bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of College Football Games on the Hotel Industry: A Market Comparison
Authors: Webb Timothy , DeSchriver Timothy D. , Tainsky Scott , Simion Adrian M.
Published: February 2025

The economic impact of sporting events on surrounding communities and industries has been debated for many years. The hospitality industry stands as a potential benefactor of sporting events as fans may travel to a destination and require food and lodging. Prior research finds conflicting results regarding the impact of sporting events on the lodging industry. This study leverages the extant research to construct a large-scale investigation of the prevalence of hotel spillovers from sporting events. Specifically, this study investigates the impact of Southeastern and Pac-12 conferences National Collegiate Athletic Association college football games on hotel demand. The findings show that games in smaller markets have a large impact on hotel demand, while larger markets see very little change. The results align with the literature outlining conditions for positive economic impact from sporting events. The study outlines implications for research and practitioners with regard to spillovers of sporting events on the lodging industry.
Thermal diffusivity microscope: Zooming in on anisotropic heat transport
Authors: Lamba Neetu , Beltrán-Pitarch Braulio , Yu Tianbo , Dawod Muhamed , Berner Alex , Guralnik Benny , Orekhov Andrey , Gauquelin Nicolas , Amouyal Yaron , Verbeeck Johan , Hansen Ole , Pryds Nini , Petersen Dirch Hjorth
Published: February 2025

Anisotropic heat–conducting materials play crucial roles in designing electronic, optoelectronic, and thermoelectric devices, where temperature and thermal stress are important. Despite substantial research efforts, a major obstacle to determining the anisotropic thermal diffusivity tensor in polycrystalline systems is the need for a robust, direct, and nondestructive technique to distinguish between distinct thermal diffusivities. Here, we demonstrate a conceptually unique thermal diffusivity microscope capable of performing high-resolution local measurements of anisotropic thermal diffusivity. The microscope features a unique micro four-point probe for fast, nondestructive scanning without calibration or extra sample preparation. It measures anisotropic thermal diffusivity based on thermal delay from a single heater. Through a series of experiments, we demonstrate that the anisotropy of the measured thermal diffusivity correlates excellently with the crystallographic direction of prototypical Bi
2
Te
3
. The anisotropic heat transport shows that the lattice contribution dominates the heat transport for both in- and out-of-plane directions.
The synaptonemal complex aligns meiotic chromosomes by wetting
Authors: Gordon Spencer G. , Rodriguez Alyssa A. , Gu Yajie , Corbett Kevin D. , Lee Chiu Fan , Rog Ofer
Published: February 2025

During meiosis, the parental chromosomes are drawn together to enable exchange of genetic information. Chromosomes are aligned through the assembly of a conserved interface, the synaptonemal complex, composed of a central region that forms between two parallel chromosomal backbones called axes. Here, we identify the axis-central region interface in
C. elegans
, containing a conserved positive patch on the axis component HIM-3 and the negative C terminus of the central region protein SYP-5. Crucially, the canonical ultrastructure of the synaptonemal complex is altered upon weakening this interface using charge-reversal mutations. We developed a thermodynamic model that recapitulates our experimental observations, indicating that the liquid-like central region can assemble by wetting the axes without active energy consumption. More broadly, our data show that condensation drives tightly regulated nuclear reorganization during sexual reproduction.
Cryo-EM structure of the bacterial intramembrane metalloprotease RseP in the substrate-bound state
Authors: Asahi Kikuko , Hirose Mika , Aruga Rie , Shimizu Yosuke , Tajiri Michiko , Tanaka Tsubasa , Adachi Yuriko , Tanaka Yukari , Kaneko Mika K. , Kato Yukinari , Akashi Satoko , Akiyama Yoshinori , Hizukuri Yohei , Kato Takayuki , Nogi Terukazu
Published: February 2025

Site-2 proteases (S2Ps), conserved intramembrane metalloproteases that maintain cellular homeostasis, are associated with chronic infection and persistence leading to multidrug resistance in bacterial pathogens. A structural model of how S2Ps discriminate and accommodate substrates could help us develop selective antimicrobial agents. We previously proposed that the
Escherichia coli
S2P RseP unwinds helical substrate segments before cleavage, but the mechanism for accommodating a full-length membrane-spanning substrate remained unclear. Our present cryo-EM analysis of
Aquifex aeolicus
RseP (
Aa
RseP) revealed that a substrate-like membrane protein fragment from the expression host occupied the active site while spanning a transmembrane cavity that is inaccessible via lateral diffusion. Furthermore, in vivo photocrosslinking supported that this substrate accommodation mode is recapitulated on the cell membrane. Our results suggest that the substrate accommodation by threading through a conserved membrane-associated region stabilizes the substrate-complex and contributes to substrate discrimination on the membrane.
Robotic locomotion through active and passive morphological adaptation in extreme outdoor environments
Authors: Polzin Max , Guan Qinghua , Hughes Josie
Published: February 2025

