bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adaptive variations in SARS-CoV-2 spike proteins: effects on distinct virus-cell entry stages
Authors: Qing Enya , Gallagher Tom 
Published: June 2023

ABSTRACT
Evolved SARS-CoV-2 variants of concern (VOCs) spread through human populations in succession. Major virus variations are in the entry-facilitating viral spike (S) proteins; Omicron VOCs have 29–40 S mutations relative to ancestral D614G viruses. The impacts of this Omicron divergence on S protein structure, antigenicity, cell entry pathways, and pathogenicity have been extensively evaluated, yet gaps remain in correlating specific alterations with S protein functions. In this study, we compared the functions of ancestral D614G and Omicron VOCs using cell-free assays that can reveal differences in several distinct steps of the S-directed virus entry process. Relative to ancestral D614G, Omicron BA.1 S proteins were hypersensitized to receptor activation, to conversion into intermediate conformational states, and to membrane fusion-activating proteases. We identified mutations conferring these changes in S protein character by evaluating domain-exchanged D614G/Omicron recombinants in the cell-free assays. Each of the three functional alterations was mapped to specific S protein domains, with the recombinants providing insights on inter-domain interactions that fine-tune S-directed virus entry. Our results provide a structure-function atlas of the S protein variations that may promote the transmissibility and infectivity of current and future SARS-CoV-2 VOCs.

IMPORTANCE
Continuous SARS-CoV-2 adaptations generate increasingly transmissible variants. These succeeding variants show ever-increasing evasion of suppressive antibodies and host factors, as well as increasing invasion of susceptible host cells. Here, we evaluated the adaptations enhancing invasion. We used reductionist cell-free assays to compare the entry steps of ancestral (D614G) and Omicron (BA.1) variants. Relative to D614G, Omicron entry was distinguished by heightened responsiveness to entry-facilitating receptors and proteases and by enhanced formation of intermediate states that execute virus-cell membrane fusion. We found that these Omicron-specific characteristics arose from mutations in specific S protein domains and subdomains. The results reveal the inter-domain networks controlling S protein dynamics and efficiencies of entry steps, and they offer insights on the evolution of SARS-CoV-2 variants that arise and ultimately dominate infections worldwide.
Mus musculus papillomavirus 1 E8^E2 represses expression of late protein E4 in basal-like keratinocytes via NCoR/SMRT-HDAC3 co-repressor complexes to enable wart formation
in vivo
Authors: Kuehner Franziska , Wong Margaret , Straub Elke , Doorbar John , Iftner Thomas , Roden Richard B. S. , Stubenrauch Frank 
Published: June 2023

ABSTRACT

High-risk human papillomaviruses (PV) account for approximately 600,000 new cancers per year. The early protein E8^E2 is a conserved repressor of PV replication, whereas E4 is a late protein that arrests cells in G2 and collapses keratin filaments to facilitate virion release. While inactivation of the Mus musculus PV1 (MmuPV1)
E8
start codon (E8-) increases viral gene expression, surprisingly, it prevents wart formation in FoxN1
nu/nu
mice. To understand this surprising phenotype, the impact of additional E8^E2 mutations was characterized in tissue culture and mice. MmuPV1 and HPV E8^E2 similarly interact with cellular NCoR/SMRT-HDAC3 co-repressor complexes. Disruption of the splice donor sequence used to generate the
E8^E2
transcript or E8^E2 mutants (mt) with impaired binding to NCoR/SMRT-HDAC3 activates MmuPV1 transcription in murine keratinocytes. These MmuPV1 E8^E2 mt genomes also fail to induce warts in mice. The phenotype of E8^E2 mt genomes in undifferentiated cells resembles productive PV replication in differentiated keratinocytes. Consistent with this, E8^E2 mt genomes induced aberrant E4 expression in undifferentiated keratinocytes. In line with observations for HPV, MmuPV1 E4-positive cells displayed a shift to the G2 phase of the cell cycle. In summary, we propose that in order to enable both expansion of infected cells and wart formation
in vivo
, MmuPV1 E8^E2 inhibits E4 protein expression in the basal keratinocytes that would otherwise undergo E4-mediated cell cycle arrest.

