bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficient and rapid one-step method to generate gene deletions in
Streptococcus pyogenes
Authors: Schiavolin Lionel , Lakhloufi Dalila , Botquin Gwenaelle , Deneubourg Geoffrey , Bruyns Corentin , Steinmetz Jenny , Henrot Charlotte , Delforge Valérie , Smeesters Pierre R. , Botteaux Anne 
Published: August 2024

ABSTRACT

Streptococcus pyogenes
or Group A
Streptococcus
(GAS) remains a significant infectious problem around the world, particularly in low- and middle-income settings. Moreover, a recent invasive GAS infection (iGAS) upsurge has been observed in high-income settings. However, to date, no vaccine is available. Finding a good vaccine antigen and understanding the role of virulence factors in GAS infections have been hampered, in part, by technical difficulties to transform the many different strains and generate knockout mutants. Using colE1-type plasmid as a suicide vector, we have set up a method allowing the generation of non-polar mutants of GAS in 3 days.

IMPORTANCE
Group A Streptococcus (GAS) is a major human pathogen, causing diseases ranging from mild and superficial infections of the skin and pharyngeal epithelium to severe systemic and invasive diseases. Since June 2022, several European countries, the US, and Australia are facing an upsurge of invasive life-threatening GAS infections. Finding a good vaccine antigen and understanding the role of virulence factors in GAS infections have been hampered, in part, by technical difficulties to transform the many different GAS strains and generate knockout mutants. Moreover, these tools must be adapted to a large range of different strains, since GAS are divided into more than 260 emm-types (M-type). We have set up a method allowing the generation of non-polar mutants of GAS in 3 days and in diverse backgrounds, which contrasts with previously published protocols.
An automated positive selection screen in yeast provides support for boron-containing compounds as inhibitors of SARS-CoV-2 main protease
Authors: Sigurdardóttir Sunniva , Silva Suélen Fernandes , Tiukova Ievgeniia , Alalam Hanna , King Ross D. , Grøtli Morten , Eriksson Leif A. , Sunnerhagen Per 
Published: August 2024

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus continues to cause severe disease and deaths in many parts of the world, despite massive vaccination efforts. Antiviral drugs to curb an ongoing infection remain a priority. The virus-encoded 3C-like main protease (MPro; nsp5) is seen as a promising target. Here, with a positive selection genetic system engineered in
Saccharomyces cerevisiae
using cleavage and release of MazF toxin as an indicator, we screened in a robotized setup small molecule libraries comprising ~2,500 compounds for MPro inhibitors. We detected eight compounds as effective against MPro expressed in yeast, five of which are characterized proteasome inhibitors. Molecular docking indicates that most of these bind covalently to the MPro catalytically active cysteine. Compounds were confirmed as MPro inhibitors in an
in vitro
enzymatic assay. Among those were three previously only predicted
in silico
; the boron-containing proteasome inhibitors bortezomib, delanzomib, and ixazomib. Importantly, we establish reaction conditions
in vitro
preserving the MPro-inhibitory activity of the boron-containing drugs. These differ from the standard conditions, which may explain why boron compounds have gone undetected in screens based on enzymatic
in vitro
assays. Our screening system is robust and can find inhibitors of a specific protease that are biostable, able to penetrate a cell membrane, and are not generally toxic. As a cellular assay, it can detect inhibitors that fail in a screen based on an
in vitro
enzymatic assay using standardized conditions, and now give support for boron compounds as MPro inhibitors. This method can also be adapted for other viral proteases.

