bluuebunny/crossref_metadata_2025_split huggingface dataset:
Area level indirect exposure to extended conflicts and early childhood anthropometric outcomes in India: a repeat cross-sectional analysis
Authors: Chatterjee Pritha , Chen Jarvis , Yousafzai Aisha , Kawachi Ichiro , Subramanian S. V. 
Published: May 2023

Abstract
Background
Protracted, internal conflicts with geographic variations within countries, are an important understudied community exposure for adverse child health outcomes.

Methods
Violent events from the Uppsala Conflict Data Program (UCDP) between January 2016–December 2020 and January 2010–December 2015, were included as exposure events for children sampled in National Family Health Surveys (NFHS) 5 (2019–21) and NFHS 4 (2015–16), respectively. Geocoded data from UCDP were merged with residential clusters from NFHS, to identify children living in villages or urban blocks situated at <= 50 km from conflict sites. Within these clusters, which we defined as conflict exposed, we studied risks of stunting, underweight and wasting in children, prenatally, and in 0–3 years. We assessed sensitivity on a subsample of siblings with discordant conflict exposures.

Results
For NFHS 5, exposure to violence between 0 and 3 years was associated with 1.16 times (95% CI 1.11–1.20) higher risks of stunting, 1.08 (1.04, 1.12) times higher risks of underweight, and no change in wasting. In-utero violence exposure was associated with 1.11 times (95% CI 1.04–1.17) higher risks of stunting, 1.08 (95% CI 1.02–1.14) times higher risks of underweight, and no change in wasting, among children <= 2 years. In 17,760 siblings of 8333 mothers, exposure to violence during 0–3 years, was associated with a 1.19 times higher risk of stunting (95% CI − 0.24 to 0.084). Incremental quartiles of violence exposure had higher risks of stunting and underweight until quartile 3.

Conclusion
In-utero and early childhood indirect exposure to protracted conflicts were associated with increased stunting and underweight in India. Given the continued exposures of such historically and contextually rooted internal conflicts in many LMICs, chronic violence exposures should be targeted in public health policies as important social and political determinant of child health.
Piperlongumine conquers temozolomide chemoradiotherapy resistance to achieve immune cure in refractory glioblastoma via boosting oxidative stress-inflamation-CD8+-T cell immunity
Authors: Liu Feng , Zhou Qian , Jiang Hai-feng , Zhang Ting-ting , Miao Cheng , Xu Xiao-hong , Wu Jia-xing , Yin Song-lin , Xu Shi-jie , Peng Jing-yi , Gao Pan-pan , Cao Xuan , Pan Feng , He Ximiao , Chen Xiao Qian 
Published: May 2023

Abstract
Background
The failure of novel therapies effective in preclinical animal models largely reflects the fact that current models do not really mimic the pathological/therapeutic features of glioblastoma (GBM), in which the most effective temozolomide chemoradiotherapy (RT/TMZ) regimen can only slightly extend survival. How to improve RT/TMZ efficacy remains a major challenge in clinic.

Methods
Syngeneic G422TN-GBM model mice were subject to RT/TMZ, surgery, piperlongumine (PL), αPD1, glutathione. Metabolomics or transcriptomics data from G422TN-GBM and human GBM were used for gene enrichment analysis and estimation of ROS generation/scavenging balance, oxidative stress damage, inflammation and immune cell infiltration. Overall survival, bioluminescent imaging, immunohistochemistry, and immunofluorescence staining were used to examine therapeutic efficacy and mechanisms of action.

Results
Here we identified that glutathione metabolism was most significantly altered in metabolomics analysis upon RT/TMZ therapies in a truly refractory and reliable mouse triple-negative GBM (G422TN) preclinical model. Consistently, ROS generators/scavengers were highly dysregulated in both G422TN-tumor and human GBM. The ROS-inducer PL synergized surgery/TMZ, surgery/RT/TMZ or RT/TMZ to achieve long-term survival (LTS) in G422TN-mice, but only one LTS-mouse from RT/TMZ/PL therapy passed the rechallenging phase (immune cure). Furthermore, the immunotherapy of RT/TMZ/PL plus anti-PD-1 antibody (αPD1) doubled LTS (50%) and immune-cured (25%) mice. Glutathione completely abolished PL-synergistic effects. Mechanistically, ROS reduction was associated with RT/TMZ-resistance. PL restored ROS level (mainly via reversing Duox2/Gpx2), activated oxidative stress/inflammation/immune responses signature genes, reduced cancer cell proliferation/invasion, increased apoptosis and CD3+/CD4+/CD8+ T-lymphocytes in G422TN-tumor on the basis of RT/TMZ regimen.