IMPORTANCE

Human papillomaviruses (PVs) initiate productive replication, which is characterized by genome amplification and expression of E4 protein strictly within suprabasal, differentiated keratinocytes. Mus musculus PV1 mutants that disrupt splicing of the E8^E2 transcript or abolish the interaction of E8^E2 with cellular NCoR/SMRT-HDAC3 co-repressor complexes display increased gene expression in tissue culture but are unable to form warts
in vivo
. This confirms that the repressor activity of E8^E2 is required for tumor formation and genetically defines a conserved E8 interaction domain. E8^E2 prevents expression of E4 protein in basal-like, undifferentiated keratinocytes and thereby their arrest in G2 phase. Since binding of E8^E2 to NCoR/SMRT-HDAC3 co-repressor is required to enable expansion of infected cells in the basal layer and wart formation
in vivo
, this interaction represents a novel, conserved, and potentially druggable target.
Presence of flavoured electronic nicotine delivery system (ENDS) products in US ENDS advertisements, 2015–2020: a content analysis
Authors: Moran M B , Czaplicki Lauren , Tadesse Lidya , Handy Jessica , Welding Kevin , Kelley Dannielle , Kennedy Ryan David 
Published: June 2023

ObjectivesElectronic nicotine delivery systems (ENDS) products come in a variety of flavours (eg, fruit, dessert, menthol). Tobacco advertising has historically used flavours as an advertising tactic, but little is known about flavour type and prevalence in ENDS advertisements. We assess the presence of flavoured ENDS in ads over time, by media outlet (eg, magazines, online) and brand.MethodsWe acquired ENDS ads (N=4546) that first ran between 2015–2017 (n=1685; study 1) and 2018–2020 (n=2861; study 2) in outlets including opt-in emails, direct-to-consumer mail (study 1 only), video (TV and online), radio (study 2 only), static online/mobile (ie, ads without video or moving graphics), social media, outdoor (eg, billboards; study 2 only) and consumer magazines. We coded for presence of flavoured ENDS products and flavour type (eg, fruit, tobacco, menthol) and merged this information with metadata on ad year, outlet and manufacturer/retailer brand.ResultsOverall, nearly half (45.5%; n=2067) of ads in our sample featured a flavoured product. Tobacco (59.1%; n=1221), menthol (42.9%; n=887) and fruit (38.6%; n=797) were the most advertised flavours. Over time, the proportion of ads containing tobacco-flavoured and menthol-flavoured ENDS generally decreased before menthol rebounded in 2020. The proportion of ads containing fruit, mint and dessert flavours generally increased over time, with a substantive drop in 2020. We found notable differences in flavoured ENDS advertising by outlet and brand.ConclusionsThe overall presence of flavoured ENDS in our sample of ads remained relatively consistent, with tobacco flavour decreasing over time and some non-tobacco flavours increasing over time until 2020 when the presence decreased.
Optimising the care for older persons with complex chronic conditions in home care and nursing homes: design and protocol of I-CARE4OLD, an observational study using real-world data
Authors: Hoogendijk Emiel O , Onder Graziano , Smalbil Louk , Vetrano Davide L , Hirdes John P , Howard Elizabeth P , Morris John N , Fialová Daniela , Szczerbińska Katarzyna , Kooijmans Eline CM , Hoogendoorn Mark , Declercq Anja , De Almeida Mello Johanna , Leskelä Riikka-Leena , Häsä Jokke , Edgren Johanna , Ruppe Georg , Liperoti Rosa , Joling Karlijn J , van Hout Hein PJ 
Published: June 2023

IntroductionIn ageing societies, the number of older adults with complex chronic conditions (CCCs) is rapidly increasing. Care for older persons with CCCs is challenging, due to interactions between multiple conditions and their treatments. In home care and nursing homes, where most older persons with CCCs receive care, professionals often lack appropriate decision support suitable and sufficient to address the medical and functional complexity of persons with CCCs. This EU-funded project aims to develop decision support systems using high-quality, internationally standardised, routine care data to support better prognostication of health trajectories and treatment impact among older persons with CCCs.Methods and analysisReal-world data from older persons aged ≥60 years in home care and nursing homes, based on routinely performed comprehensive geriatric assessments using interRAI systems collected in the past 20 years, will be linked with administrative repositories on mortality and care use. These include potentially up to 51 million care recipients from eight countries: Italy, the Netherlands, Finland, Belgium, Canada, USA, Hong Kong and New Zealand. Prognostic algorithms will be developed and validated to better predict various health outcomes. In addition, the modifying impact of pharmacological and non-pharmacological interventions will be examined. A variety of analytical methods will be used, including techniques from the field of artificial intelligence such as machine learning. Based on the results, decision support tools will be developed and pilot tested among health professionals working in home care and nursing homes.Ethics and disseminationThe study was approved by authorised medical ethical committees in each of the participating countries, and will comply with both local and EU legislation. Study findings will be shared with relevant stakeholders, including publications in peer-reviewed journals and presentations at national and international meetings.
Cognitive assessment after stroke: A qualitative study of patients’ experiences
Authors: Hobden Georgina , Tang Eugene , Demeyere Nele 
Published: June 2023

