bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small molecule inhibitors of transcriptional cyclin-dependent kinases impose HIV-1 latency, presenting “block and lock” treatment strategies
Authors: Horvath Riley M. , Brumme Zabrina L. , Sadowski Ivan 
Published: February 2024

ABSTRACT

Current antiretroviral therapy for HIV-1 infection does not represent a cure for infection as viral rebound inevitably occurs following discontinuation of treatment. The “block and lock” therapeutic strategy is intended to enforce proviral latency and durably suppress viremic reemergence in the absence of other intervention. The transcription-associated cyclin-dependent protein kinases (tCDKs) are required for expression from the 5´ HIV-1 long-terminal repeat, but the therapeutic potential of inhibiting these kinases for enforcing HIV-1 latency has not been characterized. Here, we expanded previous observations to directly compare the effect of highly selective small molecule inhibitors of CDK7 (YKL-5-124), CDK9 (LDC000067), and CDK8/19 (Senexin A), and found each of these prevented HIV-1 provirus expression at concentrations that did not cause cell toxicity. Inhibition of CDK7 caused cell cycle arrest, whereas CDK9 and CDK8/19 inhibitors did not, and could be continuously administered to establish proviral latency. Upon discontinuation of drug administration, HIV immediately rebounded in cells that had been treated with the CDK9 inhibitor, while proviral latency persisted for several days in cells that had been treated with CDK8/19 inhibitors. These results identify the mediator kinases CDK8/CDK19 as potential “block and lock” targets for therapeutic suppression of HIV-1 provirus expression.
Characterizing the flavodoxin landscape in
Clostridioides difficile
Authors: Troitzsch Daniel , Knop Robert , Dittmann Silvia , Bartel Jürgen , Zühlke Daniela , Möller Timon Alexander , Trän Linda , Echelmeyer Thaddäus , Sievers Susanne 
Published: February 2024

ABSTRACT

Clostridioides difficile
infections have become a major challenge in medical facilities. The bacterium is capable of spore formation allowing the survival of antibiotic treatment. Therefore, research on the physiology of
C. difficile
is important for the development of alternative treatment strategies. In this study, we investigated eight putative flavodoxins of
C. difficile
630. Flavodoxins are small electron transfer proteins of specifically low potential. The unusually high number of flavodoxins in
C. difficile
suggests that they are expressed under different conditions. We determined high transcription levels for several flavodoxins during the exponential growth phase, especially for
floX
. Since flavodoxins are capable of replacing ferredoxins under iron deficiency conditions in other bacteria, we also examined their expression in
C. difficile
under low iron and no iron levels. In particular, the amount of
fldX
increased with decreasing iron concentration and thus could possibly replace ferredoxins. Moreover, we demonstrated that
fldX
is increasingly expressed under different oxidative stress conditions and thus may play an important role in the oxidative stress response. While increased
fldX
expression was detectable at both RNA and protein level,
CD2825
showed increased expression only at mRNA level under H
2
O
2
stress with sufficient iron availability and may indicate hydroxyl radical-dependent transcription. Although the exact function of the individual flavodoxins in
C. difficile
needs to be further investigated, the present study shows that flavodoxins could play an important role in several physiological processes and under infection-relevant conditions.

IMPORTANCE

The gram-positive, anaerobic, and spore-forming bacterium
Clostridioides difficile
has become a vast problem in human health care facilities. The antibiotic-associated infection with this intestinal pathogen causes serious and recurrent inflammation of the intestinal epithelium, in many cases with a severe course. To come up with novel targeted therapies against
C. difficile
infections, a more detailed knowledge on the pathogen’s physiology is mandatory. Eight putative flavodoxins, an extraordinarily high copy number of this type of small electron transfer proteins, are annotated for
C. difficile
. Flavodoxins are known to be essential electron carriers in other bacteria, for instance, during infection-relevant conditions such as iron limitation and oxidative stress. This work is a first and comprehensive overview on characteristics and expression profiles of the putative flavodoxins in the pathogen
C. difficile
.
In situ
community transcriptomics illuminates CO
2
-fixation potentials and supporting roles of phagotrophy and proton pump in plankton in a subtropical marginal sea
Authors: Li Hongfei , Chen Jianwei , Yu Liying , Fan Guangyi , Li Tangcheng , Li Ling , Yuan Huatao , Wang Jingtian , Wang Cong , Li Denghui , Lin Senjie 
Published: February 2024