Conclusion
Our findings demonstrate that PL reverses RT/TMZ-reduced ROS and synergistically resets tumor microenvironment to cure GBM. RT/TMZ/PL or RT/TMZ/PL/αPD1 exacts effective immune cure in refractory GBM, deserving a priority for clinical trials.
Genome-wide association analysis reveals a novel pathway mediated by a dual-TIR domain protein for pathogen resistance in cotton
Authors: Zhang Yihao , Zhang Yaning , Ge Xiaoyang , Yuan Yuan , Jin Yuying , Wang Ye , Zhao Lihong , Han Xiao , Hu Wei , Yang Lan , Gao Chenxu , Wei Xi , Li Fuguang , Yang Zhaoen 
Published: May 2023

Abstract
Background
Verticillium wilt is one of the most devasting diseases for many plants, leading to global economic loss. Cotton is known to be vulnerable to its fungal pathogen, Verticillium dahliae, yet the related genetic mechanism remains unknown.

Results
By genome-wide association studies of 419 accessions of the upland cotton, Gossypium hirsutum, we identify ten loci that are associated with resistance against Verticillium wilt. Among these loci, SHZDI1/SHZDP2/AYDP1 from chromosome A10 is located on a fragment introgressed from Gossypium arboreum. We characterize a large cluster of Toll/interleukin 1 (TIR) nucleotide-binding leucine-rich repeat receptors in this fragment. We then identify a dual-TIR domain gene from this cluster, GhRVD1, which triggers an effector-independent cell death and is induced by Verticillium dahliae. We confirm that GhRVD1 is one of the causal gene for SHZDI1. Allelic variation in the TIR domain attenuates GhRVD1-mediated resistance against Verticillium dahliae. Homodimerization between TIR1-TIR2 mediates rapid immune response, while disruption of its αD- and αE-helices interface eliminates the autoactivity and self-association of TIR1-TIR2. We further demonstrate that GhTIRP1 inhibits the autoactivity and self-association of TIR1-TIR2 by competing for binding to them, thereby preventing the resistance to Verticillium dahliae.

Conclusions
We propose the first working model for TIRP1 involved self-association and autoactivity of dual-TIR domain proteins that confer compromised pathogen resistance of dual-TIR domain proteins in plants. The findings reveal a novel mechanism on Verticillium dahliae resistance and provide genetic basis for breeding in future.
Effectiveness of motor control exercise, aerobic walking, and muscle strengthening programs in improving outcomes in a subgroup of population with chronic low back pain positive for central sensitization: a study protocol for a randomized controlled trial
Authors: Ganesh G. Shankar , Khan Abdur Raheem , Das Sakti Prasad , Khan Ashfaque , Alqhtani Raee S. , Alshahrani Adel , Jarrar Mohammad Abdulrehman Mohammad , Ahmed Hashim 
Published: May 2023

Abstract
Background
The role of pain sensitivity in the development and maintenance of chronic pain states, impaired executive functioning, and patient recovery is being investigated. Conditioned pain modulation (CPM) is widely used to measure musculoskeletal pain associated with central sensitization (CS). Despite the recommendations of many reviews and clinical practice guidelines that exercise programs reduce pain and disability, the overall confidence in these results is considered “critically low.” The “active ingredient” of exercise programs and the dominant factor influencing CPM remain largely unknown.
The objectives of this trial are to determine:
• If different exercises cause different results on the CPM in a subgroup of people with chronic low back pain (CLBP) who are labeled as having CS pain,
• If a program of exercise interventions for 12 weeks would alter executive functioning, quality of life (QoL), disability, and pain in persons with CLBP.
• The relationship between patient characteristics, executive functions, CPM, and QoL

Methods
The trial is a randomized, controlled, multi-center study with four experimental groups and one healthy control group. Both the researchers and the people in the study will be blinded to the results. This paper describes the protocol for a trial examining the effects of 12-week individualized, twice-weekly exercise sessions lasting 30 to 60 min in persons with CLBP, who are positive for CS. Participants will be randomized to receive either patient education with motor control exercises (MCE), superficial strengthening (SS), aerobic exercises (AE), or patient education alone. Another group comprised of healthy volunteers will serve as controls. The primary outcomes are changes in CPM outcomes as measured by the cold pressor test (CPT). The secondary objectives are to evaluate executive functioning, pain, disability, quality of life, and spine muscle strength. The outcomes will be measured at 3 months and at a 6-month follow-up.

