bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mixed-Method Precooling Enhances Self-Paced 20-km Cycling Time-Trial Performance When Apparent Temperature Is >46 °C but May Not Be a Priority in <46 °C
Authors: Ramos Julian Andro P. , Ducker Kagan J. , Riddell Hugh , Girard Olivier , Landers Grant J. , Brade Carly J. 
Published: February 2024

Purpose: Precooling (PreC) may only benefit performance when thermal strain experienced by an individual is sufficiently high. We explored the effect of mixed-method PreC on 20-km cycling time-trial (CTT) performance under 3 different apparent temperatures (AT). Methods: On separate days, 12 trained or highly trained male cyclists/triathletes completed six 20-km CTTs in 3 different ATs: hot-dry (35 °C AT), moderately hot-humid (40 °C AT), and hot-humid (46 °C AT). All trials were preceded by 30 minutes of mixed-method PreC or no PreC (control [CON]). Results: Faster 2.5-km-split completion times occurred in PreC compared with CON in 46 °C AT (P = .02), but not in 40 °C AT (P = .62) or 35 °C AT (P = .57). PreC did not affect rectal and body temperature during the 20-km CTT. Skin temperature was lower throughout the CTT in PreC compared with CON in 46 °C AT (P = .01), but not in 40 °C AT (P = 1.00) and 35 °C AT (P = 1.00). Heart rate had a greater rate of increase during the CTT for PreC compared with CON in 46 °C AT (P = .01), but not in 40 °C AT (P = .57) and 35 °C AT (P = 1.00). Ratings of perceived exertion (P < .001) and thermal comfort (P = .04) were lower for PreC compared with CON in 46 °C AT only, while thermal sensation was not different between PreC and CON. Conclusion: Mixed-method PreC should be applied prior to 20-km CTTs conducted in hot-humid conditions (≥46 °C AT). Alternatively, mixed-method PreC may be a priority in moderately hot-humid (∼40 °C AT) conditions but should not be in hot-dry (∼35 °C AT) conditions for 20-km CTT.
A phase 1 study in healthy volunteers to investigate the safety, tolerability, and pharmacokinetics of VIR-2482: a monoclonal antibody for the prevention of severe influenza A illness
Authors: Plotnik David , Sager Jennifer E. , Aryal Madhukar , Fanget Marie C. , Peter Alessia , Schmid Michael A. , Cebrik Deborah , Mogalian Erik , Boundy Keith , Yeh Wendy W. , Griffin Paul , Reyes Maribel 
Published: February 2024

ABSTRACT

The objective of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of VIR-2482 in healthy adult subjects. A phase 1, first-in-human, randomized, double-blind, placebo-controlled dose-escalation study was conducted. One hundred participants were allocated to four cohorts (60 mg, 300 mg, 1,200 mg, and 1,800 mg). In each cohort, participants were randomized in a 4:1 ratio (active:placebo) to receive either VIR-2482 or volume-matched placebo by gluteal intramuscular injection. Participants remained at the investigative site under observation for 48 h, and adverse events (AEs) were collected for 56 days. PK and immunogenicity were measured up to 52 weeks post-dose. VIR-2482 was well tolerated at all doses studied. The overall incidence of AEs was comparable between VIR-2482 (68.8%) and placebo (85.0%). Nineteen VIR-2482 (23.8%) and six placebo (30.0%) recipients had Grade 1 or 2 AEs that were considered to be related to the study intervention. There were no treatment-related serious AEs. Injection-site reactions (ISRs) were reported in six (7.5%) VIR-2482 recipients, while no such reactions were reported among the placebo recipients. All ISRs were Grade 1, and there was no relationship with the dose. Median VIR-2482 serum elimination half-life ranged from 56.7 to 70.6 days across cohorts. The serum area under the curve and
C
max
were dose-proportional. Nasopharyngeal VIR-2482 concentrations were approximately 2%–5% of serum levels and were less than dose-proportional. The incidence of immunogenicity across all cohorts was 1.3%. Overall, the safety, tolerability, and pharmacokinetic profile of VIR-2482 at doses up to 1,800 mg supported its further investigation as a long-acting antibody for the prevention of influenza A illness. This study has been registered at ClinicalTrials.gov under identifier NCT04033406.
The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of
Candida albicans
Authors: Lo Tricia L. , Wang Qi , Nickson Joshua , van Denderen Bryce J. W. , Deveson Lucas Deanna , Chai Her Xiang , Knott Gavin J. , Weerasinghe Harshini , Traven Ana 
Published: February 2024