Robotic locomotion has shown substantial advancements, yet robots still lack the versatility and agility shown by animals navigating complex terrains. This limits their applicability in complex environments where they could be highly beneficial. Unlike existing robots that rely on intricate perception systems to construct models of both themselves and their surroundings, a more bioinspired approach leverages reconfiguration to adapt a robot’s morphology to its environment. Although interest in such multimodal, terrain-adaptive robots is increasing, their capacity for morphological reconfiguration often remains confined to specific body parts or comes at the expense of increased system complexity and reduced locomotion efficiency. Our study seeks to enhance robotic locomotion by developing robots that can actively reconfigure their morphology, altering their physical properties and leveraging their adaptability to navigate efficiently in diverse environments. We demonstrate how combining a compliant structure with morphological reconfiguration allowed a robot to transition between flat and spherical forms, enabling autonomous, multimodal locomotion—driving, rolling, and swimming—across complex terrains with minimal sensing. By actively reconfiguring its morphology to adapt physical properties for compliant interactions, the robot enhanced locomotion across rough, diverse environments. Leveraging its adaptability in different locomotion modes to navigate a 4.5-kilometer path across mountainous, aquatic, and urban terrains, the robot outperformed traditional and multimodal robots in terms of versatility, energy efficiency, and robustness. Developing versatile, energy-efficient, compliant robots capable of reconfiguring their morphology could substantially enhance autonomous navigation, opening up broader applications in unstructured environments, from environmental monitoring to disaster response and extraterrestrial exploration.
Wearable robot provides lumbar and arm support
Authors: Yashinski Melisa
Published: February 2025

Exosuit with two-stage mechanism transmits force from a single motor to multiple muscle groups during manual handling tasks.
mSphere of Influence: The maternal gut–mammary axis and its role in shaping neonatal health
Authors: Langel Stephanie N.
Published: February 2025

Stephanie Langel works in the field of breast milk immunity and maternal-neonatal health. In this mSphere of Influence article, she reflects on how three pivotal papers—Roux et al. (J Exp Med 146:1311–1322, 1977,
https://doi.org/10.1084/jem.146.5.1311
), Wilson and Butcher (J Exp Med 200:805–809, 2004,
https://doi.org/10.1084/jem.20041069
), and Rogier et al. (Proc Natl Acad Sci USA 111:3074–3079, 2014,
https://doi.org/10.1073/pnas.1315792111
)—made an impact on her by uncovering the critical pathways and mechanisms through which gut-derived IgA-secreting cells migrate to the mammary gland and secrete antibodies against intestinal microbes. These foundational studies shaped her understanding of the gut–mammary axis and continue to inspire her research aimed at advancing maternal and neonatal health through breast milk immunology.
mSphere of Influence:
Trypanosoma cruzi
genome in 3D action
Authors: Berná Luisa
Published: February 2025

Luisa Berná works in the field of comparative and evolutionary genomics in unicellular eukaryotes. In this mSphere of Influence article, she reflects on how advances in three-dimensional genome organization have reshaped our understanding of parasite biology. She discusses how recent findings uncover the distinctiveness of the three-dimensional architecture of
Trypanosoma cruzi’
s genome and its functional implications. Berná argues that integrating structural genomics into parasite research is essential for advancing our understanding of genome organization and its role in shaping parasite biology, particularly in the context of neglected tropical diseases.
GrcC1 mediates low-level resistance to multiple drugs in
M. marinum
,
M. abscessus,
and
M. smegmatis
Authors: Fang Cuiting , Zhang Han , He Jing , Tian Xirong , Zeng Sanshan , Han Xingli , Wang Shuai , Yusuf Buhari , Hu Jinxing , Zhong Nanshan , Gao Yamin , Hameed H. M. Adnan , Zhang Tianyu
Published: February 2025

The escalating threat of mycobacterial infectious diseases, particularly those caused by nontuberculous mycobacteria (NTM), poses a serious challenge to public health. Linezolid (LZD), an oxazolidinone antimicrobial, exhibits potent activity against
Mycobacterium tuberculosis
and NTM. Generally, mutations in the
rrl
and
rplC
genes are widely associated with resistance to LZD. However, in this study, we screened
Mycobacterium marinum
strains lacking such mutations, indicating the presence of an alternative resistance mechanism. Notably, through whole-genome sequencing, we identified a novel mutation C395T in the
MMAR_0911
(
grcC1
) gene that has never been linked to drug resistance. This mutation leads to an A132V substitution in the encoded protein, a polyprenyl diphosphate synthase potentially involved in the synthesis of cell wall components and menaquinones. We found that the overexpression of
grcC1
caused resistance to multiple drugs including LZD, clarithromycin (CLR), vancomycin (VAN), clofazimine (CFZ), rifampicin (RIF), cefoxitin (CEF), levofloxacin (LEV), and moxifloxacin (MXF) and reduced cell wall permeability, while the silence and knockout of
grcC1
showed increased cell wall permeability and susceptibility to these drugs. Using CRISPR/Cpf1-assisted gene editing, we confirmed that the A132V mutation conferred low-level resistance to the aforementioned drugs in
Mycobacterium abscessus
and
Mycobacterium smegmatis
. Furthermore, thin-layer chromatography analysis indicated reduced glycolipid polarity in the
grcC1
mutant strains, suggesting an impact on the cell envelope integrity. Our findings suggest that GrcC1 contributes to low-level drug resistance in mycobacteria by potentially reducing cell wall permeability, highlighting its potential as a novel target for antimicrobial agents and as a diagnostic marker.