IMPORTANCE
The coronavirus disease 2019 (COVID-19) pandemic triggered the realization that we need flexible approaches to find treatments for emerging viral threats. We implemented a genetically engineered platform in yeast to detect inhibitors of the virus’s main protease (MPro), a promising target to curb severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Screening molecule libraries, we identified candidate inhibitors and verified them in a biochemical assay. Moreover, the system detected boron-containing molecules as MPro inhibitors. Those were previously predicted computationally but never shown effective in a biochemical assay. Here, we demonstrate that they require a non-standard reaction buffer to function as MPro inhibitors. Hence, our cell-based method detects protease inhibitors missed by other approaches and provides support for the boron-containing molecules. We have thus demonstrated that our platform can screen large numbers of chemicals to find potential inhibitors of a viral protease. Importantly, the platform can be modified to detect protease targets from other emerging viruses.
Comparing the activity of broad-spectrum beta-lactams in combination with aminoglycosides against VIM-producing
Enterobacteriaceae
Authors: Clark Justin A. , Burgess David S. 
Published: August 2024

ABSTRACT

Metallo-beta-lactamase (MBL)-producing carbapenem-resistant
Enterobacteriaceae
(CRE) infections continue to pose a serious threat to healthcare. Due to their unique active site, MBLs evade the activity of many novel beta-lactam/beta-lactamase inhibitor combinations, which have been specifically targeted toward those carbapenemases with serine active sites. Furthermore, resistance to most, if not all, other clinically relevant antimicrobial classes leaves few reliable therapeutic options. Combination therapy has thus played a vital role in the treatment of MBL-producing CRE infections. In this study, we utilized the static time-kill assay to investigate clinically relevant concentrations of cefepime, piperacillin-tazobactam, and meropenem alone and in combination with either amikacin or the novel plazomicin to determine if combinations of routinely used beta-lactam therapy with an aminoglycoside would achieve bactericidal activity against eight clinically isolated Verona integron-encoded MBL (VIM)-producing CRE. Furthermore, we compared this activity to the combination of aztreonam/avibactam, which has shown potent activity against MBL-producing CRE. Both aztreonam/avibactam and meropenem with either aminoglycoside were rapidly bactericidal within 4 hours and remained bactericidal through 24 hours against all isolates with few exceptions. Combinations including cefepime and piperacillin-tazobactam were also rapidly bactericidal, but activity after 24 hours was inconsistent depending upon the partner aminoglycoside and isolate. Further investigation is warranted to elucidate optimal antibiotic exposures against MBL-producing CRE, including novel agents in the pipeline.

IMPORTANCE

Carbapenem-resistant
Enterobacterales
(CRE) are one of the most pressing antimicrobial-resistant threats at present. In addition to exhibiting resistance to many, if not all, commonly used antimicrobial agents, CRE achieves these resistant phenotypes through a variety of mechanisms, each of which can uniquely affect available treatment options. The present study is an
in vitro
investigation of several Verona integron-encoded metallo-beta-lactamase (VIM)-producing CRE isolated from patients at our academic medical center. Because metallo-beta-lactamases (MBLs) are inherently resistant to many of the novel treatments designed to treat CRE due to their different active site composition, we tested several antimicrobial combinations containing routinely utilized broad-spectrum beta-lactams and aminoglycosides. Our results further our understanding of combination therapy options against VIM-producing CRE, including with non-carbapenem-beta-lactams cefepime and piperacillin. By optimizing combinations of existing antimicrobial agents, we hope to expand the available armamentarium against these resistant pathogens.
Comparative treatment of homeless persons with an infectious disease in the US emergency department setting: a retrospective approach
Authors: Barnes Jessica , Segars Larry , Wasserman Jason Adam , Karabon Patrick , Taylor Tracey A H 
Published: August 2024