ABSTRACT

Lineage-wise physiological activities of plankton communities in the ocean are important but challenging to characterize. Here, we conducted whole-assemblage metatranscriptomic profiling at continental shelf and slope sites in the South China Sea to investigate carbon fixation potential in different lineages.
RuBisCO
expression, the proxy of Calvin carbon fixation (CCF) potential, was mainly contributed by Bacillariophyta, Chlorophyta, Cyanobacteria, and Haptophyta, which was differentially affected by environmental factors among lineages. CCF potential exhibited positive or negative correlations with phagotrophy gene expression, suggesting phagotrophy possibly enhances or complements CCF. Our data also reveal significant non-Calvin carbon fixation (NCF) potential, as indicated by the active expression of genes in all five currently recognized NCF pathways, mainly contributed by Flavobacteriales, Alteromonadales, and Oceanospirillales. Furthermore, in Flavobacteriales, Alteromonadales, Pelagibacterales, and Rhodobacterales, NCF potential was positively correlated with proton-pump rhodopsin (PPR) expression, suggesting that NCF might be energetically supported by PPR. The novel insights into the lineage-differential potential of carbon fixation, widespread mixotrophy, and PPR as an energy source for NCF lay a methodological and informational foundation for further research to understand carbon fixation and the trophic landscape in the ocean.

IMPORTANCE

Marine plankton plays an important role in global carbon cycling and climate regulation. Phytoplankton and cyanobacteria fix CO
2
to produce organic compounds using solar energy and mainly by the Calvin cycle, whereas autotrophic bacteria and archaea may fix CO
2
by non-Calvin cycle carbon fixation pathways. How active individual lineages are in carbon fixation and mixotrophy, and what energy source bacteria may employ in non-Calvin carbon fixation, in a natural plankton assemblage are poorly understood and underexplored. Using metatranscriptomics, we studied carbon fixation in marine plankton with lineage resolution in tropical marginal shelf and slope areas. Based on the sequencing results, we characterized the carbon fixation potential of different lineages and assessed Calvin- and non-Calvin- carbon fixation activities and energy sources. Data revealed a high number of unigenes (4.4 million), lineage-dependent differential potentials of Calvin carbon fixation and responses to environmental conditions, major contributors of non-Calvin carbon fixation, and their potential energy source.
Campylobacter jejuni
extracellular vesicles harboring cytolethal distending toxin bind host cell glycans and induce cell cycle arrest in host cells
Authors: Le Lena Hoang My , Elgamoudi Bassam , Colon Nina , Cramond Angus , Poly Frederic , Ying Le , Korolik Victoria , Ferrero Richard L. 
Published: February 2024

ABSTRACT

Cytolethal distending toxins (CDTs) are released by Gram-negative pathogens into the extracellular medium as free toxin or associated with extracellular vesicles (EVs), commonly known as outer membrane vesicles (OMVs). CDT production by the gastrointestinal pathogen
Campylobacter jejuni
has been implicated in colorectal tumorigenesis. Despite CDT being a major virulence factor for
C. jejuni
, little is known about the EV-associated form of this toxin. To address this point, C.
jejuni
mutants lacking each of the three CDT subunits (A, B, and C) were generated.
C. jejuni cdtA, cdtB,
and
cdtC
bacteria released EVs in similar numbers and sizes to wild-type bacteria, ranging from 5 to 530 nm (mean ± SEM = 118 ±6.9 nm). As the CdtAC subunits mediate toxin binding to host cells, we performed “surface shearing” experiments, in which EVs were treated with proteinase K and incubated with host cells. These experiments indicated that CDT subunits are internal to EVs and that surface proteins are probably not involved in EV-host cell interactions. Furthermore, glycan array studies demonstrated that EVs bind complex host cell glycans and share receptor binding specificities with
C. jejuni
bacteria for fucosyl GM1 ganglioside, P1 blood group antigen, sialyl, and sulfated Lewis
x
. Finally, we show that EVs from
C. jejuni
WT but not mutant bacteria induce cell cycle arrest in epithelial cells. In conclusion, we propose that EVs are an important mechanism for CDT release by
C. jejuni
and are likely to play a significant role in toxin delivery to host cells.