IMPORTANCE

Our study uncovers a novel drug resistance mechanism in mycobacteria, focusing on the previously uncharacterized
grcC1
gene. We identified a new mutation, A132V, in GrcC1, which is involved in cell wall component synthesis and menaquinone production. This mutation contributes to low-level resistance not only to linezolid but also to a broad range of drugs, including clarithromycin, vancomycin, and rifampicin. Through advanced techniques like CRISPR interference and gene editing, we demonstrated that GrcC1 plays a critical role in drug susceptibility and cell wall permeability across multiple
Mycobacterium
species. These findings represent the first connection between GrcC1 and drug resistance, offering new insights into combating infections caused by nontuberculous mycobacteria (NTM). Our work highlights the potential of GrcC1 as a target for novel therapeutic approaches and as a diagnostic marker for drug-resistant NTM infections.
Identification of
Escherichia coli
166 isolate as an effective inhibitor of African swine fever virus replication
Authors: Zhang Jinya , Cui Hongyu , Zhang Zhenjiang , Wang Wenqing , Jiang Fengwei , Sun Encheng , Zhu Yuanmao , Li Fang , Bu Zhigao , Zhao Dongming
Published: February 2025

African swine fever is a lethal disease with mortality rates approaching 100% in both domestic pigs and wild boars. With no effective vaccines or treatments available, there is an urgent need for new biologics to combat the African swine fever virus (ASFV). In this study, we isolated bacteria from the intestinal contents of wild boar using culture-based methods and identified them through 16S ribosomal DNA (rDNA) sequencing. These isolates underwent high-throughput screening to evaluate their immunomodulatory effects on J774-Dual cells and their ability to inhibit ASFV replication
in vitro
. Among them, an
Escherichia coli
strain, designated as
E. coli
166, exhibited strong inhibitory effects on various ASFV strains’ replication, including three genotype II strains: virulent strain HLJ/18, moderately virulent strain HLJ/HRB1/20, genetically modified low-virulent strain HLJ/18–6GD, and one genotype I low-virulent strain SD/DY-I/21. Notably, this inhibition did not require direct interaction between the bacteria and porcine alveolar macrophages (PAMs). Both live and heat-inactivated
E. coli
166 demonstrated a strong inhibitory effect on ASFV replication. Genetic modification of
E. coli
166 did not alter its inhibitory phenotype. Further analysis revealed that PAMs pretreated with
E. coli
166 showed upregulation of NF-κB and downregulation of CD163 at different time points post-infection, whereas PAMs only infected with ASFV exhibited the opposite trend. These findings suggest that
E. coli
166 holds promise as a biological agent for controlling ASFV infection, through indirect mechanisms involving bacterial metabolites or lysis products. Future studies should focus on identifying the specific components responsible for its antiviral effects.

IMPORTANCE

The emergence of the African swine fever virus (ASFV) as a devastating pathogen in swine populations necessitates the development of novel strategies for its control. In this study,
Escherichia coli
strain 166 (
E. coli
166) demonstrated a remarkable ability to inhibit the replication of multiple ASFV strains in porcine alveolar macrophages (PAMs), even without direct bacterial contact. Both live and heat-inactivated
E. coli
166 retained this inhibitory effect, suggesting that secreted metabolites or lysis products may play a key role. Furthermore, pretreatment of PAMs with
E. coli
166 resulted in upregulated NF-κB activity and downregulated expression of the ASFV entry receptor CD163, presenting an immune-modulatory mechanism distinct from PAMs solely infected with ASFV. These findings highlight the potential of
E. coli
166 as a biological agent to combat ASFV, offering a promising alternative or complementary approach to traditional antiviral strategies.
Vortioxetine-associated syndrome of inappropriate ADH secretion
Authors: Sugunan Sreedevi , K P Lakshmi , Menon Bindu
Published: February 2025

This case report presents the first documented instance of vortioxetine-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH) in India. Vortioxetine, a newer antidepressant, was prescribed to an elderly male in his 80s with major depressive disorder, in combination with mirtazapine. Despite initial improvement in mood, he developed hyponatraemia, a rare but serious side effect possibly linked to vortioxetine’s serotonergic action. The patient exhibited symptoms such as giddiness and confusion, prompting the discontinuation of vortioxetine and initiation of corrective treatment. His condition improved, with sodium levels returning to normal while he was maintained on mirtazapine alone. This case underscores vortioxetine’s potential to induce SIADH, highlighting the need for careful monitoring and the consideration of alternative antidepressants in vulnerable populations.
Impact of postpartum physical activity on maternal sleep: a systematic review and meta-analysis
Authors: Jones Paris A T , Ruchat Stephanie-May , Khan-Afridi Zain , Ali Muhammad Usman , Matenchuk Brittany A , Leonard Sierra , Jantz Andrew WE , Vander Leek Kier , Maier Lauren , Osachoff Laura , Hayman Melanie J , Forte Milena , Sivak Allison , Davenport Margie H
Published: February 2025

Objective

To examine the relationship between postpartum physical activity and maternal sleep.

Design

Systematic review with random-effects meta-analysis. Online databases were searched through 20 January 2025.

Study eligibility criteria

Studies of all designs (except case studies and reviews) in all languages were eligible if they contained information on the population (individuals up to 1 year post partum); interventions/exposures (including subjective or objective measures of frequency, intensity, duration, volume or type of exercise, alone (‘exercise only’) or in combination with other intervention components (eg, dietary; ‘exercise+co-intervention’)); comparator (low volume or no physical activity) and outcomes: sleep duration, quality, latency, efficiency, disturbance and fatigue.

Results

12 unique studies (n=3096) from nine countries were included. Moderate certainty of evidence showed that exercise-only interventions were associated with a greater improvement in sleep quality (five randomised controlled trials (RCTs), n=375, standardised mean difference (SMD) −0.44, 95% CI −0.79 to –0.09) compared with no exercise. High certainty of evidence showed that exercise interventions were associated with a greater improvement in daytime/general fatigue (six RCTs, n=535, SMD −0.56, 95% CI −1.06 to –0.05) compared with no exercise. No effect was found for sleep duration, latency, efficiency, or disturbance.