BackgroundResearch has long documented the increased emergency department usage by persons who are homeless compared with their housed counterparts, as well as an increased prevalence of infectious diseases. However, there is a gap in knowledge regarding the comparative treatment that persons who are homeless receive. This study seeks to describe this potential difference in treatment, including diagnostic services tested, procedures performed and medications prescribed.MethodsThis study used a retrospective, cohort study design to analyse data from the 2007–2010 United States National Hospital Ambulatory Medical Care Survey database, specifically looking at the emergency department subset. Complex sample logistic regression analysis was used to compare variables, including diagnostic services, procedures and medication classes prescribed between homeless and private residence individuals seeking emergency department treatment for infectious diseases. Findings were then adjusted for potential confounding variables.ResultsCompared with private residence individuals, persons who are homeless and presenting with an infectious disease were more likely (adjusted OR: 10.99, CI 1.08 to 111.40, p<0.05) to receive sutures or staples and less likely (adjusted OR: 0.29, CI 0.10 to 0.87, p<0.05) to be provided medications when presenting with an infectious disease in US emergency departments. Significant differences were also detected in prescribing habits of multiple anti-infective medication classes.ConclusionThis study detected a significant difference in suturing/stapling and medication prescribing patterns for persons who are homeless with an infectious disease in US emergency departments. While some findings can likely be explained by the prevalence of specific infectious organisms in homeless populations, other findings would benefit from further research.
Sex differences in early-onset atrial fibrillation in Norwegian primary care: a retrospective national database analysis
Authors: Kalstø Silje Madeleine , Nygård Ståle , Ariansen Inger , Tveit Arnljot , Christophersen Ingrid Elisabeth 
Published: August 2024

BackgroundIndividual variation in the need for healthcare constitutes knowledge gaps for young atrial fibrillation (AF) patients. We aimed to estimate the prevalence and primary care burden of early-onset AF in Norway, emphasising sex differences, in a nationwide healthcare database.MethodsWe used data from the Norwegian Control and Payment of Health Reimbursement database to identify all Norwegian residents ≥18 years of age registered with a primary care physician (PCP) in 2019, with onset of AF at ≤50 years of age (early-onset AF) in the period 2006–2019. From the accumulated number of early-onset AF cases among current residents, we calculated the prevalence in 2019. The group-level primary care burden was calculated as the total number of annual AF consultations divided by the annual number of AF patients (2014–2018), and individual burden as the mean number of consultations per AF patient per year within the study period. We analysed the distribution of AF consultations between PCP and primary care emergency room (ER) services in total and by sex.ResultsWe identified 10 925 Norwegian residents with early-onset AF in 2019 (26.3% women, mean age 48.4 years). The prevalence of early-onset AF was 0.34% (women: 0.19%, men: 0.50%). The early-onset AF population had on average one annual primary care consultation for AF. The individual burden of annual AF consultations varied widely; <1: 66% of women and 54% of men, (1–5]: 25% of women and 36% of men, (5–10]: 6% of women and 8% of men, ≥10: 2% of women and 2% of men. A higher proportion of men (71%) than women (38%) attended both PCP and ER services due to AF.ConclusionsThe study confirmed a low prevalence of early-onset AF, with substantial sex differences and individual variation in primary healthcare needs. Our results signal a need for a higher resolution with regard to age groups in future research on burden and sex differences in early-onset AF.
Nonlinear Schwinger mechanism in QCD, and Fredholm alternatives theorem
Authors: Ferreira M. N. , Papavassiliou J. 
Published: August 2024

AbstractWe present a novel implementation of the Schwinger mechanism in QCD, which fixes uniquely the scale of the effective gluon mass scale and streamlines considerably the procedure of multiplicative renormalization. The key advantage of this method stems from the nonlinear nature of the dynamical equation that generates massless poles in the longitudinal sector of the three-gluon vertex. An exceptional feature of this approach is an extensive cancellation involving the components of the integral expression that determines the gluon mass scale; it is triggered once the Schwinger–Dyson equation of the pole-free part of the three-gluon vertex has been appropriately exploited. It turns out that this cancellation is driven by the so-called Fredholm alternatives theorem, which operates among the set of integral equations describing this system. Quite remarkably, in the linearized approximation this theorem enforces the exact masslessness of the gluon. Instead, the nonlinearity induced by the full treatment of the relevant kernel evades this theorem, allowing for the emergence of a nonvanishing mass scale. The numerical results obtained from the resulting equations are compatible with the lattice findings, and may be further refined through the inclusion of the remaining fundamental vertices of the theory.
Hypoxia Stimulates PYGB Enzymatic Activity to Promote Glycogen Metabolism and Cholangiocarcinoma Progression
Authors: Pan Yani , Zhou Yue , Shen Yonghua , Xu Lei , Liu Hongwen , Zhang Nannan , Huang Tianlu , Meng Kui , Liu Yu , Wang Lishan , Bai Ge , Chen Qi , Zhu Yun , Zou Xiaoping , Wang Siliang , Wang Zhangding , Wang Lei 
Published: August 2024

