bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the Effect of Topographical Distribution of Ethnic Groups and Absence of Uniform Land Governance in the Homeland Politics of Manipur, India
Authors: Singh M. Amarjeet
Published: January 2025

Manipur, an Indian state, has long been burdened by homeland politics and the ensuing conflict. Two ethnic groups that predominantly inhabit the hills, namely the Nagas and the Kukis, wanted their self-proclaimed homelands to be recognized as state/union territory. But the Meiteis, the single largest ethnic group, who predominantly live in the valley, are against altering the territorial boundary of Manipur. The paper thus argues that the division caused by the topographic distribution of the three ethnic groups as well as the colonial and the post-colonial policies of land governance system have made Manipur conducive for homeland politics.
Legacies of Past and Present Violence: Evidence From Mosul, Iraq
Authors: Whitt Sam , Mironova Vera , Page Douglas
Published: January 2025

Scholars are increasingly drawing attention to the societal consequences of conflict-related violence. What remains unclear is the interplay between short-term and long-term legacies of wartime traumas. We consider the case of Mosul, Iraq, a setting in which inhabitants have experienced wide-ranging victimization during both recent and historical contexts. In a 2022 survey, we inquired across a broad range of self-reported conflict experiences involving personal and kinship-based victimization including physical and sexual violence, property destruction, forced imprisonment, and displacement as a result of ISIS occupation. We also probed for victimization dating back to the Iran-Iraq War. Examining altruism toward other ISIS victims in a dictator game, we find that while ISIS-related victimization increases out-group empathy and reduces in-group bias in altruism, earlier conflict experiences exert independent influence as well. We consider the implications of our findings for conflict research involving multiple layers and sources of trauma and victimization.
Samirah X’s Sense of Audience: A Case Study on Black Teen Activism on Social Media
Authors: McDaniel Dominique
Published: January 2025

This article presents a critical account of one teen’s sense of audience as she enacted literacies on social media platforms and provides strategies that can inform the teaching of audience and purpose in ways responsive to teens’ digital literacies. Informed by case-study research and insights gained from interviewing, observing, and collecting digital artifacts, I discuss how Samirah X, a self-described teen actress and social justice advocate, engaged in writing practices on social media for three different main perceived audiences: cultural and racial community audience, socially conscious audience, and parental audience. Other sub-audiences from Samirah X’s case narrative are presented: audience as Black people, culture, and identity; audience as Black women and girls; and audience as Blacks who experience injustice and acts of violence. At the conclusion of this article, I provide implications for teaching English Language Arts focused on how social media work can fulfill state standards.
Evaluation of the Pogostone in an Acetaminophen-induced Liver Injury Rat Model
Authors: Hou Yingkui , Sun Wencong , Yang Jing
Published: January 2025

Background

One of the leading causes of serious liver disease worldwide is drug-induced liver injury, which is brought on by either the direct hepatotoxic effects of a medication or one of its reactive metabolites. One often-used medication over the counter is acetaminophen (APAP). Although APAP is safe in small amounts, an overdose can result in rapid liver damage and even death from acute liver failure. It is common knowledge that the pharmaceutical business has been using more and more plant products in recent years. Traditional Chinese medicine has utilized patchouli, scientifically known as Pogostemon cablin ( P. cablin) Benth, a member of the Lamiaceae family, since the Eastern Han period.

Purpose

The current study aims to assess pogostone’s (PO) hepatoprotective effects on rats’ APAP-induced toxicity.

Materials and Methods

APAP was used to produce toxicity after two different dosages of PO were given. Liver function markers and biochemical parameters, bilirubin, and protein profile were used to determine the extent of hepatoprotection. The indicators of oxidative stress in the liver and kidney tissue were examined, including superoxide dismutase, catalase, glutathione, and malondialdehyde along with the histopathological analysis.

Results

PO has been found to return hepatic and renal antioxidant levels, as well as liver function markers, to normal, compared to the aberrant levels detected in the APAP-treated group. After being observed, it was discovered that the liver weight and liver index were comparable to the positive control. A liver histological examination was also performed, and the results indicated that co-administration with PO significantly reduced the histopathological lesions in the liver caused by APAP.

Conclusion

As a result, the current study demonstrates that PO has hepatoprotective effects against liver damage brought on by APAP.
Looking for Marai ‘on-the-fly’: mobile more-than-human methods for cultural landscape mapping with Gajerrong Country
Authors: Atchison Jennifer , Savige Thomas , Simon Bernadette , Taylor Eli
Published: January 2025

At the intersections of rapid socio-ecological transformation, Indigenous people in Northern Australia are articulating their aspirations for land management. However, while people reconcile goals, knowledges and practices to care for Country, the available toolkit that might facilitate planning and activities has often constrained ideas because technologies and systems have tended to be both inaccessible and incompatible with non-Western representations of place. In this paper, we report on a cultural landscape mapping project with Marralam Community of the Northern Territory, Australia, undertaken to analyze, advocate and communicate community ideas, knowledge and visions for managing Country. Prioritizing culturally respectful ways of working, we articulate mobile mapping methods that speak to the experiential, emergent and performative, and political aspects of how our research collaboration is mapping together with Country. Harnessing the innovations of qualitative GIS, mapping with Country ‘on-the-fly’ facilitates what may otherwise be conceived of as competing demands and interests, highlighting Indigenous expertise in navigating the complex terrain of natural resource management and knowledge sharing. Mapping with Country foreshadows lively possibilities for mapping as more-than-human collaborative research practice.
Synthesis and characterization of BODIPY-DPA-Cu(II)-conjugate HNO fluorescent probes: Effect of linker length on imaging properties
Authors: Liu Wenbo , Zou Yufeng , Zhou Yu , Zheng Jiangwei , Liu Xiaoguang , Jiang Dengzhao
Published: January 2025