Conclusion

Postpartum physical activity improves maternal sleep quality and daytime/general fatigue.
Development of a virtual asylum medicine curriculum: applying a medical education model to a global health priority
Authors: DeFries Triveni , Emery Eleanor , Cuneo C Nicholas , Mei Emily , Folsom Emilie , Mishori Ranit , McKenzie Katherine
Published: February 2025

Each year, millions of people fleeing persecution seek asylum in the USA and elsewhere. Many have experienced psychological and/or physical trauma that can be documented with objective forensic medical and mental evaluations (FMEs) performed by trained clinicians. FMEs can assist adjudicators in deciding claims, and asylum seekers who undergo an FME are significantly more likely to be granted asylum. However, there is a shortage of clinicians trained to perform FMEs, and existing training models have shortcomings, including lack of accessibility and consensus-driven best practices. To meet the rising need for FMEs and improve training in the burgeoning field of asylum medicine, we used Kern’s model to design an interdisciplinary, consensus-driven, virtual curriculum that prepares clinicians to conduct FMEs. The curriculum development process involved a diverse group of 80 contributors from over 40 US organisations and academic centres. We used a staged needs assessment to identify critical issues in the existing training paradigm. Through an iterative process, we then developed an introductory curriculum consisting of eleven modules paired with assessments. Contributors reported high rates of satisfaction with the curriculum development process. To our knowledge, this is the first consensus-based training in asylum medicine that is national in scope, and it has since been adopted by Physicians for Human Rights as the standard for FME training. The process employed here offers a model for developing and improving training relevant to other global health priorities internationally.
Long-term outcomes of bilateral salpingo-oophorectomy in women with personal history of breast cancer
Authors: Hassan Hend , Rahman Tameera , Bacon Andrew , Knott Craig , Allen Isaac , Huntley Catherine , Loong Lucy , Walburga Yvonne , Morris Eva , Hardy Steven , Torr Bethany , Eccles Diana M , Turnbull Clare , Tischkowitz Marc , Pharoah Paul , Antoniou Antonis C
Published: February 2025

Objectives

To investigate the association between bilateral salpingo-oophorectomy (BSO) and long-term health outcomes in women with a personal history of breast cancer.

Methods and analysis

We used data on women diagnosed with invasive breast cancer between 1995 and 2019 from the National Cancer Registration Dataset (NCRD) in England. The data were linked to the Hospital Episode Statistics-Admitted Patient Care dataset to identify BSO delivery. Long-term health outcomes were selected from both datasets. Multivariable Cox regression was used to examine the associations, with BSO modelled as a time-dependent covariate. The associations were investigated separately by age at BSO.

Results

We identified 568 883 women, 23 401 of whom had BSO after the breast cancer diagnosis. There was an increased risk of total cardiovascular diseases with an HR of 1.10 (95% CI 1.04 to 1.16) in women who had BSO<55 years and 1.07 (95% CI 1.01 to 1.13) for women who had BSO≥55 years. There was an increased risk of ischaemic heart diseases, but there was no association with cerebrovascular diseases. BSO at any age was associated with an increased risk of depression (HR 1.20, 95% CI 1.12 to 1.28) and increased risk of second non-breast cancer in older women (HR 1.21, 95%CI 1.08 to 1.35). BSO in older women was associated with reduced risk of all-cause mortality (HR 0.92, 95% CI 0.87 to 096), but not in women who had BSO<55 years.

Conclusion

In women with a personal history of breast cancer, BSO before and after the age of 55 years is associated with an increased risk of long-term outcomes. BSO after 55 years is associated with reduced all-cause mortality. Family history or genetic predisposition may confound these associations.
Narrative enhancement and cognitive therapy for self-stigma among youth with bipolar disorder or multiple mental health conditions: protocol for a pilot randomised basket trial
Authors: Hawke Lisa D , Husain Muhammad Ishrat , Amartey Abigail , Ma Clement , Osuch Elizabeth , Yanos Philip T , Gallagher Louise , Jordan Adam , Orson Joshua , Lee Alina , Kozloff Nicole , Kidd Sean A , Goldstein Benjamin I , Sheikhan Natasha Y , Ortiz Abigail , Szatmari Peter
Published: February 2025

Introduction

Self-stigma occurs when individuals internalise negative stereotypes about their mental health conditions. Self-stigma is common among those with serious mental illnesses, including youth, and is considered a major barrier to recovery through its impact on hope, self-esteem and self-identity. This patient-oriented protocol aims to assess the feasibility of conducting a future full-scale randomised controlled trial (RCT) of a youth-oriented adaptation of narrative enhancement and cognitive therapy for self-stigma among youth (NECT-Y).

Methods and analysis

This is a two-site, two-arm pilot basket RCT with 1:1 randomisation to NECT-Y or treatment as usual (TAU). Participants are youth, ages 16–29 diagnosed with bipolar disorder, any subtype (Basket 1) or with any two or more mental health conditions (Basket 2). After informed consent, we will conduct baseline assessments and randomisation, then either a 14-week NECT-Y group intervention or TAU. Diagnostic interviews will be used to confirm diagnosis at baseline. A range of self-report questionnaires will be administered at baseline, post-treatment and 3 month follow-up. The primary outcome is feasibility as indicated by the achievement of recruitment goals, retention and adherence, intervention fidelity and the absence of serious adverse events. Secondary outcomes include acceptability and the intervention’s impact on self-stigma, wellness, symptomatology, treatment-seeking attitudes and other related constructs. A youth advisory group is informing all stages of the study process.