ObjectivesClinical guidelines recommend early cognitive assessment after stroke to inform rehabilitation and discharge decisions. However, little is known about stroke survivors’ experiences of the cognitive assessment process. This qualitative study aimed to explore patients’ experiences of poststroke cognitive assessments.DesignStroke survivors were purposively sampled in an iterative process through a pool of research volunteers who had previously taken part in the Oxford Cognitive Screen Recovery study. Stroke survivors and their family caregivers were invited to participate in a semistructured interview steered by a topic guide. Interviews were audio recorded, transcribed and analysed using reflexive thematic analysis. Demographic, clinical and cognitive data were acquired from patients’ previous research data.SettingStroke survivors were originally recruited from the acute inpatient unit at Oxford University Hospital (John Radcliffe), UK. Participants were interviewed after discharge either at their homes or via telephone or videocall.ParticipantsTwenty-six stroke survivors and eleven caregivers participated in semi-structured interviews.ResultsWe identified three key phases of the cognitive assessment process and themes pertaining to each phase. The phases (numbered) and themes (lettered) were as follows: (1) before the cognitive assessment: (A) lack of explanation, (B) considering the assessment useless; (2) during the cognitive assessment: varied emotional responses, moderated by (D) perception of the purpose behind cognitive assessment, (E) perception of cognitive impairment, (F) confidence in cognitive abilities, (G) assessment administration style and (3) after the cognitive assessment: (H) feedback can impact self-confidence and self-efficacy, (I) vague feedback and clinical jargon are unhelpful.ConclusionsStroke survivors require clear explanations about the purpose and outcomes of poststroke cognitive assessments, including constructive feedback, to promote engagement with the process and protect their psychological wellbeing.
Carbohydrate ligand engagement with CD11b enhances differentiation of tumor-associated myeloid cells for immunotherapy of solid cancers
Authors: Roche Veronique , Sandoval Victor , Wolford Claire , Senders Zachary , Kim Julian Anthony , Ribeiro Susan Pereira , Huang Alex Yicheng , Sekaly Rafick-Pierre , Lyons Joshua , Zhang Mei 
Published: June 2023

BackgroundEfforts to modulate the function of tumor-associated myeloid cell are underway to overcome the challenges in immunotherapy and find a cure. One potential therapeutic target is integrin CD11b, which can be used to modulate the myeloid-derived cells and induce tumor-reactive T-cell responses. However, CD11b can bind to multiple different ligands, leading to various myeloid cell functions such as adhesion, migration, phagocytosis, and proliferation. This has created a major challenge in understanding how CD11b converts the differences in the receptor-ligand binding into subsequent signaling responses and using this information for therapeutic development.MethodsThis study aimed to investigate the antitumor effect of a carbohydrate ligand, named BG34-200, which modulates the CD11b+cells. We have applied peptide microarrays, multiparameter FACS (fluorescence-activated cell analysis) analysis, cellular/molecular immunological technology, advanced microscopic imaging, and transgenic mouse models of solid cancers, to study the interaction between BG34-200 carbohydrate ligand and CD11b protein and the resulting immunological changes in the context of solid cancers, including osteosarcoma, advanced melanoma, and pancreatic ductal adenocarcinoma (PDAC).ResultsOur results show that BG34-200 can bind directly to the activated CD11b on its I (or A) domain, at previously unreported peptide residues, in a multisite and multivalent manner. This engagement significantly impacts the biological function of tumor-associated inflammatory monocytes (TAIMs) in osteosarcoma, advanced melanoma, and PDAC backgrounds. Importantly, we observed that the BG34-200-CD11b engagement triggered endocytosis of the binding complexes in TAIMs, which induced intracellular F-actin cytoskeletal rearrangement, effective phagocytosis, and intrinsic ICAM-1 (intercellular adhesion molecule I) clustering. These structural biological changes resulted in the differentiation in TAIMs into monocyte-derived dendritic cells, which play a crucial role in T-cell activation in the tumor microenvironment.ConclusionsOur research has advanced the current understanding of the molecular basis of CD11b activation in solid cancers, revealing how it converts the differences in BG34 carbohydrate ligands into immune signaling responses. These findings could pave the way for the development of safe and novel BG34-200-based therapies that modulate myeloid-derived cell functions, thereby enhancing immunotherapy for solid cancers.
High-Flow Nasal Oxygen versus Noninvasive Ventilation in Acute Exacerbation of Chronic Obstructive Pulmonary Disease Patients: A Meta-Analysis of Randomized Controlled Trials
Authors: Du Yanping , Zhang Huaping , Ma Zhiyi , Liu Jun , Wang Zhiyong , Lin Meixia , Ni Fayu , Li Xi , Tan Hui , Tan Shifan , Chai Yanling , Zhong Xiangzhu 
Published: June 2023