Nitroxyl, which was acknowledged as a vital constituent among the reactive nitrogen species, poses significant challenges when it comes to its swift and precise identification and measurement. Recently, a kind of BODIPY-DAP-Cu(II)-conjugate fluorescent probes has been broadly used to detect nitroxyl. However, the impact of varying linker chain lengths on the physicochemical attributes and imaging performance of dipyrromethene boron difluoride–based fluorescent probes remained uncertain. In this study, we engineered three new dipyrromethene boron difluoride–based nitroxyl fluorescent probes CuII[BD1] (3.88 Å), CuII[BD2] (5.02 Å), CuII[BD3] (6.67 Å), CuII[BD4] (10.77 Å) which were composed of dipyrromethene boron difluoride as fluorescence indicator and a tripodal-DPA-Cu(II) unit as nitroxyl recognition site, using increasing lengths of linker chain. The new probe CuII[BD3] (6.67 Å) showed fast response (within 1 min) toward nitroxyl with remarkable sensitivity, capable of detecting as low as 0.25 μM, superior specificity for nitroxyl, and relative stability under physiological pH condition. Furthermore, the probe CuII[BD3] was applied to bioimaging of nitroxyl in rat blood. In conclusion, those results revealed that the imaging characteristics of dipyrromethene boron difluoride derivatives were significantly influenced by the length of the linker chain. The fluorescence detection efficiency increases with the growth of the linker chains within 6.67 Å. Consequently, these probes hold promise as valuable chemical instruments for probing the detailed functions and mechanisms of nitroxyl within biological organisms and offered an innovative approach for the construction of dipyrromethene boron difluoride–based nitroxyl fluorescent probes.
Perceptions and experiences of commercial virtual reality games in early postoperative rehabilitation among cardiac surgical patients: A qualitative study
Authors: Wu Zhongkang , Li Xihan , Li Lin , Zhang Yan , Shen Xiao
Published: January 2025

Background

Although numerous studies have focused on the outcomes of virtual reality games for early rehabilitation in postoperative cardiac surgical patients, research on these patients’ perceptions and experiences with virtual reality games has been limited.

Objectives

The aim of this qualitative study was to provide insights into the perceptions and experiences of postoperative cardiac surgery patients in using commercial virtual reality games during early rehabilitation.

Methods

A cohort of postoperative cardiac surgery patients ( n = 12) who used the same VR games during the early rehabilitation period at the cardiac surgery intensive care unit (ICU) of a tertiary hospital in Nanjing, China, was enrolled in this study, conducted between January 2023 and December 2023. Data were collected through individual in-depth interviews and analyzed using Colaizzi's phenomenological method.

Results

Two themes emerged from the interviews: (1) the benefits of virtual reality games for rehabilitation, including (i) enhancing enthusiasm for rehabilitation, (ii) helping patients to focus attention, (iii) increasing individual exercise, (iv) providing enjoyment, and (v) regulating negative emotions; (2) shortcomings in the use of virtual reality games, including (i) producing stress, (ii) insufficient operating space, (iii) discomfort while wearing, (iv) difficulty in mastering the application, and (v) individualized needs.

Conclusion

Cardiac patients believed that the use of commercial virtual reality games during early postoperative rehabilitation was beneficial to rehabilitation, but they highlighted some shortcomings that require improvement. The results of this study provide a certain theoretical basis for the further promotion and application of commercial virtual reality games in clinical practice in the future.
Goal-based performance metrics for ice hockey accounting for goal importance
Authors: Lambrix Patrick , Carlsson Niklas , Säfvenberg Rasmus
Published: January 2025

The evaluation of player performance is an important topic in sports analytics and is used for team management, scouting, and in sports broadcasts. When evaluating the performance of ice hockey players, many metrics are used, including traditional metrics such as goals, assists, and points and more recent metrics such as Corsi and expected goals. One weakness of such metrics is that they do not consider the context in which the value for the metric was assigned. Other advanced metrics have been introduced, but as they are not easily explainable to practitioners, they may not make it into the hockey discourse. In this paper we introduce new goal-based metrics that (i) are based on traditional, well-known metrics, and thus easily understandable, (ii) take context into account in the form of time, manpower differential, and goal differential and (iii) add a new aspect by taking into account the importance of goals regarding their contribution to team wins and ties. We describe the intuitions behind the metrics, give formal definitions, evaluate the metrics and show correlations to the traditional metrics. We have used data from seven NHL seasons and show which players stand out with respect to the number of goals and the importance of goals.
Protocol for the INFORM ASTHMA Trial: Budesonide-formoterol reliever in adults with asthma on maintenance inhaled corticosteroid
Authors: Noble Jonathan , Bean Orlagh , Bruce Pepa , Black Melissa , Sayers Ross , Cullen Ryan , Black Bianca , Holliday Mark , Kirton Louis , Perry Blake , Eathorne Allie , Pavord Ian , Weatherall Mark , Beasley Richard
Published: January 2025

Background

International asthma guidelines recommend inhaled corticosteroid (ICS)/formoterol in preference to short-acting beta2-agonist (SABA) reliever-based regimens as reliever therapy in adults and adolescents of all asthma severities. A major limitation to this recommendation is the absence of randomised controlled trial (RCT) efficacy and safety data for this approach in patients who continue to use maintenance ICS. The anti-inflammatory effect of ICS/formoterol reliever therapy on airway inflammation is also not well characterised.