Ethics and dissemination

The Research Ethics Board for Centre for Addiction and Mental Health (#062/2024) has approved this study protocol. Ethics is also approved at London Health Sciences Centre (Western Health Sciences Research Ethics Board (HSREB) #125812). Results will be published in international peer-reviewed journals and presented at relevant conferences. Summaries will be provided to the funders of the study, as well as to lay audiences, including study participants.

Trial registration number

NCT06672562
.
Barriers and enablers to pharmacist involvement in social prescribing: a protocol for a systematic review of qualitative studies
Authors: Shankar Ravi , Bundele Anjali , Low Joshua , Mukhopadhyay Amartya
Published: February 2025

Introduction

Social prescribing is an innovative approach to healthcare that involves referring patients to non-medical services and activities in the community to improve health and well-being. Pharmacists are well-positioned to contribute to social prescribing initiatives given their accessibility and expertise, but their involvement remains limited. Qualitative studies have explored pharmacists’ perspectives and experiences regarding social prescribing, but their findings have not been systematically synthesised. This protocol outlines a systematic review of qualitative studies to identify and synthesise the barriers and enablers influencing pharmacist involvement in social prescribing.

Methods and analysis

We will conduct a comprehensive search of electronic databases (PubMed, Web of Science, Embase, CINAHL, MEDLINE, The Cochrane Library, PsycINFO, Scopus) and grey literature sources for qualitative studies published in English from each database inception to January 2025 that explore barriers and facilitators to pharmacist involvement in social prescribing. Two reviewers will independently screen titles, abstracts and full texts for eligibility based on predefined criteria. Eligible studies will include those that use qualitative methods (eg, interviews, focus groups, observations) to explore the perspectives of pharmacists on factors influencing their involvement in social prescribing initiatives. Data will be extracted using a standardised form and synthesised using thematic analysis. The methodological quality of included studies will be appraised using the Critical Appraisal Skills Programme Qualitative Checklist. Confidence in the review findings will be assessed using the Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative research approach.

Ethics and dissemination

Ethics approval is not required as this study will merely synthesise data from published studies. The results will be disseminated through peer-reviewed publications as well as conference presentations.

PROSPERO registration number

CRD42024600968.
Rehabilitation interventions and outcomes for post-COVID condition: a scoping review
Authors: Saunders Emily G , Pouliopoulou Dimitra V , Miller Erin , Billias Nicole , MacDermid Joy C , Brunton Laura , Pereira Tiago V , Quinn Kieran L , Bobos Pavlos
Published: February 2025

Objective

Several rehabilitation interventions have been proposed to support people with post-COVID-19 condition (PCC). However, the full spectrum of these interventions remains unclear, partly due to the complexity of PCC, which encompasses a broad range of symptoms affecting multiple organ systems and health domains. This scoping review aimed to identify the available rehabilitation interventions for PCC and the outcome measures used to evaluate them, to facilitate the development of multifaceted interventions and improve patient care.

Methods

Following the Joanna Briggs Institute Framework, we searched CINAHL, EMBASE, MEDLINE, PsychINFO, CENTRAL and Scopus databases from inception to 22 January 2024 for experimental and observational studies investigating rehabilitation interventions for adults with PCC. Interventions and their corresponding outcome measures were synthesised based on targeted outcomes aligned with the most common manifestations of PCC. The quality of intervention reporting was assessed using the Template for Intervention Description and Replication (TIDieR) checklist.

Results

We identified 74 studies; 28 randomised trials (37.8%) and 46 observational and quasi-experimental designs (62.2%). Most interventions consisted of different combinations of education, exercises and therapies to manage dyspnoea, fatigue and psychological symptoms, such as anxiety and depression. Few studies addressed postexertional malaise, cognitive function, memory, balance and coordination. At least half of the included studies required a confirmed SARS-CoV-2 infection for participant inclusion. Reporting on adherence rates was limited, and 65% of the studies did not report adverse events.

Conclusion

There is a need for more comprehensive and inclusive approaches that address the full spectrum of PCC symptomatology to improve patient care and enhance the reproducibility of future studies.
Phase I study of ribociclib (CDK4/6 inhibitor) with spartalizumab (PD-1 inhibitor) with and without fulvestrant in metastatic hormone receptor-positive breast cancer or advanced ovarian cancer
Authors: Garrido-Castro Ana C , Graham Noah , Ali Lestat R , Herold Christina , Desrosiers Jennifer , Do Khanh , Parsons Heather , Li Tianyu , Goel Shom , DiLullo Molly , Wrabel Eileen , Williams Amy J , Liu Joyce F , Mittendorf Elizabeth A , Dougan Stephanie K , Tayob Nabihah , Shapiro Geoffrey I , Tolaney Sara M
Published: February 2025

Background

Preclinical evidence suggests that cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors enhance antitumor immunity. We conducted a phase I trial of ribociclib (CDK4/6 inhibitor) plus spartalizumab (PD-1 inhibitor) in patients with hormone receptor (HR)-positive/HER2-negative metastatic breast cancer (MBC) or advanced ovarian cancer (AOC). The combination was also evaluated with fulvestrant in MBC.