Abstract
Cholangiocarcinoma (CCA) displays enhanced glycolysis, pivotal for fulfilling the heightened energy demands intrinsic to its malignant progression. Recent research has indicated that endogenous glycogen rather than exogenous glucose acts as the major carbon source for glycolysis, highlighting the need to better understand the regulation of glycogen homeostasis in CCA. Here, through comprehensive integrative analysis, we identified that glycogen phosphorylase brain form (PYGB), the main enzyme involved in glycogen homeostasis, was markedly upregulated in CCA tissues, serving as an independent prognostic indicator for human patients with CCA. Moreover, elevated PYGB expression potentiated cholangiocarcinogenesis and augmented CCA cell proliferation in both organoid and xenograft models. Hypoxia stimulated PYGB activity in a phosphoglycerate kinase 1–dependent manner, leading to glycogenolysis and the subsequent release of glucose-6-phosphate (G6P) and thereby facilitating aerobic glycolysis. Notably, a virtual screening pinpointed the β-blocker carvedilol as a potent pharmacologic inhibitor of PYGB that could attenuate CCA progression. Collectively, these findings position PYGB as a promising prognostic biomarker and therapeutic target for CCA.
Significance: Cholangiocarcinoma cells exhibit high glycogen phosphorylase activity under hypoxic conditions that mediates metabolic reprograming to promote glycolysis and support tumor development.
A Large Cohort Study of Height and Mammographic Density in Relation to Breast Cancer Risk among Korean Women
Authors: Park Ga Eun , Kim Sung Hun , Han Kyungdo 
Published: August 2024

Abstract

Background:
Height and mammographic breast density are well-known risk factors for breast cancer. This study aims to investigate the association between height and mammographic density with breast cancer risk in a large population-based cohort of Korean women.

Methods:
This retrospective cohort study included 4,851,115 women ages 40 and older who underwent screening mammography through the Korean National Cancer Screening Program between 2009 and 2014 and were followed up until 2016. Multivariable Cox proportional hazard models were used to estimate adjusted HRs and 95% confidence intervals (CI) for the associations among height, mammographic density, and breast cancer risk.

Results:
A taller stature was associated with an increased risk of breast cancer, with women in the highest quintile of height (Q5) having a 1.54-fold (95% CI, 1.49–1.59) greater risk than those in the lowest quintile (Q1). When analyzing breast cancer risk based on height and mammographic density, women in the highest quintile for height (Q5) with extremely dense breasts had a 4.51-fold (95% CI, 4.24–4.79) greater risk than those in the lowest quintile (Q1) with almost entirely fatty breasts (Ptrend &lt; 0.001).

Conclusions:
This first study to simultaneously examine these two variables found that height and mammographic density were independently associated with breast cancer risk in this large cohort of Korean women.

Impact:
Height and mammographic density can help stratify risk in screening populations for breast cancer. Careful consideration of screening strategies may be beneficial for taller women with dense breasts.
A passibilidade no gesto de pintar
Authors: Resende José Manuel , Carvalho José Maria 
Published: August 2024

The concept of experience, as suggested by pragmatism, forces us to think about activity together with passibility. The objective of the article is to substantiate the centrality of the latter in artistic creation and to think under what modalities it is experienced empirically by painters in the pictorial gesture. Based on ethnographic research carried out in a social and psychiatric support institution where there is a painting studio with the aim of empowering its users, we conclude that passibility (i) can turn outwards during the pictorial process, or (ii) towards the interior, giving rise to an introspective moment that serves as a motto for painting. We thus demonstrate that passivity and activity are intrinsically coupled in painting.
O lugar da crítica na teoria dos meios de comunicação de massa de Niklas Luhmann
Authors: Palmieri Emerson 
Published: August 2024