Objective

To determine the anti-inflammatory effect, efficacy and safety of budesonide-formoterol reliever therapyversusterbutaline reliever therapy in adults with asthma on maintenance ICS therapy. Fractional exhaled nitric oxide (FeNO) will specifically be examined to determine the time-course and magnitude of anti-inflammatory effect.

Methods

A 26-week, open-label, parallel-group, 2-arm, phase IV, two-sided superiority RCT will recruit 180 adults aged 16–75 with a clinical diagnosis of asthma using reliever only therapy, or SABA reliever therapy with maintenance ICS at baseline, and with baseline FeNO at screening ≥25 ppb. Enrolled participants will be allocated to maintenance budesonide with the dose based on their baseline treatment step and randomised 1:1 to either budesonide-formoterol or terbutaline reliever therapy. All participants will perform at home FeNO measurements at regular intervals for the first 12 weeks of the study. The primary outcome is FeNO at 26 weeks. Key secondary outcomes include FeNO time-course, asthma exacerbations, asthma control and spirometry.

Conclusion

This will be the first RCT comparing ICS-formoterolversusSABA reliever therapy in patients who use maintenance ICS therapy.
Lifestyle scores and their potential to estimate the risk of multiple non-communicable disease-related endpoints: a systematic review
Authors: Ding Jie , Fu Ruojin , Yuan Tanwei , Brenner Hermann , Hoffmeister Michael
Published: January 2025

Background

Lifestyle scores have emerged as a practical tool to assess the risk of major non-communicable diseases (NCDs). However, most of them are primarily developed for single NCDs. Given the common risk factors for some of the major NCDs, we conducted a systematic review to evaluate the potential of existing lifestyle scores in predicting the risk of multiple NCD-related endpoints.

Methods

PubMed, Web of Science, the Cochrane Library, Embase, and Google Scholar were searched from inception to October 2024. We included observational studies assessing the association between lifestyle scores and the risk of morbidity or mortality of multiple NCDs, including type 2 diabetes (T2D), cardiovascular disease (CVD), and cancer.

Results

Of 16,138 unique records identified by the search, 56 eligible studies were included in the systematic review, consisting of 48 cohort studies, 5 case-control studies, 2 case-cohort studies, and 1 cross-sectional study from 16 countries. 15 lifestyle scores were identified to estimate the risk of 32 NCDs, with HLIBMI being the most reported score (14/56, 25.0%). Moderate to strong associations were found between the 15 lifestyle scores and the risk of developing and dying from multiple types of cancers, CVDs, and T2D. Healthy lifestyle scores including additional risk factors (i.e., blood pressure, blood glucose, and waist circumference) aside from major risk factors (i.e., Body Mass Index (BMI), smoking, and diet) seemed to have a stronger ability to estimate NCDs risk than scores including only major risk factors.

Conclusion

All 15 simple lifestyle scores were shown to estimate the risk of multiple NCDs endpoints, although some scores were originally developed to estimate the risk of single diseases only. Therefore, further research is required to identify which lifestyle score is most effective for assessing the risk of multiple NCD-related endpoints in a head-to-head comparison.
Differences in influenza testing and treatment in micropolitan versus metropolitan areas in the U.S. using medicare claims data from 2010 to 2016
Authors: Couture Alexia , Dahlgren F. Scott , Izurieta Hector S. , Forshee Richard A. , Lu Yun , Reed Carrie
Published: January 2025

Background

To improve understanding of influenza and rurality, we investigated differences in influenza testing and anti-viral treatment rates between micropolitan (muSAs) and metropolitan statistical areas (MSAs) using national medical claims data over multiple influenza seasons.

Methods

Using billing data from the Centers for Medicare and Medicaid Services for those aged 65 years and older, we estimated weekly rates of ordered rapid influenza diagnostic tests (RIDT) and antivirals (AV) among Medicare enrollees by core-based statistical areas (CBSAs) during 2010–2016. We used Negative Binomial generalized mixed models to estimate adjusted rate ratios (aRR) between MSAs and muSAs, adjusting for clustering by CBSA plus explanatory variables. We ran models for all weeks and only high influenza activity weeks.

Results

For all weeks, the unadjusted rate of RIDTs was 1.97 per 10,000 people in MSAs compared with 2.69 in muSAs (Rate ratio (RR) = 0.73, 95% Confidence Interval (CI): 0.73–0.74) and of AVs was 1.85 in MSAs compared with 1.40 in muSAs (RR = 1.32, CI: 1.31–1.32). From the multivariate model, aRR for RIDTs was 0.82 (0.73–0.94) and for AVs was 1.12 (1.04–1.22) in MSAs versus muSAs. For high influenza activity weeks, aRR for RIDTs was 0.82 (0.73–0.92) and for AVs was 1.15 (1.06–1.24). All models found influenza testing rates higher in muSAs and treatment rates higher in MSAs.