ABSTRACT

Fungal infections cause a large health burden but are treated by only a handful of antifungal drug classes. Chromatin factors have emerged as possible targets for new antifungals. These targets include the reader proteins, which interact with posttranslationally modified histones to influence DNA transcription and repair. The YEATS domain is one such reader recognizing both crotonylated and acetylated histones. Here, we performed a detailed structure/function analysis of the
Candida albicans
YEATS domain reader Yaf9, a subunit of the NuA4 histone acetyltransferase and the SWR1 chromatin remodeling complex. We have previously demonstrated that the homozygous deletion mutant
yaf9Δ/Δ
displays growth defects and is avirulent in mice. Here we show that a YEATS domain mutant expected to inactivate Yaf9’s chromatin binding does not display strong phenotypes
in vitro
, nor during infection of immune cells or in a mouse systemic infection model, with only a minor virulence reduction
in vivo
. In contrast to the YEATS domain mutation, deletion of the C-terminal domain of Yaf9, a protein–protein interaction module necessary for its interactions with SWR1 and NuA4, phenocopies the null mutant. This shows that the C-terminal domain is essential for Yaf9 roles
in vitro
and
in vivo
, including
C. albicans
virulence. Our study informs on the strategies for therapeutic targeting of Yaf9, showing that approaches taken for the mammalian YEATS domains by disrupting their chromatin binding might not be effective in
C. albicans
, and provides a foundation for studying YEATS proteins in human fungal pathogens.

IMPORTANCE

The scarcity of available antifungal drugs and rising resistance demand the development of therapies with new modes of action. In this context, chromatin regulation may be a target for novel antifungal therapeutics. To realize this potential, we must better understand the roles of chromatin regulators in fungal pathogens. Toward this goal, here, we studied the YEATS domain chromatin reader Yaf9 in
Candida albicans
. Yaf9 uses the YEATS domain for chromatin binding and a C-terminal domain to interact with chromatin remodeling complexes. By constructing mutants in these domains and characterizing their phenotypes, our data indicate that the Yaf9 YEATS domain might not be a suitable therapeutic drug target. Instead, the Yaf9 C-terminal domain is critical for
C. albicans
virulence. Collectively, our study informs how a class of chromatin regulators performs their cellular and pathogenesis roles in
C. albicans
and reveals strategies to inhibit them.
Bacteriophage specificity is impacted by interactions between bacteria
Authors: Bisesi Ave T. , Möbius Wolfram , Nadell Carey D. , Hansen Eleanore G. , Bowden Steven D. , Harcombe William R. 
Published: February 2024

ABSTRACT

Predators play a central role in shaping community structure, function, and stability. The degree to which bacteriophage predators (viruses that infect bacteria) evolve to be specialists with a single bacterial prey species versus generalists able to consume multiple types of prey has implications for their effect on microbial communities. The presence and abundance of multiple bacterial prey types can alter selection for phage generalists, but less is known about how interactions between prey shape predator specificity in microbial systems. Using a phenomenological mathematical model of phage and bacterial populations, we find that the dominant phage strategy depends on prey ecology. Given a fitness cost for generalism, generalist predators maintain an advantage when prey species compete, while specialists dominate when prey are obligately engaged in cross-feeding interactions. We test these predictions in a synthetic microbial community with interacting strains of
Escherichia coli
and
Salmonella enterica
by competing a generalist T5-like phage able to infect both prey against P22
vir
, an
S. enterica
-specific phage. Our experimental data conform to our modeling expectations when prey species are competing or obligately mutualistic, although our results suggest that the
in vitro
cost of generalism is caused by a combination of biological mechanisms not anticipated in our model. Our work demonstrates that interactions between bacteria play a role in shaping ecological selection on predator specificity in obligately lytic bacteriophages and emphasizes the diversity of ways in which fitness trade-offs can manifest.

