bluuebunny/crossref_metadata_2025_split huggingface dataset:
Capsule production promotes Group B
Streptococcus
intestinal colonization
Authors: Vaz Michelle J. , Dongas Sophia , Ratner Adam J. 
Published: September 2023

ABSTRACT

Late-onset disease is the most common clinical presentation of Group B
Streptococcus
(GBS) infection during infancy, and gastrointestinal (GI) colonization is an important precursor. Previously, we described a murine model of postnatal GBS GI colonization that resulted in sustained colonization and progression to invasive disease. Capsular polysaccharide is an important GBS virulence factor. Vaccines based on a subset of capsular serotypes are in clinical trials. However, little is known regarding the role of specific GBS capsular serotypes in GI colonization. We examined the role of GBS capsule in GI colonization using capsule-producing and acapsular strains derived from GBS strain A909 (serotype Ia) in a murine model. Using isogenic GBS strains differing only in capsular serotypes, we explored the role of specific serotypes in GI colonization by determining competitive indices during cocolonization. We found that GBS A909 colonizes the murine GI tract without causing invasive disease. In monocolonization experiments, there was colonization persistence with the capsule-producing strain (100%) compared to the acapsular mutant strain (13%). In cocolonization experiments, the capsule-producing strain outcompeted its isogenic acapsular mutant, with a geometric mean competitive index of 8, 95% confidence interval (CI) [1.7, 38.9] in the colon at 7 days post-colonization. A909 expressing its native serotype Ia capsule outcompeted an isogenic mutant that expresses serotype III capsule, with a geometric mean competitive index of 2.5, 95% CI [1.2, 5.1] in the colon at 7 days post-colonization. Thus, polysaccharide capsule production enhances GBS GI colonization
in vivo
. In an A909 genetic background, the production of a serotype Ia capsule provides a competitive advantage over an isogenic strain producing type III capsule. The murine model is a valuable tool to understand the role of GBS capsule types in GI colonization.

IMPORTANCE

The establishment of GBS intestinal colonization is believed to be a critical precursor to late-onset disease in neonates, which has a significant impact on neurodevelopment outcomes in this population. Our prior work described a murine model of postnatal Group B
Streptococcus
(GBS) acquisition and invasive disease. Using this model, we explored the importance of GBS polysaccharide capsule production on gastrointestinal colonization. We found that the expression of capsule (compared to isogenic acapsular strains) provides an advantage in intestinal colonization and, importantly, that capsule type Ia has an advantage over capsule type III in a GBS A909 strain background. We speculate that specific serotypes may differ in colonization fitness, which may play a role in serotype distribution in neonatal disease.
Inhibitory effect of natural flavone luteolin on
Streptococcus mutans
biofilm formation
Authors: Rudin Lucille , Roth Noelle , Kneubühler Julien , Dubey Badri Nath , Bornstein Michael M. , Shyp Viktoriya 
Published: September 2023

ABSTRACT

Streptococcus mutans
is one of the key pathogens responsible for dental caries, which is known to be one of the most prevalent biofilm-associated diseases worldwide.
S. mutans
virulence strongly depends on its biofilm formation and enamel demineralization abilities due to the production of surface adhesins, exopolysaccharides, and acid in the presence of sugar. Luteolin is an abundant natural flavone with a prominent anti-bacterial function. However, it remains unclear how luteolin affects
S. mutans
pathogenicity including its acidogenicity and biofilm formation. In this study, the effect of luteolin on
S. mutans
growth, acid production, and its early and late biofilm formation and biofilm disruption was tested. Luteolin shows strong anti-biofilm activity, while it remains non-toxic for bacterial cell viability. In the biofilm, luteolin reduces the expression of
S. mutans
virulence genes such as
gbpC
,
spaP
,
gtfBCD
, and
ftf
encoding for surface adhesins and extracellular polysaccharides (EPS)-producing enzymes, which reflects in the strong reduction of bacteria and EPS. Further, it reduces water-insoluble glucan production in the biofilm, potentially, via direct interference with glucosyltransfereases (Gtfs). Moreover, at biofilm inhibitory concentrations, luteolin significantly reduces acid production by
S. mutans
. Finally, luteolin could target
S. mutans
amyloid proteins to disrupt the biofilm based on the observation that it inhibits the uptake of the amyloid dye, thioflavin T, by
S. mutans
extracellular proteins and failed to inhibit biofilm formation by the mutant strain lacking three main amyloid proteins. In conclusion, luteolin appears to be a potent natural compound with pleiotropic anti-biofilm properties against one of the main cariogenic human pathogens,
S. mutans
.