Conclusions

Our study found lower testing and higher treatment in U.S. metropolitan versus micropolitan areas from 2010 to 2016 for those aged 65 years and older in our population. Identifying differences in influenza rates by rurality may improve public health response. Further research into the relationship of rurality and health disparities is needed.
VA physicians intent to leave and correlations to drivers of burnout: a cross-sectional study
Authors: Oh Robert C. , Mohr David C. , Schult Tamara M.
Published: January 2025

Background

Physician well-being and workforce retention within the healthcare system is of critical importance. Understanding physicians’ intent to leave the organization will inform efforts on optimizing the physician workforce. In this study, we examine the association of burnout and specific drivers of burnout on turnover intentions.

Methods

The study was a cross-sectional design using data collected from an organization-wide workforce survey. The sample included 16,363 respondents from the Veterans Health Administration (VA). A multinomial model was run to compare physicians indicating turnover intent because they were: a.) changing internal jobs; b.) leaving the organization for another job; or c.) retiring, against physicians indicating they had no plans to turnover. Explanatory variables in the model included burnout, drivers of burnout, and demographics. We also asked about the primary reason behind turnover intent.

Results

Most physicians responding to the survey (n = 13,083, 80%) indicated they would stay within their current job, while 5.8% indicated they would look for another VA job, 5% indicated planning to retire, and 9.3% said they would leave the VA workforce altogether. Burnout and less favorable senior leadership perceptions were associated with greater odds of turnover intent specific to finding another VA job, leaving VA, or retire. Experiencing discrimination was related to turnover intent for another VA job and leaving VA, while satisfaction with workload and recognition were related to lower odds of finding another VA job or leaving VA. Culture of well-being was associated with lower odds of leaving VA.

Conclusions

The study highlights how burnout is associated with turnover intentions with physicians have differing rationales for leaving. Several drivers of burnout were related to turnover intentions for both finding another VA job and leaving VA altogether. Efforts to improve workforce well-being and drivers of burnout may help address the different rationales physicians may have for considering leaving.
From bench to bedside: elucidating VEGF(R) inhibitor-related heart failure in cancer treatment
Authors: Peng Shengkun , Cai MinHong , Kuang Hongyu , Lin Anqi , Ma Qinghua , Dai Xiaoqin , Luo Peng , Liu Yijun , Zhang Guo , Bai Yifeng
Published: January 2025

Background

Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors play a pivotal role in treating various tumors; however, the clinical characteristics and molecular mechanisms of their associated heart failure (HF) remain incompletely understood.

Methods

We investigated the epidemiological characteristics of VEGF or VEGFR inhibitors [VEGF(R)i]-related heart failure (VirHF) using the global pharmacovigilance database Vigibase. The phenotypic features and molecular mechanisms of VirHF were characterized using VEGF(R)i-treated mouse models through a combination of echocardiography, histopathological analysis, and transcriptome sequencing. Furthermore, we performed a retrospective analysis of cardiac function parameters in patients undergoing VEGF(R)i treatment at local hospitals.

Results

In the analysis of 1871 VirHF cases, elderly patients (≥ 65 years) and female subjects demonstrated an elevated risk of occurrence. Experimental studies in mice revealed that both acute and chronic VEGF(R)i administration resulted in reduced left ventricular EF, cardiomyocyte hypertrophy, and myocardial fibrosis. Transcriptomic analysis identified significant dysregulation of multiple key signaling pathways, including DNA repair (R = 0.46), mitochondrial ATP synthesis (R = 0.39), glycogen metabolism regulation (R = 0.45), and proteasome-mediated protein degradation (R = 0.45). Moreover, significant upregulation was observed in inflammatory pathways, specifically those involving IL-1, IL-6, TNF-α, and IRF3/IRF7-mediated immune responses. Clinical cohort analyses demonstrated significant elevations in both cardiac injury biomarkers (NT-proBNP, CK-MB, cTnT) and inflammatory mediators (CRP) following VEGF(R)i administration.

Conclusions

Our findings present the first comprehensive characterization of VirHF clinical features and elucidate its underlying molecular mechanisms, thereby providing a theoretical framework for optimizing the clinical safety of VEGF(R)i therapy.
Sleep-driven prefrontal cortex coordinates temporal action and multimodal integration
Authors: Ibrahim Ahmed Z. , Abdou Kareem , Nomoto Masanori , Yamada-Nomoto Kaori , Okubo-Suzuki Reiko , Inokuchi Kaoru
Published: January 2025

Cognitive processes such as action planning and decision-making require the integration of multiple sensory modalities in response to temporal cues, yet the underlying mechanism is not fully understood. Sleep has a crucial role for memory consolidation and promoting cognitive flexibility. Our aim is to identify the role of sleep in integrating different modalities to enhance cognitive flexibility and temporal task execution while identifying the specific brain regions that mediate this process. We have designed “Auditory-Gated Patience-to-Action” Task in which mice should process different auditory signals before action execution as well as analyzing the visual inputs for feedback of their action. Mice could learn the task rule and apply it only after sleeping period and could keep the performance constant across sessions. c-fos positive cells showed the involvement of prelimbic cortex (PrL) during task execution. Chemo-genetic inhibition verified that PrL is required for proper signal response and action timing. These findings emphasize that sleep and cortical activity are keys for cognitive flexibility in adapting to different modalities.
DNA copy number variations and craniofacial abnormalities in 1,457 children with neurodevelopmental disorders
Authors: Wu Dandan , Chen Ran , Zhang Jerry , Yan Wu , Chen Mengyin , Xia Dongqing , Li Xiaonan , Dai Yanyan , Chen Yinhua , Li Rong
Published: January 2025

Background

This study aimed to investigate deoxyribonucleic acid (DNA) copy number variations (CNVs) in children with neurodevelopmental disorders and their association with craniofacial abnormalities.