Methods

In Cohort A, ribociclib was administered on Days 1–21 (28-day cycle) starting at 400 mg, and spartalizumab at 400 mg on Day 1. Dose escalation was followed by expansion in AOC. Fulvestrant was added (Cohort B) with a safety run-in followed by expansion in MBC. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), and safety and tolerability of the combinations.

Results

33 patients enrolled (n=18, Cohort A; n=15, Cohort B). The RP2D of ribociclib in both cohorts was 600 mg. Treatment-related adverse events in >20% of patients in either cohort were neutropenia, fatigue, anemia, thrombocytopenia, hypertransaminasemia, maculopapular rash, fatigue, and nausea. Hypertransaminasemia occurred in 66.7% (AST) and 46.7% (ALT) of patients in Cohort B, including 46.7% and 40.0%, respectively, of grade 3 or 4 events. Two confirmed partial responses were observed (13.3%) in Cohort B, in patients with low baseline serum thymidine kinase activity, coupled with an increase on-treatment. Peripheral blood flow cytometry across patients demonstrated on-target drug binding with increases in PD-1 occupancy and activated CD8+T cells during treatment, irrespective of response. PD-L1-positivity, tumor-infiltrating lymphocytes, or tumor mutational burden did not correlate with progression-free survival (PFS). Several copy-number variations detected with next-generation sequencing correlated with PFS.

Conclusions

Ribociclib with spartalizumab and fulvestrant showed limited efficacy and elevated hepatotoxicity, precluding further development. Correlative analyses revealed treatment-induced immunological effects, and genomic alterations associated with PFS.
Immunological biomarkers of response and resistance to treatment with cabozantinib and nivolumab in recurrent endometrial cancer
Authors: Roudko Vladimir , Del Valle Diane Marie , Radkevich Emir , Kelly Geoffrey , Hui Xie , Patel Manishkumar , Gonzalez-Kozlova Edgar , Tuballes Kevin , Streicher Howard , Atale Swati , Wang Lisa , CzinCzin Benito , Kim-Schulze Seunghee , Wistuba Ignacio I , Haymaker Cara L , Al-Atrash Gheath , Manyam Ganiraju , Zhang Jianjun , Thompson Ryan , Suarez-Farinas Mayte , Lheureux Stephanie , Gnjatic Sacha
Published: February 2025

Background

Antiangiogenics combined with immune checkpoint blockade have become standard of care for recurrent endometrial cancer after standard platinum-based chemotherapy. To dissect mechanisms and define biomarkers associated with clinical outcomes to these combinations, we applied multidimensional immune monitoring to peripheral blood specimens collected from a randomized phase 2 trial of nivolumab with or without cabozantinib in 75 evaluable patients with recurrent endometrial cancer (NCI ETCTN 10104,NCT03367741). This trial demonstrated superiority of the combination to nivolumab alone.

Methods and results

Using Olink proteomics, mass cytometry, tumor antigen-specific ELISA, and whole exome tumor sequencing, we identified longitudinal immune signatures specific to cabozantinib use, including an increase in plasma HO-1 and reduction in plasma vascular endothelial growth factor receptor 2, interleukin-12, and circulating plasmacytoid dendritic cells. Prior exposure to immunotherapy and carcinosarcoma histology had no adverse impact on clinical benefit or biomarkers, and copy-number high tumors were associated with increased plasma granzymes on combination treatment. Higher baseline plasma levels of myeloid-related markers (chemokine ligand 23/CCL23, colony-stimulating factor-1/macrophage colony-stimulating factor/CSF1) were associated with poor overall and progression-free survival, and lack of clinical benefit (defined as progressive or stable disease <6 months) following combination treatment (Kaplan-Meier, multivariate Cox, false discover rate <0.05). Patients with favorable outcomes had higher levels of activated T-cell markers (plasma ICOS-L, CD28) and exhibited spontaneous autoantibody titers to tumor antigen NY-ESO-1. Patients experiencing severe adverse events from the combination therapy had higher baseline levels of neutrophil-derived markers (CXCL1).

Conclusions

Overall, this study highlights potential resistance and response mechanisms to nivolumab+cabozantinib and suggests prioritizing combination treatment in patients with activated T-cell immunogenicity profiles while exploring future combinatorial therapies targeting myeloid populations to overcome resistance.
Novel post-translational modification learning signature reveals B4GALT2 as an immune exclusion regulator in lung adenocarcinoma
Authors: Zhang Pengpeng , Wang Dingli , Zhou Guangyao , Jiang Shuai , Zhang Ge , Zhang Lianmin , Zhang Zhenfa
Published: February 2025

Background

Lung adenocarcinoma (LUAD) presents significant challenges in prognosis and treatment efficacy evaluation. While post-translational modifications are known to influence tumor progression, their prognostic value in LUAD remains largely unexplored.

Methods

We developed a post-translational modification learning signature (PTMLS) using machine learning techniques, analyzing data from 1231 LUAD patients across seven global cohorts. The signature’s efficacy in predicting immunotherapy response was evaluated using 12 immunotherapy cohorts spanning multiple cancer types (n=1201). An in-house LUAD tissue cohort (n=171) was used to validate beta-1,4-galactosyltransferase 2’s (B4GALT2’s) prognostic significance. The role of B4GALT2 in immune exclusion was investigated through in vivo and in vitro experiments.