Although Niklas Luhmann did not produce a work with a critical objective, his sociological theory holds unexplored potential that can be used to advance critical analyzes of various social dimensions (economics, law, politics, etc.). We chose, here, to use these potentials to observe thepossibilities of making a critique regarding the dimension of the mass media system. We argue that, in it, criticism reveals itself (1) in the observation of the arbitrariness of the social values that the media construct and (2) in the ignorance of the communicative plurality of modernity, which in turn (3) allows us to see the theory of Luhmann as one that reveals absurdities.
Entrevista com Yves Sintomer
Authors: Sierra Vânia Morales , Cruz Fernanda Natasha Bravo 
Published: August 2024

Yves Sintomer é referência em inúmeros trabalhos acadêmicos relacionados às teorias da democracia e às novas formas de representação política, incluindo as experiências de democracia participativa, democracia deliberativa, assembleias cidadãs, sorteio político, orçamento participativo. Professor de ciência política da Universidade Paris 8 e pesquisador do Centro de Pesquisas e Estudos Sociológicos e Políticos de Paris (CRESPPA), ele também é membro associado do Nuffield College, na Universidade de Oxford, e professor associado na Universidade dos Países Bascos e na Universidade de Neuchâtel. Esta entrevista versa sobre a crise das democracias e as inovações políticas experimentadas em diversos lugares no mundo, inclusive no Brasil. A abordagem se concentrou sobre os desafios, possibilidades e limites dos regimes democráticos no contexto atual.
First record of male-male combat in the Yellow-bellied Puffing Snake Spilotes sulphureus (Wagler, 1824)
Authors: Araújo Gabrieli , Ramalho Renan , Almeida-Santos Selma 
Published: August 2024

Abstract
Male ritual combat is an intraspecific agonistic interaction associated with competition for food, mating and territory and has been described for several neotropical snakes. Here, we provide the first record of male-male combat in Spilotes sulphureus in Brazilian Atlantic Forest based on one fortuitous videotaped encounter. Males remained partially coiled in a vertical position during combat and performed various displays (e.g., downward push, tumble, vertical display and orientation, dorsal hyperextension, pinning and lyre-shaped) including some that were also observed during defensive behaviour (e.g., gular inflation, neck S-coil and latero-lateral flattening). Our observations bring new information about the natural history of S. sulphureus and show that this species shares some aspects of male-male combat with other colubrids, including S. pullatus, but a more in-depth study is necessary to understand the reproductive biology of this species.
Longitudinal Trajectories of Self-Reported Cognitive Function and Associated Factors Among Older Cancer Survivors
Authors: Son Youn-Jung , Baek Kyoung-Hwa , Kim Eun Young 
Published: August 2024

Background: Cancer-associated cognitive decline may result in difficulties in maintaining daily life activities for older patients with cancer. It is, therefore, critical to identify changes in cognitive function throughout illness trajectories. Aim: To determine the longitudinal patterns and factors associated with cognitive function among older cancer survivors. Methods: A secondary analysis was conducted using data from the 2012 to 2020 Korean Longitudinal Study of Aging database. A total of 207 cancer survivors aged 60 years and above were included in the analysis. Latent class growth modeling was employed to identify the trajectories of self-reported cognitive function, and logistic regression analysis was used to identify factors associated with these trajectories. Results: The cognitive function of older adults with cancer was divided into 2 distinct trajectories, characterized by differences in intercept (8) and slope (0.7): the “low and declining class” and the “high and sustainable class.” The proportion of individuals belonging to the “high and sustainable class” (n = 153, 73.9%) was significantly and considerably higher than those in the “low and declining class” (n = 54, 26.1%). Individuals with low and declining cognitive function were more likely to be older, have a lower education level, live in rural areas, have poor handgrip strength, experience depression, and have lower social participation compared to those with high and sustainable cognitive function. Conclusions: Our findings can help health care professionals develop tailored interventions for older cancer survivors with low cognitive function based on their physical and mental health status, as well as their environmental backgrounds.