Background. High-flow nasal cannula (HFNC) can be used in stable chronic obstructive pulmonary disease (COPD) patients, but the effect of HFNC on clinical outcomes in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is still uncertain. Methods. We searched electronic literature databases for randomized controlled trials (RCTs) comparing HFNC with noninvasive ventilation (NIV) in hypercapnic patients with AECOPD. The primary endpoint of this meta-analysis was PaCO2, PaO2, and SpO2. The secondary outcomes were the respiratory rate, mortality, complications, and intubation rate. Results. We included 7 RCTs with a total of 481 patients. There were no significant differences on measures of PaCO2 (MD = −0.42, 95%CI −3.60 to 2.75, Z = 0.26, and

P

= 0.79), PaO2 (MD = −1.36, 95%CI −4.69 to 1.97, Z = 0.80, and

P

= 0.42), and SpO2 (MD = −0.78, 95%CI −1.67 to 0.11, Z = 1.72,

P

= 0.08) between the HFNC group and the NIV group. There was no significant difference in measures of the mortality and intubation rate between the HFNC group (OR = 0.72, 95%CI 0.30 to 1.69, Z = 0.76, and

P

= 0.44) and the NIV group (OR = 2.38, 95%CI 0.49 to 11.50, Z = 1.08, and

P

= 0.28), respectively. But the respiratory rate in the HFNC group was lower than that in the NIV group (MD = −1.13, 95%CI −2.13 to −0.14, Z = 2.23, and

P

= 0.03), and fewer complications were found in the HFNC group (OR = 0.26, 95%CI 0.14 to 0.47, Z = 4.46, and

P

< 0.00001). Conclusion. NIV was noninferior to HFNC in decreasing PaCO2 and increasing PaO2 and SpO2. Similarly, the mortality and intubation rate was similar among the two groups. The respiratory rate and complications were inferior in the AECOPD group treated with HFNC.
Enfermedad renal crónica: de cómo políticas públicas se transforman en herramientas terapéuticas eficaces en la práctica clínica.
Authors: González Fuenzalida Fernando 
Published: June 2023

Las enfermedades crónicas no transmisibles son las principales causas de días de actividad laboral perdidos, deterioro de calidad de vida y mortalidad en Chile y el mundo. La enfermedad renal crónica (ERC) y, particularmente, la diabética es la cuarta causa de mortalidad en Chile (Global Burden of Diseases, 2019). (leer más)
Abemaciclib Is Effective in Palbociclib-Resistant Hormone Receptor–Positive Metastatic Breast Cancers
Authors: Navarro-Yepes Juliana , Kettner Nicole M. , Rao Xiayu , Bishop Cassandra Santaella , Bui Tuyen N. , Wingate Hannah F. , Singareeka Raghavendra Akshara , Wang Yan , Wang Jing , Sahin Aysegul A. , Meric-Bernstam Funda , Hunt Kelly K. , Damodaran Senthil , Tripathy Debu , Keyomarsi Khandan 
Published: June 2023

