MethodsAdult participants with asthma at recruitment were classified using their prescription data into mild and moderate-to-severe asthma and matched separately to asthma-free controls by age, sex, ethnicity and location. The associations of asthma, by severity, with the annual number of all-cause hospital admissions, days spent in hospital and hospital costs were estimated over a 10-year follow-up period using three specifications of negative binomial regression models that differed according to the sociodemographic and clinical characteristics adjusted for.ResultsOf the 25 031 participants with active asthma, 80% had mild asthma and 20% had moderate-to-severe asthma. Compared with participants with mild asthma, those with moderate-to-severe asthma were on average 2.7 years older, more likely to be current (13.7% vs 10.4%) or previous (40.2% vs 35.2%) smokers, to have a higher body mass index (BMI), and to be suffering from a variety of comorbid diseases. Following adjustments for age, sex, ethnicity and location, people with mild asthma experienced on average 36% more admissions (95% CI 28% to 40%), 43% more days in hospital (95% CI 35% to 51%) and 36% higher hospital costs (95% CI 31% to 41%) annually than asthma-free individuals, while people with moderate-to-severe asthma experienced excesses of 93% (95% CI 81% to 107%), 142% (95% CI 124% to 162%) and 98% (95% CI 88% to 108%), respectively. Further adjustments for socioeconomic deprivation, smoking status, BMI and comorbidities resulted in smaller though still highly significant positive associations, graded by severity, between asthma and hospital use and costs.ConclusionsStrong graded associations are reported between asthma severity and the extent of hospital use and costs in the UK. These findings could inform future assessments of the value of asthma management interventions.
Additional Higgs Bosons near 95 and 650 GeV in the NMSSM
Authors: Ellwanger Ulrich , Hugonie Cyril 
Published: December 2023

AbstractHints for an additional Higgs boson with a mass of about 95 GeV originate from LEP and searches in the diphoton channel by CMS and ATLAS. A search for resonant production of SM plus BSM Higgs bosons in the diphoton plus $$b\bar{b}$$

b

b

¯

channel by CMS showed some excess for a 650 GeV resonance decaying into the SM Higgs plus a 95 GeV Higgs boson. We investigate whether these phenomena can be interpreted simultaneously within the NMSSM subject to the latest constraints on couplings of the SM Higgs boson, on extra Higgs bosons from the LHC, and on dark matter direct detection cross sections. We find that the hints for a 95 GeV Higgs boson in the diphoton channel by CMS and ATLAS and in the diphoton plus $$b\bar{b}$$

b

b

¯

channel by CMS can be fitted simultaneously within the $$2\,\sigma $$

2

σ

level.
HEG1 Protects Against Atherosclerosis by Regulating Stable Flow-Induced KLF2/4 Expression in Endothelial Cells
Authors: Tamargo Ian A. , Baek Kyung In , Xu Chenbo , Kang Dong Won , Kim Yerin , Andueza Aitor , Williams Darian , Demos Catherine , Villa-Roel Nicolas , Kumar Sandeep , Park Christian , Choi Rachel , Johnson Janie , Chang Seowon , Kim Paul , Tan Sheryl , Jeong Kiyoung , Tsuji Shoutaro , Jo Hanjoong 
Published: December 2023

BACKGROUND:
Atherosclerosis preferentially occurs in arterial regions of disturbed blood flow, and stable flow (s-flow) protects against atherosclerosis by incompletely understood mechanisms.

METHODS:

Our single-cell RNA-sequencing data using the mouse partial carotid ligation model was reanalyzed, which identified Heart-of-glass 1 (HEG1) as an s-flow–induced gene. HEG1 expression was studied by immunostaining, quantitive polymerase chain reaction, hybridization chain reaction, and Western blot in mouse arteries, human aortic endothelial cells (HAECs), and human coronary arteries. A small interfering RNA–mediated knockdown of HEG1 was used to study its function and signaling mechanisms in HAECs under various flow conditions using a cone-and-plate shear device. We generated endothelial-targeted, tamoxifen-inducible HEG1 knockout (HEG1
iECKO
) mice. To determine the role of HEG1 in atherosclerosis, HEG1
iECKO
and littermate-control mice were injected with an adeno-associated virus–PCSK9 [proprotein convertase subtilisin/kexin type 9] and fed a Western diet to induce hypercholesterolemia either for 2 weeks with partial carotid ligation or 2 months without the surgery.

RESULTS:

S-flow induced HEG1 expression at the mRNA and protein levels in vivo and in vitro. S-flow stimulated HEG1 protein translocation to the downstream side of HAECs and release into the media, followed by increased messenger RNA and protein expression. HEG1 knockdown prevented s-flow–induced endothelial responses, including monocyte adhesion, permeability, and migration. Mechanistically, HEG1 knockdown prevented s-flow–induced KLF2/4 (Kruppel-like factor 2/4) expression by regulating its intracellular binding partner KRIT1 (Krev interaction trapped protein 1) and the MEKK3-MEK5-ERK5-MEF2 pathway in HAECs. Compared with littermate controls, HEG1
iECKO
mice exposed to hypercholesterolemia for 2 weeks and partial carotid ligation developed advanced atherosclerotic plaques, featuring increased necrotic core area, thin-capped fibroatheroma, inflammation, and intraplaque hemorrhage. In a conventional Western diet model for 2 months, HEG1
iECKO
mice also showed an exacerbated atherosclerosis development in the arterial tree in both sexes and the aortic sinus in males but not in females. Moreover, endothelial HEG1 expression was reduced in human coronary arteries with advanced atherosclerotic plaques.

CONCLUSIONS:
Our findings indicate that HEG1 is a novel mediator of atheroprotective endothelial responses to flow and a potential therapeutic target.
Testing the Predictions of Surprisal Theory in 11 Languages
Authors: Wilcox Ethan G. , Pimentel Tiago , Meister Clara , Cotterell Ryan , Levy Roger P. 
Published: December 2023

Abstract
Surprisal theory posits that less-predictable words should take more time to process, with word predictability quantified as surprisal, i.e., negative log probability in context. While evidence supporting the predictions of surprisal theory has been replicated widely, much of it has focused on a very narrow slice of data: native English speakers reading English texts. Indeed, no comprehensive multilingual analysis exists. We address this gap in the current literature by investigating the relationship between surprisal and reading times in eleven different languages, distributed across five language families. Deriving estimates from language models trained on monolingual and multilingual corpora, we test three predictions associated with surprisal theory: (i) whether surprisal is predictive of reading times, (ii) whether expected surprisal, i.e., contextual entropy, is predictive of reading times, and (iii) whether the linking function between surprisal and reading times is linear. We find that all three predictions are borne out crosslinguistically. By focusing on a more diverse set of languages, we argue that these results offer the most robust link to date between information theory and incremental language processing across languages.