Discussion
The outcomes of the study will help in gaining more information and evidence about exercise-induced analgesia from the perspective of CPM. Measuring exercise outcomes will aid in scientifically prescribing exercise prescriptions in people with CLBP. The study outcomes will also assist in identifying the characteristics of individuals who will respond or respond indifferently to exercises. Investigating the relationship between the study’s various outcomes could provide information for future trials.

Trial registration
Clinical Trials Registry of India (CTRI) identifier: CTRI/2022/03/041143. Registered on 16 March 2022.
High level of complexity and global diversity of the 3q29 locus revealed by optical mapping and long-read sequencing
Authors: Yilmaz Feyza , Gurusamy Umamaheswaran , Mosley Trenell J. , Hallast Pille , Kim Kwondo , Mostovoy Yulia , Purcell Ryan H. , Shaikh Tamim H. , Zwick Michael E. , Kwok Pui-Yan , Lee Charles , Mulle Jennifer G. 
Published: May 2023

AbstractBackgroundHigh sequence identity between segmental duplications (SDs) can facilitate copy number variants (CNVs) via non-allelic homologous recombination (NAHR). These CNVs are one of the fundamental causes of genomic disorders such as the 3q29 deletion syndrome (del3q29S). There are 21 protein-coding genes lost or gained as a result of such recurrent 1.6-Mbp deletions or duplications, respectively, in the 3q29 locus. While NAHR plays a role in CNV occurrence, the factors that increase the risk of NAHR at this particular locus are not well understood.MethodsWe employed an optical genome mapping technique to characterize the 3q29 locus in 161 unaffected individuals, 16 probands with del3q29S and their parents, and 2 probands with the 3q29 duplication syndrome (dup3q29S). Long-read sequencing-based haplotype resolved de novo assemblies from 44 unaffected individuals, and 1 trio was used for orthogonal validation of haplotypes and deletion breakpoints.ResultsIn total, we discovered 34 haplotypes, of which 19 were novel haplotypes. Among these 19 novel haplotypes, 18 were detected in unaffected individuals, while 1 novel haplotype was detected on the parent-of-origin chromosome of a proband with the del3q29S. Phased assemblies from 44 unaffected individuals enabled the orthogonal validation of 20 haplotypes. In 89% (16/18) of the probands, breakpoints were confined to paralogous copies of a 20-kbp segment within the 3q29 SDs. In one del3q29S proband, the breakpoint was confined to a 374-bp region using long-read sequencing. Furthermore, we categorized del3q29S cases into three classes and dup3q29S cases into two classes based on breakpoints. Finally, we found no evidence of inversions in parent-of-origin chromosomes.ConclusionsWe have generated the most comprehensive haplotype map for the 3q29 locus using unaffected individuals, probands with del3q29S or dup3q29S, and available parents, and also determined the deletion breakpoint to be within a 374-bp region in one proband with del3q29S. These results should provide a better understanding of the underlying genetic architecture that contributes to the etiology of del3q29S and dup3q29S.
Sex differences in the polygenic architecture of hearing problems in adults
Authors: De Angelis Flavio , Zeleznik Oana A. , Wendt Frank R. , Pathak Gita A. , Tylee Daniel S. , De Lillo Antonella , Koller Dora , Cabrera-Mendoza Brenda , Clifford Royce E. , Maihofer Adam X. , Nievergelt Caroline M. , Curhan Gary C. , Curhan Sharon G. , Polimanti Renato 
Published: May 2023

Abstract
Background
Hearing problems (HP) in adults are common and are associated with several comorbid conditions. Its prevalence increases with age, reflecting the cumulative effect of environmental factors and genetic predisposition. Although several risk loci have been already identified, HP biology and epidemiology are still insufficiently investigated by large-scale genetic studies.