IMPORTANCE

Campylobacter jejuni
is the leading cause of foodborne gastroenteritis in humans worldwide and a significant cause of childhood mortality due to diarrheal disease in developing countries. A major factor by which
C. jejuni
causes disease is a toxin, called cytolethal distending toxin (CDT). The biology of this toxin, however, is poorly understood. In this study, we report that
C. jejuni
CDT is protected within membrane blebs, known as extracellular vesicles (EVs), released by the bacterium. We showed that proteins on the surfaces of EVs are not required for EV uptake by host cells. Furthermore, we identified several sugar receptors that may be required for EV binding to host cells. By studying the EV-associated form of
C. jejuni
CDT, we will gain a greater understanding of how
C. jejuni
intoxicates host cells and how EV-associated CDT may be used in various therapeutic applications, including as anti-tumor therapies.
Urinary 8-hydroxy-2′-deoxyguanosine levels and preterm births: a prospective cohort study from the Japan Environment and Children’s Study
Authors: Murata Tsuyoshi , Kyozuka Hyo , Fukuda Toma , Imaizumi Karin , Isogami Hirotaka , Kanno Aya , Yasuda Shun , Yamaguchi Akiko , Sato Akiko , Ogata Yuka , Shinoki Kosei , Hosoya Mitsuaki , Yasumura Seiji , Hashimoto Koichi , Nishigori Hidekazu , Fujimori Keiya 
Published: February 2024

ObjectivesTo evaluate the association between urinary 8-hydroxy-2′-deoxyguanosine (U8-OHdG) level—a marker of oxidative stress—and the incidence of preterm births (PTBs).DesignProspective cohort study.SettingThe Japan Environment and Children’s Study (JECS).ParticipantsData from 92 715 women with singleton pregnancies at and after 22 weeks of gestation who were enrolled in the JECS, a nationwide birth cohort study, between 2011 and 2014 were analysed. U8-OHdG levels were assessed once in the second/third trimester using liquid chromatography–tandem mass spectrometry. Participants were categorised into the following three or five groups: low (<1.95 ng/mg urinary creatinine (Cre)), moderate (1.95–2.94 ng/mg Cre) and high (≥2.95 ng/mg Cre) U8-OHdG groups, or groups with <1.87, 1.87–2.20, 2.21–2.57, 2.58–3.11 and ≥3.12 ng/mg Cre. For stratification, participants with representative causes for artificial PTB were excluded.Primary and secondary outcome measuresAdjusted OR (aOR) for PTB before 37 and 34 weeks of gestation were calculated using a multivariable logistic regression model while adjusting for confounding factors; the moderate or lowest U8-OHdG group was used as the reference, respectively.ResultsThe aORs for PTB before 37 weeks of gestation in the high U8-OHdG group were 1.13 (95% CI 1.05 to 1.22) and 1.13 (95% CI 1.04 to 1.23) after stratification. The aOR for PTB before 37 weeks in the fourth group was 0.90 (95% CI 0.81 to 0.99). After stratification, the aORs for PTB before 37 and 34 weeks in the fifth group were 1.15 (95% CI 1.03 to 1.29) and 1.46 (95% CI 1.08 to 1.97), respectively.ConclusionsHigh U8-OHdG levels were associated with increased PTB incidence, especially in participants without representative causes for artificial PTB. Our results can help identify the mechanisms leading to PTB, considering the variable aetiologies of this condition; further validation is needed to clarify clinical impacts.
Protocol for the Gut Bugs in Autism Trial: a double-blind randomised placebo-controlled trial of faecal microbiome transfer for the treatment of gastrointestinal symptoms in autistic adolescents and adults
Authors: Tweedie-Cullen Ry Y , Leong Karen , Wilson Brooke C , Derraik José G B , Albert Benjamin B , Monk Ruth , Vatanen Tommi , Creagh Christine , Depczynski Marysia , Edwards Taygen , Beck Kathryn , Thabrew Hiran , O'Sullivan Justin M , Cutfield Wayne S 
Published: February 2024