Results

The established PTMLS exhibited exceptional predictive capabilities in LUAD patient outcomes, surpassing the efficacy of 98 existing LUAD prognostic indicators. The system’s predictive value was validated across diverse malignancy categories for immunotherapeutic response assessment. From a biological perspective, significant correlations were observed between PTMLS and immunological parameters, whereby elevated PTMLS levels were characterized by attenuated immune responses and immunologically cold neoplastic features. Within the PTMLS framework, B4GALT2 was identified as a crucial molecular component (r=0.82, p<0.05), and its heightened expression was linked to unfavorable clinical outcomes in LUAD cases, particularly in specimens exhibiting CD8-depleted phenotypes. The spatial distribution patterns between B4GALT2 and immune cell populations, specifically CD8+ T lymphocytes and CD20+ B lymphocytes, were elucidated through multiplexed immunofluorescence analysis. Laboratory investigations subsequently established B4GALT2’s regulatory influence on LUAD cellular expansion in both laboratory cultures and animal models. Significantly, suppression of B4GALT2 was found to enhance CD8+ T lymphocyte populations and their functional status, thereby potentiating anti-programmed cell death protein 1 immunotherapeutic efficacy in animal studies. This phenomenon was characterized by reduced CD62L+CD8 T lymphocyte levels alongside elevated GZMB+/CD44+/CD69+CD8 T cell populations.

Conclusion

The developed PTMLS system represents an effective instrument for individualized prognostic evaluation and immunotherapy stratification in both LUAD and diverse cancer populations. The identification of B4GALT2 as a previously unrecognized oncogenic factor involved in immune exclusion presents a novel therapeutic avenue for LUAD treatment and immunotherapy optimization.
Neutrophil extracellular traps impede cancer metastatic seeding via protease-activated receptor 2-mediated downregulation of phagocytic checkpoint CD24
Authors: Liu Yu , Ma Jianhui , Ma Yiming , Wang Bing-zhi , Wang Yinong , Yuan Junhu , Zhang Fanyu , Zhao Xinhua , Chen Kun , Zhang Xiaoli , Wang Hongying
Published: February 2025

Background

Phagocytic clearance by macrophages represents a critical immune surveillance mechanism in cancer liver metastasis. Neutrophils, the most abundant immune cells encountered by cancer cells in circulation, play key roles in metastasis through neutrophil extracellular traps (NETs). Although NETs promote macrophage phagocytosis during infection, whether they regulate phagocytosis during cancer metastasis is unknown. The present study aimed to explore the roles of NETs in regulating macrophage phagocytosis during the seeding process of liver metastasis and the mechanisms underlying the roles.

Methods

A lipopolysaccharide-induced NET model was applied to study the role of NETs on colorectal cancer (CRC) liver metastasis. The neutrophils isolated from human peripheral blood were stimulated with PMA to release NETs, which were collected and added to the cultures of different CRC cell lines for in vitro studies. Macrophage phagocytosis was assessed with flow cytometry in vitro and in vivo. RNA-seq and microRNA array analyses were performed to identify key pathways regulated by NETs and downstream key molecules. The macrophage phenotypes were evaluated using immunohistochemistry, flow cytometry, and cytokine and chemokine arrays.

Results

NETs promote macrophage phagocytosis both in vitro and in vivo. Neutrophil elastase (NE), which was able to inactivate the canonical signal of protease-activated receptor 2 (PAR2), downregulated the phagocytotic checkpoint CD24. Notably, PAR2 deficiency imitated the effect of NETs on phagocytosis and CD24. Mechanistic studies indicated that inhibiting PAR2 expression upregulated miR-34a and miR-146a and downregulated CD24 in cancer cells. In addition, PAR2 depletion enhanced the recruitment and M1 polarization of macrophages by upregulating CSF-1 and CXCL1. The correlation of NETs/NE and CD24 was corroborated using human CRC specimens. Furthermore, PAR2 blockade combined with an anti-EGFR antibody (cetuximab (CTX)) synergistically enhanced the phagocytic ability of macrophages and suppressed liver metastasis in vivo.

Conclusions

NET-derived elastase inactivated PAR2 canonical signaling and promoted phagocytosis by downregulating CD24, which functions as a phagocytotic checkpoint in CRC liver metastasis. Thus, PAR2 inhibitors combined with CTX may serve as a novel therapeutic strategy against advanced CRC.
Targeting mesothelin-CD24 axis repolarizes tumor-associated macrophages to potentiate PD-1 blockade therapy in high-grade serous ovarian cancer
Authors: Zhong Yujing , Wang Yiying , Wang Chenyang , Cao Kankan , Wang Xueling , Xu Xuyao , Yang Moran , Zhang Guodong , Liu Haiou , Lu Jiaqi
Published: February 2025

Background

High-grade serous ovarian cancer (HGSOC) is a highly aggressive malignancy marked by an immunosuppressive tumor microenvironment that hinders effective immune responses. A key feature of this environment is the extensive infiltration of myeloid cells, which contributes to immune evasion. This study explored how mesothelin (MSLN), a tumor-associated antigen, modulates the expression of CD24, an emerging target for immune modulation, and its role in promoting immune evasion in HGSOC. Understanding these underlying mechanisms is crucial for enhancing the efficacy of immune checkpoint blockade (ICB) therapies and improving outcomes in patients with HGSOC.

Methods

We analyzed the expression of MSLN in HGSOC samples and examined its correlation with clinical outcome. In vitro and in vivo models were used to explore how MSLN influences CD24 expression and the polarization of tumor-associated macrophages (TAMs). We also investigated the role of MSLN in the activation of Wnt/β-catenin signaling and its impact on T-cell function and antitumor immunity. The effects ofMslnknockdown on CD24 expression and the response to anti-programmed cell death protein-1 (PD-1) therapy were evaluated in syngeneic mouse models.