IMPORTANCE

There is significant natural diversity in how many different types of bacteria a bacteriophage can infect, but the mechanisms driving this diversity are unclear. This study uses a combination of mathematical modeling and an
in vitro
system consisting of
Escherichia coli
,
Salmonella enterica
, a T5-like generalist phage, and the specialist phage P22
vir
to highlight the connection between bacteriophage specificity and interactions between their potential microbial prey. Mathematical modeling suggests that competing bacteria tend to favor generalist bacteriophage, while bacteria that benefit each other tend to favor specialist bacteriophage. Experimental results support this general finding. The experiments also show that the optimal phage strategy is impacted by phage degradation and bacterial physiology. These findings enhance our understanding of how complex microbial communities shape selection on bacteriophage specificity, which may improve our ability to use phage to manage antibiotic-resistant microbial infections.
A genome-wide CRISPR screen identified host genes essential for intracellular
Brucella
survival
Authors: Xu Heling , Lu Jingjing , Huang Fang , Zhang Qi , Liu Shuang , Chen Zeliang , Li Shanhu 
Published: February 2024

ABSTRACT

Brucella
is a zoonotic intracellular bacterium that poses threats to human health and economic security. Intracellular infection is a hallmark of the agent
Brucella
and a primary cause of distress, through which the bacterium regulates the host intracellular environment to promote its own colonization and replication, evading host immunity and pharmaceutical killing. Current studies of
Brucella
intracellular processes are typically premised on bacterial phenotype such as intracellular bacterial survival, followed by biochemical or molecular biological approaches to reveal detailed mechanisms. While such processes can deepen the understanding of
Brucella
-host interaction, the insights into host alterations in infection would be easily restricted to known pathways. In the current study, we applied CRISPR Cas9 screen to identify host genes that are most affected by
Brucella
infection on cell viability at the genomic level. As a result of CRISPR screening, we firstly identified that knockout of the negatively selected genes
GOLGA6L6
,
DEFB103B
,
OR4F29
, and
ERCC6
attenuate the viability of both the host cells and intracellular
Brucella
, suggesting these genes to be potential therapeutic targets for
Brucella
control. In particular, knockout of
DEFB103B
diminished
Brucella
intracellular survival by altering host cell autophagy. Conversely, knockout of positive screening genes promoted intracellular proliferation of
Brucella
. In summary, we screened host genes at the genomic level throughout
Brucella
infection, identified host genes that are previously not recognized to be involved in
Brucella
infection, and provided targets for intracellular infection control.

IMPORTANCE

Brucella
is a Gram-negative bacterium that infects common mammals causing arthritis, myalgia, neuritis, orchitis, or miscarriage and is difficult to cure with antibiotics due to its intracellular parasitism. Therefore, unraveling the mechanism of
Brucella
-host interactions will help controlling
Brucella
infections. CRISPR-Cas9 is a gene editing technology that directs knockout of individual target genes by guided RNA, from which genome-wide gene-knockout cell libraries can be constructed. Upon infection with
Brucella
, the cell library would show differences in viability as a result of the knockout and specific genes could be revealed by genomic DNA sequencing. As a result, genes affecting cell viability during
Brucella
infection were identified. Further testing of gene function may reveal the mechanisms of
Brucella
-host interactions, thereby contributing to clinical therapy.
Effects of glucose and lactate on
Streptococcus mutans
abundance in a novel multispecies oral biofilm model
Authors: Sangha Jay S. , Barrett Paul , Curtis Thomas P. , Métris Aline , Jakubovics Nicholas S. , Ofiteru Irina D. 
Published: February 2024