Methods

A total of 1,457 children who visited the Child Health Department of our hospital for unexplained Neurodevelopmental disorders (NDDs) between November 2019 and December 2022 were enrolled. Peripheral venous blood samples (2 mL) were collected from the children and their parents for whole-exome sequencing. Positive results were verified through Sanger sequencing for locus and pedigree validation. Simultaneously, a specific sign-scoring scale was created to evaluate characteristics related to the developments of eyes, nose, ears, eyebrows, head, mouth, face, trunk, limbs, and reproductive, urinary, and cardiovascular systems.

Results

A total of 536 children (36.78%, 536/1,457) were found to have genetic variations, with 379 (70.71%, 379/536) exhibiting pathogenic monogenic mutations. Furthermore, 157 children (29.29%, 157/536) harbored DNA copy number variants, encompassing microdeletions (68.15%, 107/157) and microduplications (31.85%, 50/157). Regarding the pathogenicity of CNVs, 91 (57.96%, 91/157) were identified as pathogenic, 28 (17.83%, 28/157) as variants of uncertain clinical significance (VOUS), and 38 (24.20%, 38/157) as benign according to the American College of Medical Genetics and Genomics (ACMG).Using a specific sign-scoring scale, the proportion of pathogenic CNVs in children graded 1 point or higher (64%, 58/91) was significantly higher than that of non-pathogenic CNVs (43%, 29/66) (P < 0.05). Furthermore, the proportion of microdeletions in children graded 1 point or higher (60.75%, 65/107) was significantly higher than those carrying microduplications (44%, 22/50) (P < 0.05). The proportion of pathogenic microdeletions in children graded 1 point or higher (73.43%,47/64) was significantly higher than those carrying pathogenic microduplications (40.74%, 11/27) (P < 0.05).

Conclusion

The positive rate of whole-exome sequencing for children with combined craniofacial abnormalities and NDDs exceeds the international average in our study cohort. Thus, whole-exome sequencing may be recommended for precise diagnosis of neurogenetic diseases in such cases.
Evolutionary constrained genes associated with autism spectrum disorder across 2,054 nonhuman primate genomes
Authors: Kikuchi Yukiko , Uddin Mohammed , Veltman Joris A. , Wells Sara , Morris Christopher , Woodbury-Smith Marc
Published: January 2025

Background

Significant progress has been made in elucidating the genetic underpinnings of Autism Spectrum Disorder (ASD). However, there are still significant gaps in our understanding of the link between genomics, neurobiology and clinical phenotype in scientific discovery. New models are therefore needed to address these gaps. Rhesus macaques (Macaca mulatta) have been extensively used for preclinical neurobiological research because of remarkable similarities to humans across biology and behaviour that cannot be captured by other experimental animals.

Methods

We used the macaque Genotype and Phenotype (mGAP) resource consisting of 2,054 macaque genomes to examine patterns of evolutionary constraint in known human neurodevelopmental genes. Residual variation intolerance scores (RVIS) were calculated for all annotated autosomal genes (N = 18,168) and Gene Set Enrichment Analysis (GSEA) was used to examine patterns of constraint across ASD genes and related neurodevelopmental genes.

Results

We demonstrated that patterns of constraint across autosomal genes are correlated in humans and macaques, and that ASD-associated genes exhibit significant constraint in macaques (p = 9.4 × 10− 27). Among macaques, many key ASD-implicated genes were observed to harbour predicted damaging mutations. A small number of key ASD-implicated genes that are highly intolerant to mutation in humans, however, showed no evidence of similar intolerance in macaques (CACNA1D, MBD5, AUTS2 and NRXN1). Constraint was also observed across genes associated with intellectual disability (p = 1.1 × 10− 46), epilepsy (p = 2.1 × 10− 33) and schizophrenia (p = 4.2 × 10− 45), and for an overlapping neurodevelopmental gene set (p = 4.0 × 10− 10).

Limitations

The lack of behavioural phenotypes among the macaques whose genotypes were studied means that we are unable to further investigate whether genetic variants have similar phenotypic consequences among nonhuman primates.

Conclusion

The presence of pathological mutations in ASD genes among macaques, along with evidence of similar genetic constraints to those in humans, provides a strong rationale for further investigation of genotype-phenotype relationships in macaques. This highlights the importance of developing primate models of ASD to elucidate the neurobiological underpinnings and advance approaches for precision medicine and therapeutic interventions.
Spatial deconvolution from bulk DNA methylation profiles determines intratumoral epigenetic heterogeneity
Authors: Liu Binbin , Xie Yumo , Zhang Yu , Tang Guannan , Lin Jinxin , Yuan Ze , Liu Xiaoxia , Wang Xiaolin , Huang Meijin , Luo Yanxin , Yu Huichuan
Published: January 2025

Background

Intratumoral heterogeneity emerges from accumulating genetic and epigenetic changes during tumorigenesis, which may contribute to therapeutic failure and drug resistance. However, the lack of a quick and convenient approach to determine the intratumoral epigenetic heterogeneity (eITH) limit the application of eITH in clinical settings. Here, we aimed to develop a tool that can evaluate the eITH using the DNA methylation profiles from bulk tumors.