Abstract

Cyclin-dependent kinases 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is standard of care for patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). However, resistance to CDK4/6is plus ET remains a clinical problem with limited therapeutic options following disease progression. Different CDK4/6is might have distinct mechanisms of resistance, and therefore using them sequentially or targeting their differentially altered pathways could delay disease progression. To understand pathways leading to resistance to the CDK4/6is palbociclib and abemaciclib, we generated multiple in vitro models of palbociclib-resistant (PR) and abemaciclib-resistant (AR) cell lines as well as in vivo patient-derived xenografts (PDX) and ex vivo PDX-derived organoids (PDxO) from patients who progressed on CDK4/6i. PR and AR breast cancer cells exhibited distinct transcriptomic and proteomic profiles that sensitized them to different classes of inhibitors; PR cells upregulated G2–M pathways and responded to abemaciclib, while AR cells upregulated mediators of the oxidative phosphorylation pathway (OXPHOS) and responded to OXPHOS inhibitors. PDX and organoid models derived from patients with PR breast cancer remained responsive to abemaciclib. Resistance to palbociclib while maintaining sensitivity to abemaciclib was associated with pathway-specific transcriptional activity but was not associated with any individual genetic alterations. Finally, data from a cohort of 52 patients indicated that patients with HR-positive/HER2-negative MBC who progressed on palbociclib-containing regimens can exhibit a meaningful overall clinical benefit from abemaciclib-based therapy when administered after palbociclib. These findings provide the rationale for clinical trials evaluating the benefit of abemaciclib treatment following progression on a prior CDK4/6i.

Significance:
Palbociclib-resistant breast cancers respond to abemaciclib and express pathway-specific signatures of sensitivity, providing a biomarker-driven therapeutic option for patients with metastatic breast cancer following disease progression on cyclin-dependent kinases 4/6 inhibitors.
Lack of Incremental Prognostic Value of Pericoronary Adipose Tissue Computed Tomography Attenuation Beyond Coronary Artery Disease Reporting and Data System for Major Adverse Cardiovascular Events in Patients With Acute Chest Pain
Authors: Wen Didi , Ren Zilong , Xue Ruijia , An Rui , Xu Jian , Li Jiayi , Zheng Minwen 
Published: June 2023

BACKGROUND:
Pericoronary adipose tissue (PCAT) and Coronary Artery Disease Reporting and Data System (CAD-RADS) category had prognostic values for major adverse cardiovascular events (MACEs). However, little is known about the difference between CAD-RADS and PCAT computed tomography (CT) attenuation for predicting MACEs. This study was to compare the prognostic value of PCAT and CAD-RADS for MACEs in patients with acute chest pain.

METHODS:
Between January 2010 and December 2021, all consecutive emergency patients with acute chest pain referred for coronary computed tomography angiography were enrolled in this retrospective study. MACEs included unstable angina requiring hospitalization, coronary revascularization, nonfatal myocardial infarction, and all-cause death. Patients’ clinical characteristics, CAD-RADS, and PCAT CT attenuation were used to evaluate risk factors of MACEs using multivariable Cox regression analysis.

RESULTS:

A total of 1313 patients were evaluated (mean age, 57.13±12.57 years; 782 men). During a median follow-up of 38 months, 142 of the 1313 patients (10.81%) experienced MACEs. Multivariable Cox regression analysis showed that CAD-RADS categories 2, 3, 4, 5 (hazard ratio range, 2.286–8.325; all
P
<0.005) and right coronary artery PCAT CT attenuation (hazard ratio, 1.033;
P
=0.006) were independent predictors of MACEs after adjusting for clinical risk factors. The C statistics revealed that CAD-RADS improved risk stratification compared with PCAT CT alone (C-index, 0.760 versus 0.712;
P
=0.036). However, the benefit of right coronary artery PCAT CT attenuation combined with CAD-RADS was not significant compared with CAD-RADS alone (0.777 versus 0.760;
P
=0.129).

CONCLUSIONS:
Right coronary artery PCAT CT attenuation and CAD-RADS were independent predictors of MACEs. However, no incremental prognostic value of right coronary artery PCAT CT attenuation beyond CAD-RADS was detected for MACEs in patients with acute chest pain.
Older Children Negotiating Relationships Between Home and School
Authors: Macleod Gale , Cebula Carla , Renwick Anne , Love-Gajardo Evelyn , McNeill Mhairi , Jones Cleo , Clark Antonia , Laburn Rachael , Harwood Jennifer , Hearn Iskra 
Published: June 2023

Abstract
Most research into parental involvement and engagement examines the perspectives of teachers and parents, but often not pupils. Additionally, the focus is commonly on younger children. This study addresses these gaps. A questionnaire was distributed to pupils in Primaries 5, 6 and 7 (ages 9–12), which, after data cleaning, resulted in a sample of 842 responses. The questionnaire asked about frequency of and attitudes towards support with learning at home and pupils’ attitudes towards adults from home coming in to school. Findings show that changes in attitude towards home support previously reported in secondary pupils are also evident in this younger group. The oldest pupils in the study showed increased apathy, but no increased embarrassment, about adults from home coming in to school. Most children were happy with the support they received, with children at all stages wanting more help with writing than reading. Implications for practice are considered.