IntroductionAutism (formally autism spectrum disorder) encompasses a group of complex neurodevelopmental conditions, characterised by differences in communication and social interactions. Co-occurring chronic gastrointestinal symptoms are common among autistic individuals and can adversely affect their quality of life. This study aims to evaluate the efficacy of oral encapsulated faecal microbiome transfer (FMT) in improving gastrointestinal symptoms and well-being among autistic adolescents and adults.Methods and analysisThis double-blind, randomised, placebo-controlled trial will recruit 100 autistic adolescents and adults aged 16–45 years, who have mild to severe gastrointestinal symptoms (Gastrointestinal Symptoms Rating Scale (GSRS) score ≥2.0). We will also recruit eight healthy donors aged 18–32 years, who will undergo extensive clinical screening. Recipients will be randomised 1:1 to receive FMT or placebo, stratified by biological sex. Capsules will be administered over two consecutive days following an overnight bowel cleanse with follow-up assessments at 6, 12 and 26 weeks post-treatment. The primary outcome is GSRS score at 6 weeks. Other assessments include anthropometry, body composition, hair cortisol concentration, gut microbiome profile, urine/plasma gut-derived metabolites, plasma markers of gut inflammation/permeability and questionnaires on general well-being, sleep quality, physical activity, food diversity and treatment tolerability. Adverse events will be recorded and reviewed by an independent data monitoring committee.Ethics and disseminationEthics approval for the study was granted by the Central Health and Disability Ethics Committee on 24 August 2021 (reference number: 21/CEN/211). Results will be published in peer-reviewed journals and presented to both scientific and consumer group audiences.Trial registration numberACTRN12622000015741.
Oral Probiotic Supplementation in Pregnancy to Reduce Group B Streptococcus Colonisation (OPSiP trial): study protocol for a double-blind parallel group randomised placebo trial
Authors: Hayes Kelly , Janssen Patricia , Payne Beth A , Jevitt Cecilia , Johnston Will , Johnson Patricia , Butler Michelle 
Published: February 2024

IntroductionGroup B streptococcus(GBS), orStreptococcus agalactiae, remains a leading cause of neonatal morbidity and mortality. Canadian guidelines advise universal maternal screening for GBS colonisation in pregnancy in conjunction with selective antibiotic therapy. This results in over 1000 pregnant individuals receiving antibiotic therapy to prevent one case of early-onset neonatal GBS disease, and over 20 000 pregnant individuals receiving antibiotic therapy to prevent one neonatal death. Given the growing concern regarding the risk of negative sequela from antibiotic exposure, it is vital that alternative approaches to reduce maternal GBS colonisation are explored.Preliminary studies suggest some probiotic strains could confer protection in pregnancy against GBS colonisation.Methods and analysisThis double-blind parallel group randomised trial aims to recruit 450 pregnant participants in Vancouver, BC, Canada and will compare GBS colonisation rates in those who have received a daily oral dose of three strains of probiotics with those who have received a placebo. The primary outcome will be GBS colonisation status, measured using a vaginal/rectal swab obtained between 35 weeks’ gestation and delivery. Secondary outcomes will include maternal antibiotic exposure and urogenital infections. Analysis will be on an intention-to-treat basis.Patient or public involvementThere was no patient or public involvement in the design of the study protocol.Ethics and disseminationThis study protocol received ethics approval from the University of British Columbia’s Clinical Research Ethics Board, Dublin City University and Health Canada. Findings will be presented at research rounds, conferences and in peer-reviewed publications.Trial registration numberNCT03407157.
Beating the empty pelvis syndrome: the PelvEx Collaborative core outcome set study protocol
Authors:   PelvEx Collaborative
Published: February 2024