ABSTRACT

The oral microbiome plays an important role in protecting oral health. Here, we established a controlled mixed-species
in vitro
biofilm model and used it to assess the impact of glucose and lactate on the ability of
Streptococcus mutans
, an acidogenic and aciduric species, to compete with commensal oral bacteria. A chemically defined medium was developed that supported the growth of
S. mutans
and four common early colonizers of dental plaque:
Streptococcus gordonii
,
Actinomyces oris
,
Neisseria subflava
, and
Veillonella parvula
. Biofilms containing the early colonizers were developed in a continuous flow bioreactor, exposed to
S. mutans
, and incubated for up to 7 days. The abundance of bacteria was estimated by quantitative polymerase chain reaction (qPCR). At high glucose and high lactate, the pH in bulk fluid rapidly decreased to approximately 5.2, and
S. mutans
outgrew other species in biofilms. In low glucose and high lactate, the pH remained above 5.5, and
V. parvula
was the most abundant species in biofilms. By contrast, in low glucose and low lactate, the pH remained above 6.0 throughout the experiment, and the microbial community in biofilms was relatively balanced. Fluorescence
in situ
hybridization confirmed that all species were present in the biofilm and the majority of cells were viable using live/dead staining. These data demonstrate that carbon source concentration is critical for microbial homeostasis in model oral biofilms. Furthermore, we established an experimental system that can support the development of computational models to predict transitions to microbial dysbiosis based on metabolic interactions.

IMPORTANCE

We developed a controlled (by removing host factor) dynamic system metabolically representative of early colonization of
Streptococcus mutans
not measurable
in vivo
. Hypotheses on factors influencing
S. mutans
colonization, such as community composition and inoculation sequence and the effect of metabolite concentrations, can be tested and used to predict the effect of interventions such as dietary modifications or the use of toothpaste or mouthwash on
S. mutans
colonization. The defined
in vitro
model (species and medium) can be simulated in an
in silico
model to explore more of the parameter space.
Effect of a physiotherapy-directed rehabilitation programme on patients with multidirectional instability of the glenohumeral joint: a multimodal interventional MRI study protocol
Authors: Warby Sarah Ann , Ganderton Charlotte , Watson Lyn , Pizzari Tania , Balster Simon , Hoy Gregory , Barwood Shane , Kerr Bonnie , Lawrence Sam , Lenssen Ross , Rotstein Andrew , Takla Annalaise , Civier Oren , Hughes Matthew 
Published: February 2024

IntroductionAltered neuromuscular control of the scapula and humeral head is a typical feature of multidirectional instability (MDI) of the glenohumeral joint, suggesting a central component to this condition. A previous randomised controlled trial showed MDI patients participating in the Watson Instability Program 1 (WIP1) had significantly improved clinical outcomes compared with a general shoulder strength programme. The aim of this paper is to outline a multimodal MRI protocol to identify potential ameliorative effects of the WIP1 on the brain.Methods and analysisThirty female participants aged 18–35 years with right-sided atraumatic MDI and 30 matched controls will be recruited. MDI patients will participate in 24 weeks of the WIP1, involving prescription and progression of a home exercise programme. Multimodal MRI scans will be collected from both groups at baseline and in MDI patients at follow-up. Potential brain changes (primary outcome 1) in MDI patients will be probed using region-of-interest (ROI) and whole-brain approaches. ROIs will depict areas of functional alteration in MDI patients during executed and imagined shoulder movements (MDI vs controls at baseline), then examining the effects of the 24-week WIP1 intervention (baseline vs follow-up in MDI patients only). Whole-brain analyses will examine baseline versus follow-up voxel-wise measures in MDI patients only. Outcome measures used to assess WIP1 efficacy will include the Western Ontario Shoulder Index and the Melbourne Instability Shoulder Score (primary outcomes 2 and 3). Secondary outcomes will include the Tampa Scale for Kinesiophobia, Short Form Orebro, Global Rating of Change Score, muscle strength, scapular upward rotation, programme compliance and adverse events.DiscussionThis trial will establish if the WIP1 is associated with brain changes in MDI.Ethics and disseminationParticipant confidentiality will be maintained with publication of results. Swinburne Human Research Ethics Committee (Ref: 20202806-5692).Trial registration numberAustralian New Zealand Clinical Trial Registry (ACTRN12621001207808).
Clinical and organisational quality indicators for the optimal management of acute ischaemic stroke in the era of thrombectomy: a scoping review and expert consensus study
Authors: Bélanger Amélie , Beaudet Line , Lapointe Thalia , Houle Julie 
Published: February 2024