Methods

Genomic DNA of three laser micro-dissected tumor regions, including digestive tract surface, central bulk, and invasive front, was extracted from formalin-fixed paraffin-embedded sections of colorectal cancer patients. The genome-wide methylation profiles were generated with methylation array. The most variable methylated probes were selected to construct a DNA methylation-based heterogeneity (MeHEG) estimation tool that can deconvolve the proportion of each reference tumor region with the support vector machine model-based method. A PCR-based assay for quantitative analysis of DNA methylation (QASM) was developed to specifically determine the methylation status of each CpG in MeHEG assay at single-base resolution to realize fast evaluation of epigenetic heterogeneity.

Results

In the discovery set with 79 patients, the differentially methylated CpGs among the three tumor regions were found. The 7 most representative CpGs were identified and subsequently selected to develop the MeHEG algorithm. We validated its performance of deconvolution of tumor regions in an independent cohort. In addition, we showed the significant association of MeHEG-based epigenetic heterogeneity with the genomic heterogeneity in mutation and copy number variation in our in-house and TCGA cohorts. Besides, we found that the patients with higher MeHEG score had worse disease-free and overall survival outcomes. Finally, we found dynamic change of epigenetic heterogeneity based on MeHEG score in cancer cells under the treatment of therapeutic drugs.

Conclusion

By developing a 7-loci panel using a machine learning approach combined with the QASM assay for PCR-based application, we present a valuable method for evaluating intratumoral heterogeneity. The MeHEG algorithm offers novel insights into tumor heterogeneity from an epigenetic perspective, potentially enriching current knowledge of tumor complexity and providing a new tool for clinical and research applications in cancer biology.
TC2N maintains stem cell-like characteristics to accelerate lung carcinogenesis by blockade of dual specificity protein phosphatase 3
Authors: Gu Jing , Lv Yang-fan , Xia Ji-ying , Bai Fu-hai , Gong Ji , Pan Guang-qiang , Liu Bo , Huang Lu , Guo Qiao-nan , Hao Xiang-lin
Published: January 2025

Background

Tandem C2 domains, nuclear (TC2N) is a protein that has been characterized to contain C2A domain, C2B domain, and a short C-terminus with a WHXL motif. In previous studies, we have uncovered the oncogenic role and mechanisms of TC2N in lung cancer: TC2N achieves this by inhibiting the p53 signaling pathway and activating the NF-kappaB signaling pathway. Beyond that, its precise function in tumorigenesis is not fully understood.

Methods

TC2N-engineered mice model was used to assess the effect of TC2N knockout on normal lung and urethane-induced carcinogenesis. Tumor tissues of 395 lung cancer patients were subjected to tissue microarray and further assessed the associations of TC2N expression with tumor differentiation degree. The protein levels of TC2N and stem cell markers in cell lines and tissue specimens were monitored by WB and immunohistochemistry. In vitro cell assays were performed to assess the effect of TC2N ectopic expression on the stem cell-like characteristics of lung cancer cells. The downstream signaling pathway or target molecule of TC2N was mined using a combination of transcriptomics and proteomics, and the underlying mechanism was explored by WB and co-IP assays.

Results

Herein, TC2N appeared to have a strong effect in promoting lung tumorigenesis caused by urethane, whereas it seemed to lose its function in the normal lung. Meanwhile, we found that the functional differences of TC2N between lung tumor and normal lung were linked to its potential role in cancer cell stemness. Function-wise, TC2N overexpression maintained stem-like properties of lung cancer cell. Mechanism-wise, TC2N upregulated the phosphorylation of EGFR, ERK, STAT3 and FAK1 to activate these signaling pathways by the inhibition of DUSP3 phosphatase via a dual mechanism. Firstly, TC2N competes with EGFR, ERK, STAT3 and FAK1 for binding to DUSP3. This competition prevents these signaling molecules from being dephosphorylated by DUSP3, resulting in their sustained activation. Secondly, TC2N bind to DUSP3 and restrict the enzyme’s ability to dephosphorylate the signaling molecules.

Conclusions

Overall, this study revealed a previously unknown role and mechanism of TC2N in the regulation of tumorigenesis and stemness in lung cancer cells.
The resilience of parents and carers who administer medicines to children at home: a qualitative systematic review protocol
Authors: Morris Stephen , Pini Simon , Fylan Beth , Wilson Franki , Faulkner Helen , Alldred David P.
Published: January 2025

Background

Parents and carers are increasingly expected to administer prescribed medicines to their children at home. However, parents and carers are not always able to administer medicines as directed by the prescriber and ultimately must rely on their own judgment to administer medicines safely. This process is often unseen but may contain important learning for professionals, academics, and wider society. Studying safety in everyday healthcare work presents researchers with many challenges. However, recent developments in our understanding of resilience and how it manifests within healthcare can provide an effective framework for enquiry. The aim of this review is to use resilience theory to explore parents’ and carers’ experiences when administering medicines to children at home.