IMPORTANCE

Flavonoids are natural compounds with proven anti-bacterial and anti-biofilm properties. Here, we describe the anti-biofilm properties of natural flavone luteolin against the main cariogenic bacteria,
S. mutans
. Luteolin inhibited gene expression of cell surface adhesins, fructosyltransferases, and glucosyltransferases, which promotes a significant reduction of bacterial and EPS biomass in early and late biofilms. Moreover, luteolin could directly target
S. mutans
Gtfs and functional amyloids to modulate pathogenic biofilms. These observations provide important insights into the anti-biofilm properties of luteolin while laying out a framework for future therapeutic strategies targeting biofilm-associated virulence factors of oral pathogens.
Socioeconomic inequalities in physical activity among older adults before and during the COVID-19 pandemic: evidence from the English Longitudinal Study of Ageing
Authors: Malkowski Olivia S , Townsend Nick P , Kelson Mark J , Foster Charlie E M , Western Max J 
Published: September 2023

IntroductionThe influence of the COVID-19 pandemic on physical activity behaviour in older adults is of particular concern. However, little is yet known about how pre-existing socioeconomic inequalities in older adults’ physical activity have been affected by the COVID-19 pandemic. The aim of this study was to explore socioeconomic disparities in physical activity levels and change over time among older adults in England, using data collected before and during the COVID-19 pandemic.MethodsThis longitudinal cohort study analysed data from 3720 older adults (aged 60+ years) who participated in wave 9 (2018/2019) of the main English Longitudinal Study of Ageing (ELSA) survey and wave 2 of the ELSA COVID-19 substudy (November/December 2020). Using multilevel ordinal logistic models, we investigated associations between socioeconomic variables (education, occupational class and wealth) and physical activity, adjusting for potential confounders. We also examined interactions between socioeconomic variables and time (prepandemic vs intrapandemic) to investigate changes in the magnitude of inequalities in physical activity across the two survey periods.ResultsThe proportion of participants considered ‘inactive’ rose from 5.7% before the COVID-19 pandemic to 12.5% in November and December 2020. Higher education, occupational class and wealth were positively associated with physical activity before the lockdown. These socioeconomic disparities generally persisted during the COVID-19 pandemic. There was some evidence that differences in physical activity based on education and occupational class reduced during the COVID-19 pandemic, relative to prepandemic data. However, these associations were no longer statistically significant when the three socioeconomic variables and their interactions with time corrected for one another (p>0.05).ConclusionOur results suggest there was no additional influence of the COVID-19 pandemic on pre-existing socioeconomic inequalities in older adults’ physical activity levels.
Topological solitons in the sigma-cuscuton model
Authors: Lima F. C. E. , Almeida C. A. S. 
Published: September 2023

AbstractBuilding a multi-field theory with canonical and non-canonical contributions, one studies the topological solitons of the O(3)-sigma model. We propose a model constituted by the O(3)-sigma field, the cuscuton-like neutral scalar field, and Maxwell’s field. We investigate BPS properties considering a theory without interaction. One performs this study by adopting the first-order formalism in a model with contribution non-canonical. Thus, these contributions will preserve the spontaneous symmetry breaking of the system. Concurrently, a non-minimal coupling between the sigma and the Maxwell field is assumed. In this scenario, interesting results arise, i.e., one notes that the solitons have an internal structure and ring-like profile. Furthermore, one observes that the ring-like configurations that emerge are directly related to the contribution of the cuscuton-like term.
Understanding and Predicting User Satisfaction with Conversational Recommender Systems
Authors: Siro Clemencia , Aliannejadi Mohammad , De Rijke Maarten 
Published: September 2023

User satisfaction depicts the effectiveness of a system from the user’s perspective. Understanding and predicting user satisfaction is vital for the design of user-oriented evaluation methods forconversational recommender systems (CRSs). Current approaches rely on turn-level satisfaction ratings to predict a user’s overall satisfaction with CRS. These methods assume that all users perceive satisfaction similarly, failing to capture the broader dialogue aspects that influence overall user satisfaction.We investigate the effect of several dialogue aspects on user satisfaction when interacting with a CRS. To this end, we annotate dialogues based on six aspects (i.e.,relevance,interestingness,understanding,task-completion,interest-arousal, andefficiency) at the turn and dialogue levels. We find that the concept of satisfaction varies per user. At the turn level, a system’s ability to make relevant recommendations is a significant factor in satisfaction. We adopt these aspects as features for predicting response quality and user satisfaction. We achieve an F1-score of 0.80 in classifying dissatisfactory dialogues, and a Pearson’srof 0.73 for turn-level response quality estimation, demonstrating the effectiveness of the proposed dialogue aspects in predicting user satisfaction and being able to identify dialogues where the system is failing.With this article, we release our annotated data.1
ATM Mutations Associate with Distinct Co-Mutational Patterns and Therapeutic Vulnerabilities in NSCLC
Authors: Vokes Natalie I. , Galan Cobo Ana , Fernandez-Chas Margarita , Molkentine David , Treviño Santiago , Druker Vitaly , Qian Yu , Patel Sonia , Schmidt Stephanie , Hong Lingzhi , Lewis Jeff , Rinsurongkawong Waree , Rinsurongkawong Vadeerat , Lee J. Jack , Negrao Marcelo V. , Gibbons Don L. , Vaporciyan Ara , Le Xiuning , Wu Jia , Zhang Jianjun , Rigney Una , Iyer Sonia , Dean Emma , Heymach John V. 
Published: September 2023