IntroductionThe empty pelvis syndrome is a significant source of morbidity following pelvic exenteration surgery. It remains poorly defined with research in this field being heterogeneous and of low quality. Furthermore, there has been minimal engagement with patient representatives following pelvic exenteration with respect to the empty pelvic syndrome. ‘PelvEx—Beating the empty pelvis syndrome’ aims to engage both patient representatives and healthcare professionals to achieve an international consensus on a core outcome set, pathophysiology and mitigation of the empty pelvis syndrome.Methods and analysisA modified-Delphi approach will be followed with a three-stage study design. First, statements will be longlisted using a recent systematic review, healthcare professional event, patient and public engagement, and Delphi piloting. Second, statements will be shortlisted using up to three rounds of online modified Delphi. Third, statements will be confirmed and instruments for measurable statements selected using a virtual patient-representative consensus meeting, and finally a face-to-face healthcare professional consensus meeting.Ethics and disseminationThe University of Southampton Faculty of Medicine ethics committee has approved this protocol, which is registered as a study with the Core Outcome Measures in Effectiveness Trials Initiative. Publication of this study will increase the potential for comparative research to further understanding and prevent the empty pelvis syndrome.Trial registration numberNCT05683795.
Development and psychometric properties evaluation of nurses’ innovative behaviours inventory in Iran: protocol for a sequential exploratory mixed-method study
Authors: Shahidi Delshad Elham , Soleimani Mohsen , Zareiyan Armin , Ghods Ali Asghar 
Published: February 2024

IntroductionNurses’ innovative behaviours play a crucial role in addressing the challenges including adapting to emerging technologies, resource limitations and social realities such as population ageing that are intricately tied to today’s healthcare landscape. Innovative behaviours improve healthcare quality, patient safety and satisfaction. Organisational factors and individual attributes influence nurses’ inclination to innovate. With the rise of artificial intelligence and novel technology, healthcare institutions are actively engaged in the pursuit of identifying nurses who demonstrate innovative qualities. Developing a comprehensive protocol to elucidate the various dimensions of nurses’ innovative behaviours and constructing a valid measuring instrument, rooted in this protocol represents a significant step in operationalising this concept.Methods and analysisThe study encompasses two phases: a qualitative study combined with a literature review, followed by the design and psychometric evaluation of the instrument. To ensure diversity, a maximum variation purposive sampling method will be used during the qualitative phase to select clinical nurses. In-depth semistructured interviews will be conducted and analysed using conventional content analysis. Additionally, a comprehensive literature review will supplement any missing features not captured in the qualitative phase, ensuring their inclusion in the primary tool. The subsequent quantitative phase will focus on evaluating the questionnaire’s psychometric properties, including face, content and construct validity through exploratory factor analyses (including at least 300 samples) and confirmatory factor analyses (including at least 200 samples). Internal consistency (Cronbach’s alpha), reliability (test–retest), responsiveness, interpretability and scoring will also be assessed.Ethics and disseminationThis study originates from a doctoral dissertation in nursing. Permission and ethical approval from Semnan University of Medical Sciences has been obtained with reference code IR.SEMUMS.1401.226. The study’s findings will ultimately be submitted as a research paper to a peer-reviewed journal.
Study to evaluate the readability and visual appearance of online resources for blunt chest trauma: an evaluation of online resources using mixed methods
Authors: Hutchings Hayley Anne , Cochrane Max , Battle Ceri 
Published: February 2024

ObjectivesBlunt chest trauma (BCT) is characterised by forceful and non-penetrative impact to the chest region. Increased access to the internet has led to online healthcare resources becoming used by the public to educate themselves about medical conditions. This study aimed to determine whether online resources for BCT are at an appropriate readability level and visual appearance for the public.DesignWe undertook a (1) a narrative overview assessment of the website; (2) a visual assessment of the identified website material content using an adapted framework of predetermined key criteria based on the Centers for Medicare and Medicaid Services toolkit and (3) a readability assessment using five readability scores and the Flesch reading ease score using Readable software.Data sourcesUsing a range of key search terms, we searched Google, Bing and Yahoo websites on 9 October 2023 for online resources about BCT.ResultsWe identified and assessed 85 websites. The median visual assessment score for the identified websites was 22, with a range of −14 to 37. The median readability score generated was 9 (14–15 years), with a range of 4.9–15.8. There was a significant association between the visual assessment and readability scores with a tendency for websites with lower readability scores having higher scores for the visual assessment (Spearman’s r=−0.485; p<0.01). The median score for Flesch reading ease was 63.9 (plain English) with a range of 21.1–85.3.ConclusionsAlthough the readability levels and visual appearance were acceptable for the public for many websites, many of the resources had much higher readability scores than the recommended level (8–10) and visually were poor.Better use of images would improve the appearance of websites further. Less medical terminology and shorter word and sentence length would also allow the public to comprehend the contained information more easily.