Methods

This systematic review will follow the framework synthesis method. An iterative search strategy, using a scoping search of the major databases (Embase, PyscINFO, CINAHL, Cochrane and PubMed) will be used. The three main search terms are parents and carers, administration of medicines, and the home environment. Included studies will contain qualitative data and investigate the experiences of parents or carers who administer prescribed medicines to children at home. Relevant studies will be quality assessed using the Joanna Briggs Institute critical appraisal checklist for qualitative research.

Framework synthesis will be completed by following five stages: familiarisation, thematic framework identification, indexing, charting, mapping, and interpretation. The findings identified in the data extraction phase will be indexed and charted according to the three elements of Moments of Resilience theory.

Discussion

This protocol describes a novel method to address an important patient safety issue. A strength of this review will be not only to identify, describe and collate existing studies, but also to learn about the application of resilience theory to a medication safety topic. The knowledge generated from this will inform intervention development to improve the support for families to administer medicines safely at home.

Systematic review registration

This review has been registered on the International Prospective Register of Systematic Reviews database (PROSPERO) #487154.
The Effect of Strength Training Targeting Medial Thigh Muscles on Neuromuscular and Biomechanical Risk Factors for Anterior Cruciate Ligament Injury: A Randomized Controlled Trial
Authors: Jeong Jiyoung , Choi Dai-Hyuk , Shin Choongsoo S.
Published: January 2025

Background

Knee valgus loading is thought to be an important contributor to noncontact anterior cruciate ligament (ACL) injuries, but the effects of training programs focusing on decreasing knee valgus loading on lower extremity biomechanics with respect to ACL injury risk remain unclear. Thus, this study aimed to examine the effect of strength training designed to strengthen the medial thigh muscles on lower extremity joint kinematics, kinetics and muscle activity during single-leg landing.

Methods

A total of 35 healthy participants randomly conducted either exercises targeting medial thigh muscles (intervention group) or exercises that did not target specific lower extremity muscles (control group). Three-dimensional hip, knee, and ankle kinematic/kinetic data and muscle activity for lower extremity muscles were obtained during single-leg landing. Two-way analyses of variance were conducted for each dependent variable to determine the effect of 8-week of strength training targeting medial thigh muscles.

Results

The intervention group showed decreased knee varus-valgus excursion (P = 0.009), peak valgus moment (P = 0.032), and peak hip internal rotation moment (P = 0.009) but increased gluteus medius activity in the precontact phase (P = 0.012) and vastus medialis-to-vastus lateralis (VM: VL) coactivation ratio in the postcontact phase (P = 0.043). The change in coronal plane knee excursion was negatively correlated with both the change in gluteus medius activity (R2 = 0.321, P = 0.014) and the change in VM: VL coactivation ratio (R2 = 0.276, P = 0.025).

Conclusions

Strength training targeting medial thigh muscles can modify the biomechanics associated with ACL injuries; thus, this intervention might be considered when designing ACL injury prevention programs to reduce dynamic knee valgus during sports-related tasks.
Cultural foundations of global health: a critical examination of universal child feeding recommendations
Authors: Scheidecker Gabriel , Funk Leberecht , Chaudhary Nandita , Chapin Bambi L. , Schmidt Wiebke J. , El Ouardani Christine
Published: January 2025

There has been a rising call to decolonize global health so that it more fully includes the concerns, knowledge, and research from people all over the world. This endeavor can only succeed, we argue, if we also recognize that much of established global health doctrine is rooted in Euro-American beliefs, values, and practice rather than being culturally neutral. This paper examines the cultural biases of child feeding recommendations as a case in point. We argue that the global promotion of Responsive Feeding—a set of allegedly best practices for child feeding promulgated by the WHO and others—is based on a tacit conviction that certain Western middle-class feeding practices are universally best, along with a promise that future evidence will demonstrate their superiority. These recommendations denounce feeding practices that diverge from this style as Non-Responsive Feeding, thereby pathologizing the many valued ways of feeding children in communities all over the world without sound scientific evidence. Drawing on ethnographic research, we show that there is a wide variety in feeding practices around the world and these are closely interlinked with the understandings and priorities of caregivers, as well as with favored forms of relationships and ways of maintaining them. For global health nutrition interventions to be justified and effective, they would need to be based on more pertinent, culturally responsive research than they currently are. We suggest the use of ethnographic research as an important tool in building empirically grounded, epistemically inclusive, and locally meaningful approaches to improving nutritional support for children in communities around the world and to global health efforts more broadly.
Updates on CAD risk assessment: using the coronary artery calcium score in combination with traditional risk factors
Authors: Rezaie-Kalamtari Kiara , Norouzi Zeinab , Salmanipour Alireza , Mehrali Hossein
Published: January 2025

Background

Coronary artery disease (CAD) is the third leading cause of death worldwide, so prevention and early diagnosis play important roles to reduce mortality and morbidity. Traditional risk-score assessments were used to find the at-risk patients in order to prevent or early treatment of CAD. Adding imaging data to traditional risk-score systems will able us to find these patients more confidently and reduce the probable mismanagements.