Abstract

Purpose:
Ataxia-telangiectasia mutated (ATM) is the most frequently mutated DNA damage repair gene in non–small cell lung cancer (NSCLC). However, the molecular correlates of ATM mutations and their clinical implications have not been fully elucidated.

Experimental Design:
Clinicopathologic and genomic data from 26,587 patients with NSCLC from MD Anderson, public databases, and a de-identified nationwide (US-based) NSCLC clinicogenomic database (CGDB) were used to assess the co-mutation landscape, protein expression, and mutational processes in ATM-mutant tumors. We used the CGDB to evaluate ATM-associated outcomes in patients treated with immune checkpoint inhibitors (ICI) with or without chemotherapy, and assessed the effect of ATM loss on STING signaling and chemotherapy sensitivity in preclinical models.

Results:
Nonsynonymous mutations in ATM were observed in 11.2% of samples (2,980/26,587) and were significantly associated with mutations in KRAS, but mutually exclusive with EGFR (q &lt; 0.1). KRAS mutational status constrained the ATM co-mutation landscape, with strong mutual exclusivity with TP53 and KEAP1 within KRAS-mutated samples. Those ATM mutations that co-occurred with TP53 were more likely to be missense mutations and associate with high mutational burden, suggestive of non-functional passenger mutations. In the CGDB cohort, dysfunctional ATM mutations associated with improved OS only in patients treated with ICI-chemotherapy, and not ICI alone. In vitro analyses demonstrated enhanced upregulation of STING signaling in ATM knockout cells with the addition of chemotherapy.

Conclusions:
ATM mutations define a distinct subset of NSCLC associated with KRAS mutations, increased TMB, decreased TP53 and EGFR co-occurrence, and potential increased sensitivity to ICIs in the context of DNA-damaging chemotherapy.
PERK Inhibition by HC-5404 Sensitizes Renal Cell Carcinoma Tumor Models to Antiangiogenic Tyrosine Kinase Inhibitors
Authors: Stokes Michael E. , Calvo Veronica , Fujisawa Sho , Dudgeon Crissy , Huang Sharon , Ballal Nupur , Shen Leyi , Gasparek Jennifer , Betzenhauser Matthew , Taylor Simon J. , Staschke Kirk A. , Rigby Alan C. , Mulvihill Mark J. , Bose Nandita , Lightcap Eric S. , Surguladze David 
Published: September 2023

Abstract

Purpose:
Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI).

Experimental Design:
HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then cotreated with both HC-5404 and VEGFR-TKI in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC.

Results:
VEGFR-TKI including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKI across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ∼20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, nine out of 18 models responded with ≥50% tumor regression from baseline in the combination group.

Conclusions:
By disrupting an adaptive stress response evoked by VEGFR-TKI, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard-of-care therapies in RCC.
PD-1 Blockade Induces Reactivation of Nonproductive T-Cell Responses Characterized by NF-κB Signaling in Patients with Pancreatic Cancer
Authors: Ali Lestat R. , Lenehan Patrick J. , Cardot-Ruffino Victoire , Dias Costa Andressa , Katz Matthew H.G. , Bauer Todd W. , Nowak Jonathan A. , Wolpin Brian M. , Abrams Thomas A. , Patel Anuj , Clancy Thomas E. , Wang Jiping , Mancias Joseph D. , Reilley Matthew J. , Stucky Chee-Chee H. , Bekaii-Saab Tanios S. , Elias Rawad , Merchant Nipun , Slingluff Craig L. , Rahma Osama E. , Dougan Stephanie K. 
Published: September 2023

Abstract

Purpose:
Pancreatic ductal adenocarcinoma (PDAC) trials have evaluated CTLA-4 and/or PD-(L)1 blockade in patients with advanced disease in which bulky tumor burden and limited time to develop antitumor T cells may have contributed to poor clinical efficacy. Here, we evaluated peripheral blood and tumor T cells from patients with PDAC receiving neoadjuvant chemoradiation plus anti–PD-1 (pembrolizumab) versus chemoradiation alone. We analyzed whether PD-1 blockade successfully reactivated T cells in the blood and/or tumor to determine whether lack of clinical benefit could be explained by lack of reactivated T cells versus other factors.