ObjectiveThe purpose of this study is to identify clinical and organisational quality indicators conducive to the optimal interdisciplinary management of acute-phase ischaemic stroke.MethodA scoping review based on the six-step methodological framework of Arksey and O’Malley (2005) was conducted including a Delphi process with an experts committee.Data sourcesMEDLINE, CINAHL, Academic search complete, Cochrane Library databases, in addition to Google Scholar and Google were searched through January 2015 to February 2023.Eligibility criteriaFrench and English references, dealing with clinical and organisational indicators for the management and optimal care of adults with acute ischaemic stroke.Data extraction and synthesisAfter duplicate removal, all publications were checked for title and abstract. The full text of articles meeting the inclusion criteria was reviewed. Two independent reviewers performed 10% of the study selection and data extraction. Data collected underwent descriptive statistics.ResultsOf the 4343 references identified, 31 were included in the scoping review. About 360 indicators were identified and preliminary screened by two stroke experts. Fifty-four indicators were evaluated for validity, relevance and feasibility by a committee of experts including a partner patient using a Delphi method. A total of 34 indicators were selected and classified based on dimensions of care performance such as accessibility of services, quality of care and resource optimisation. Safety accounted for about one-third of the indicators, while there were few indicators for sustainability, equity of access and responsiveness.ConclusionThis scoping review shows there are many clinical and organisational indicators in the literature that are relevant, valid and feasible for improving the quality of care in the acute phase of ischaemic stroke. Future research is essential to highlight clinical and organisational practices in the acute phase.Registration detailshttps://osf.io/qc4mk/
Lessons learnt and best practices in scaling up an emergency transportation system to tackle maternal and neonatal mortality: a qualitative study of key stakeholders in Shinyanga, Tanzania
Authors: Sunguya Bruno F , Ngowi Jackline E , Njiro Belinda J , Munishi Castory , Ndumwa Harrieth Peter , Kengia James , Kapologwe Ntuli A , Deng Linda , Timbrell Alice , Kitinya Wilson J , Mlunde Linda B 
Published: February 2024

ObjectiveThis study aimed to document lessons learnt and best practices for scaling up an innovative emergency transportation system, drawing insights from the m-mama programme implemented in Shinyanga, Tanzania. The m-mama pilot programme was implemented in phases from 2014 to 2016 in two districts and later scaled up to include all districts in Shinyanga region in 2017. The programme employed an emergency transportation system and technical and operational support of the health system to address the three delays leading to maternal and neonatal mortality.DesignCross-sectional, qualitative research with key healthcare system stakeholders from the national, regional and district levels.SettingThe study was conducted in Kahama and Kishapu districts in Shinyanga, Tanzania. The two districts were selected purposefully to represent the programme implementation districts’ rural and urban or semiurban settings.ParticipantsDistrict, regional and national stakeholders involved in implementing the m-mama pilot programme in Shinyanga were interviewed between February and March 2022.ResultsLessons learnt from implementing the m-mama programme were grouped into four key themes: community engagement, emergency transportation system, government engagement, and challenges and constraints in technical implementation. Stakeholder engagement and collaboration at all levels, community involvement in implementation, adherence to local contexts and effective government partnerships were identified as key drivers for programme success. Coordination, supervision and infrastructure enhancement were crucial in implementing the emergency transportation system.ConclusionsFacilitating community involvement, understanding the local context and adapting to existing structures can enhance programme ownership and utilisation. The government serves as the central coordinator, overseeing resource mobilisation and distribution. A well-executed and coordinated emergency transportation system holds promise in addressing delays and curbing maternal and neonatal mortality. Collaborative knowledge-sharing among implementers is essential for identifying best practices and gaining insights into practical strategies for addressing anticipated challenges.