Main text

Measuring the vascular calcification by coronary artery calcium (CAC) score can prepare valuable data for this purpose. Using CAC became more popular in recent years. The most applicable method to evaluate CAC is Agatston scoring using computed tomography (CT) scanning. Patients are classified into several subgroups: no evidence of CAD (score 0), mild CAD (score 1–10), minimal CAD (score 11–100), moderate CAD (score 101–400), and severe CAD (score > 400) and higher than1000 as the extreme risk of CVD events.

Conclusions

CAC assessment was recommended in the patients older than 40 years old with CAD risk factors, the ones with stable angina, borderline-to-intermediate-risk group, etc. According to the results of the CAC the patients may be candidate for further evaluation for needing revascularization, medical treatment, or routine follow-up. Adding artificial intelligence (AI) to CAC will prepare more data and can increase the reliability of our approach to the patients promising a bright future to improve this technology.
The Future Is Child's Play
Authors: Kim Ava L.J.
Published: January 2025

This essay analyzes Lucía Puenzo's 2007 film, XXY, to articulate a collaborative process of gender-ambiguous becoming, what the author ultimately calls a theory of child's play. Building on María Josefina Saldaña-Portillo's theorization of developmentalism and an extended engagement with work by Marlene Wayar and Mauro Cabral Grinspan, the article argues that XXY reveals an emergent “transition ideology” that aligns gender development with national development and internalizes a buried history of national racism. It then contextualizes XXY in a longer history of neoliberal politics in Argentina, connecting current divides between an older generation of travesti activists and younger trans people to long-standing invocations of generational kinship at the national level. The second part of the essay scales beyond scenes of individual and national transition to transnational notions of trans progress. Taking critiques from trans studies and anticolonial thought, the essay explains how the transnational abstraction of a “right to gender identity” in transition has shifted from its original activist framings of material access to limited notions of self-declaration.
From Theater to Social Movement
Authors: Prado Fernandes André
Published: January 2025

During its military dictatorship's toughest years, Brazil witnessed the emergence and meteoric rise to (inter)national fame of the theater and dance group/family Dzi Croquettes in the 1970s. Their queer performances were so contagious that an increasingly visible entourage began to adopt the Dzi way of being and “philosophy of life.” This article examines the Dzi movement based on the existing literature and primary data generated through archival research and oral history interviews. It begins with an overview of the state of affairs surrounding the Croquettes's emergence and proceeds with two thematic sections where the primary data are presented and examined: the first one regarding the multidirectional identifications that formed between/among performers and spectators before, during, and after performances; and the second, focused on the enhanced but “costly” sense of freedom and transgression in/as the aftermath of the Dzi performances. Lastly, the article elaborates on the notion of the Dzi contagion and charts its affective and sociopolitical potentials by analyzing the articulation and dissemination of ontologies, subjectivities, and vocabularies (such as freedom, difference, and equality) beyond/against the liberal episteme. This piece contributes, both empirically and theoretically, to broader debates about the world-making and political powers of queer performances and utopias in/from the global South.
High-Throughput Chemotherapeutic Drug Screening System for Gastric Cancer (Cure-GA)
Authors: Lee Jieun , Kim In Hee , Seol Donghyeok , Lee Sangjun , Yoo Mira , Lee Tae-Kyeong , Yoon So Hee , Lee Eunju , Hwang Duyeong , Kang So Hyun , Park Young Suk , Ku Bosung , Jeon Sang Youl , Choi Yongmun , Jung Keehoon , Kim Ji-Won , Kim Jin Won , Ahn Sang-Hoon , Lee Keun-Wook , Kim Hyung-Ho , Oh Hyeon Jeong , Lee Dong Woo , Suh Yun-Suhk
Published: January 2025

Background

Three dimensional (3D) cell cultures can be effectively used for drug discovery and development but there are still challenges in their general application to high-throughput screening. In this study, we developed a novel high-throughput chemotherapeutic 3D drug screening system for gastric cancer, named 'Cure-GA', to discover clinically applicable anticancer drugs and predict therapeutic responses.

Methods

Primary cancer cells were isolated from 143 fresh surgical specimens by enzymatic treatment. Cell-Matrigel mixtures were automatically printed onto the micropillar surface then stabilized in an optimal culture medium for 3 days to form tumoroids. These tumoroids were exposed in the drug-containing media for 7 days. Cell viability was measured by fluorescence imaging and adenosine triphosphate assays. On average, 0.31 ± 0.23 g of fresh tumor tissue yielded 4.05×106 ± 4.38×106 viable cells per sample.

Results

Drug response results were successfully acquired from 103 gastric cancer tissues (success rate = 72%) within 13 ± 2 days, averaging 6.4 ± 2.7 results per sample. Pearson correlation analysis showed viable cell numbers significantly impacted drug data acquisition (p < 0.00001). Tumoroids retained immunohistochemical characteristics, mutation signatures, and gene expression consistent with primary tumors. Drug reactivity data enabled prediction of synergistic drug correlations. Additionally, a multiparameter index-based prognosis model for patients undergoing gastrectomy followed by adjuvant XELOX was developed, showing significant differences in 1-year recurrence-free survival rates between drug responders and non-responders (p < 0.0001).

Conclusions

The Cure-GA platform enables rapid evaluation of chemotherapeutic responses using patient-derived tumoroids, providing clinicians with crucial insights for personalized treatment strategies and improving therapeutic outcomes.