Experimental Design:
We used single-cell transcriptional profiling and TCR clonotype tracking to identify TCR clonotypes from blood that match clonotypes in the tumor.

Results:
PD-1 blockade increases the flux of TCR clonotypes entering cell cycle and induces an IFNγ signature like that seen in patients with other GI malignancies who respond to PD-1 blockade. However, these reactivated T cells have a robust signature of NF-κB signaling not seen in cases of PD-1 antibody response. Among paired samples between blood and tumor, several of the newly cycling clonotypes matched activated T-cell clonotypes observed in the tumor.

Conclusions:
Cytotoxic T cells in the blood of patients with PDAC remain sensitive to reinvigoration by PD-1 blockade, and some have tumor-recognizing potential. Although these T cells proliferate and have a signature of IFN exposure, they also upregulate NF-κB signaling, which potentially counteracts the beneficial effects of anti–PD-1 reinvigoration and marks these T cells as non-productive contributors to antitumor immunity.
See related commentary by Lander and DeNardo, p. 474
Chromatin Accessibility Landscape of Human Triple-negative Breast Cancer Cell Lines Reveals Variation by Patient Donor Ancestry
Authors: Harris Alexandra R. , Panigrahi Gatikrushna , Liu Huaitian , Koparde Vishal N. , Bailey-Whyte Maeve , Dorsey Tiffany H. , Yates Clayton C. , Ambs Stefan 
Published: September 2023

AbstractAfrican American (AA) women have an excessive risk of developing triple-negative breast cancer (TNBC). We employed Assay for Transposase-Accessible Chromatin using sequencing to characterize differences in chromatin accessibility between nine commonly used TNBC cell lines derived from patients of European and African ancestry. Principal component and chromosome mapping analyses of accessibility peaks with the most variance revealed separation of chromatin profiles by patient group. Motif enrichment and footprinting analyses of disparate open chromatin regions revealed differences in transcription factor activity, identifying 79 with ancestry-associated binding patterns (FDR &lt; 0.01). AA TNBC cell lines exhibited increased accessibility for 62 transcription factors associated with epithelial-to-mesenchymal transition, cancer stemness/chemotherapeutic resistance, proliferation, and aberrant p53 regulation, as well as KAISO, which has been previously linked to aggressive tumor characteristics in AA patients with cancer. Differential Assay for Transposase-Accessible Chromatin signal analysis identified 1,596 genes located within promoters of differentially open chromatin regions in AA-derived TNBC, identifying DNA methyltransferase 1 as the top upregulated gene associated with African ancestry. Pathway analyses with these genes revealed enrichment in several pathways, including hypoxia. Culturing cells under hypoxia showed ancestry-specific stress responses that led to the identification of a core set of AA-associated transcription factors, which included members of the Kruppel-like factor and Sp subfamilies, as well as KAISO, and identified ZDHHC1, a gene previously implicated in immunity and STING activation, as the top upregulated AA-specific gene under hypoxia. Together, these data reveal a differential chromatin landscape in TNBC associated with donor ancestry. The open chromatin structure of AA TNBC may contribute to a more lethal disease.Significance:We identify an ancestry-associated open chromatin landscape and related transcription factors that may contribute to aggressive TNBC in AA women. Furthermore, this study advocates for the inclusion of diversely sourced cell lines in experimental in vitro studies to advance health equity at all levels of scientific research.
Amphibian Diversity: Where everything starts to flood, Cáceres Municipality, North Pantanal, Central-West Brazil
Authors: Silva-Alves Vancleber Divino , Neves Matheus Oliveira , Seba Mariany de Fatima Rocha , Santos Filho Manoel dos , Silva Dionei José da 
Published: September 2023

Faunal inventories contribute to our understanding of regional diversity, and are fundamental for policy and decision-making regarding the management and conservation of large natural areas. This study aimed to inventory and compile information on amphibian species occurring in the North Pantanal region, in the municipal limits of Cáceres, Mato Grosso, Brazil. We used three methods to inventory amphibian species: (1) fieldwork, (2) analysis of specimens deposited in scientific collections, and (3) literature reviews. We registered 49 amphibian species in Cáceres. Of them, 48 species belonged to the Anura order and were distributed across eight families and 20 genera, and one species belonged to the Gymnophiona order (Siphonops paulensis). The families Leptodactylidae (20 spp.) and Hylidae (17 spp.) were dominant in terms of richness, accounting for 75.5% of all species found in Cáceres. The remaining families had between four and one species each. The municipality is strongly influenced by non-forested formations (e.g., the Cerrado and Pantanal) and presents a high species richness for a non-forested location in Brazil. Our findings highlight Cáceres as one of the richest areas in amphibian species in the North Pantanal region, expanding our knowledge regarding frog diversity. This study provides a foundation for future conservation strategies and additional assessments of amphibian species in light of potential population declines and other emerging threats.