Results

MSLN expression was found to be significantly elevated in HGSOC, with high MSLN levels correlating with poor prognosis and resistance to ICB. MSLN upregulated CD24 and promoted the protumorigenic polarization of TAMs, contributing to T-cell dysfunction. Mechanistically, MSLN activated Wnt/β-catenin signaling, which in turn enhanced CD24 expression. This activation forms a positive feedback loop that further promotes MSLN transcription. In contrast,Mslnknockdown reduced CD24 expression, relieved cytotoxic T-cell suppression, and significantly improved the efficacy of anti-PD-1 therapy in syngeneic models.

Conclusions

This study elucidates the critical role of MSLN in immune evasion in HGSOC and its underlying mechanisms. Targeting MSLN in combination with ICB is a promising strategy to enhance the efficacy of immunotherapy and improve patient outcomes in HGSOC.
Effects of eccentric versus stretching exercise training on cognitive function of older women
Authors: Huang Min-Jyue , Singh Favil , Taaffe Dennis , Chen Trevor C , Nosaka Kazunori
Published: February 2025

Exercises focusing on eccentric contractions may stimulate the brain better, improving cognitive function. We tested the hypothesis that executive function and attention would improve more after eccentric resistance exercise (ECC) than stretching exercise (STRETCH) training. Healthy older women (65-75y) underwent either ECC (n=14) or STRETCH (n=14) intervention for 8 weeks. ECC consisted of 7 exercises emphasizing eccentric contractions while STRETCH performed 12 stretching exercises, with supervised sessions undertaken twice weekly accompanied by a home-based program. Executive function and attention were assessed using the Stroop test of color naming (STCN) and conflicting color words, symbol digit modalities test, digit span test (DST), and trail making tests (TMT-A, TMT-B), and 6 physical function tests were undertaken before and after the 8-week training period. Fasting blood samples were obtained before and after the training. A significant (p<0.05) group x time interaction effect was evident for STCN, DST and TMT-A, with only ECC showing improvements (DST:14.7±27% and TMT-A:10.2±12%) from pre- to post-training. No significant changes in other cognitive function tests were found for either group. All physical function tests except one-leg balance test showed greater improvement (p<0.05) for ECC than STRETCH. No significant changes in blood lipid profile and brain-derived neurotrophic factor were found, but serum glucose concentration and glycosylated hemoglobin decreased (p<0.05) in ECC. These results suggest that a short-term eccentric exercise intervention was effective in enhancing components of cognitive and physical function of older women and may prove a useful strategy in combating age-related decline in cognitive and physical function.
Polarization and kinematic properties of the splitting functions q→W±+q′ and q→Z0+q
Authors: Bagdatova Alsu G. , Baranov Sergey P.
Published: February 2025

In this paper, we consider the processes [Formula: see text] and [Formula: see text] and derive the respective splitting functions as functions of two kinematic variables: the longitudinal momentum fraction z and transverse momentum [Formula: see text] of the produced bosons with respect to the parent quark. We take into account kinematic (phase space) restrictions connected with nonzero masses of the gauge bosons and with limited initial energy. We separately consider three different polarization states of the bosons.
An empirical analysis of the effect of COVID-19 on the Indian mutual funds industry
Authors: Mahapatra Rupsa , Das Kishore Kumar , Ali Shahnawaz , Banerjee Pradeepta
Published: February 2025

Purpose: This research aims to examine and study the direct impact of change in COVID-19 cases and IIP index on the performance of NIFTY and selected mutual funds NAV performance for one year from the date WHO declared COVID-19 pandemic on 11 March 2020.

Approach/Methodology/Design: The study applies using daily NAV series of four mutual funds across sectors. ANOVA, Correlation, Regression, Descriptive Statistics.

Findings: There is a strong relation among NIFTY 50 and all the four mutual funds’ NAV performance, however, the relation between daily reported COVID-19 cases and NAV performance couldn’t be established.

Practical Implications: Economic turmoil has affected the disposable income of investors, the capital market is very volatile. This study will help the researchers and analysts to understand the relationship between COVID-19, NIFTY 50 index and select mutual funds NAV movements. And they can make a better decision under a similar situation.
Many-Objective Self-adaptation under Model Uncertainty
Authors: Camilli Matteo , Mirandola Raffaela , Scandurra Patrizia
Published: February 2025

The field of uncertainty quantification and mitigation in software-intensive and self-adaptive systems is garnering increased interest, especially with the rise of statistical inference methodologies like Bayesian reasoning. These methods typically address uncertain quality attributes embedded within system models by adjusting model parameters. However, the uncertainty related to selecting a specific system model over plausible alternatives has received limited attention. Our work focuses on self-adaptation, exploring methods to tackle uncertainty in model selection. This includes scenarios where one model is chosen over competing alternatives to encapsulate the system’s understanding and anticipate future observations. Our proposed solution augments the conventional feedback loop of self-adaptive systems by combining Bayesian model averaging to mitigate uncertainty and many-objective optimization to take into account multiple, possibly many, dependability requirements at the same time.

We carry out an empirical evaluation to study the effectiveness, cost, and scalability of the proposed approach using two case studies with increasing structural complexity and number of dependability requirements. Results show that our approach based on model averaging is significantly better than model selection in terms of satisfied requirements after adaptation (adaptation success frequency). We also show that our approach can deal with large model spaces (

\(\sim\!10^{19}\)

) using efficient sampling methods rather than exhaustive model space exploration.