Methods
Leveraging the UK Biobank, the Nurses’ Health Studies (I and II), the Health Professionals Follow-up Study, and the Million Veteran Program, we conducted a comprehensive genome-wide investigation of HP in 748,668 adult participants (discovery N = 501,825; replication N = 226,043; cross-ancestry replication N = 20,800). We leveraged the GWAS findings to characterize HP polygenic architecture, exploring sex differences, polygenic risk across ancestries, tissue-specific transcriptomic regulation, cause-effect relationships with genetically correlated traits, and gene interactions with HP environmental risk factors.

Results
We identified 54 risk loci and demonstrated that HP polygenic risk is shared across ancestry groups. Our transcriptomic regulation analysis highlighted the potential role of the central nervous system in HP pathogenesis. The sex-stratified analyses showed several additional associations related to peripheral hormonally regulated tissues reflecting a potential role of estrogen in hearing function. This evidence was supported by the multivariate interaction analysis that showed how genes involved in brain development interact with sex, noise pollution, and tobacco smoking in relation to their HP associations. Additionally, the genetically informed causal inference analysis showed that HP is linked to many physical and mental health outcomes.

Conclusions
The results provide many novel insights into the biology and epidemiology of HP in adults. Our sex-specific analyses and transcriptomic associations highlighted molecular pathways that may be targeted for drug development or repurposing. Additionally, the potential causal relationships identified may support novel preventive screening programs to identify individuals at risk.
CRISPR-Cas9 knockout screen identifies novel treatment targets in childhood high-grade glioma
Authors: Wenger Anna , Karlsson Ida , Kling Teresia , Carén Helena 
Published: May 2023

AbstractBackgroundBrain tumours are the leading cause of cancer-related death in children, and there is no effective treatment. A growing body of evidence points to deregulated epigenetics as a tumour driver, particularly in paediatric cancers as they have relatively few genomic alterations, and key driver mutations have been identified in histone 3 (H3). Cancer stem cells (CSC) are implicated in tumour development, relapse and therapy resistance and thus particularly important to target. We therefore aimed to identify novel epigenetic treatment targets in CSC derived from H3-mutated high-grade glioma (HGG) through a CRISPR-Cas9 knockout screen.ResultsThe knockout screen identified more than 100 novel genes essential for the growth of CSC derived from paediatric HGG with H3K27M mutation. We successfully validated 12 of the 13 selected hits by individual knockout in the same two CSC lines, and for the top six hits we included two additional CSC lines derived from H3 wild-type paediatric HGG. Knockout of these genes led to a significant decrease in CSC growth, and altered stem cell and differentiation markers.ConclusionsThe screen robustly identified essential genes known in the literature, but also many novel genes essential for CSC growth in paediatric HGG. Six of the novel genes (UBE2N, CHD4,LSM11, KANSL1, KANSL3andEED)were validated individually thus demonstrating their importance for CSC growth in H3-mutated and wild-type HGG. These genes should be further studied and evaluated as novel treatment targets in paediatric HGG.
Granuloma annulare with alopecia areata in a 6-year-old girl: a case report
Authors: Mohaghegh Fatemeh , Moeine Reza , Saber Mina , Fatemeh Safdarian , Nekooeian Mohammad , Shahriarirad Reza 
Published: May 2023

Abstract
Background
Dermatologic signs and symptoms can be the manifestations of a single disease or different diseases, and it is proven that some are associated with one another. These connections are not fully understood, but the answer lies in the pathophysiology of each disease.

Case presentation
We report the case of a 6-year-old Middle-Eastern girl who presented with two skin lesions on the dorsum of her foot, along with scaling of her soles and palms, face skin discoloration, and areas of patchy alopecia on her scalp. She was diagnosed as a case of acute onset of granuloma annulare with alopecia areata and dermatitis. The treatment regimen for the patient’s scalp consisted of topical minoxidil and betamethasone and three sessions with 1-month intervals of triamcinolone acetonide intralesional injections, which demonstrated modest effectiveness in treating alopecia areata.

Conclusion
Granuloma annulare is a benign inflammatory illness with no known cause that might be difficult to cure. The clinical course and prognosis might vary greatly depending on the disease subtype, and associating symptoms and diseases, such as alopecia areata, should be considered.
Anomalous aortic origin of right coronary artery from left coronary cusp: a management conundrum: a case report
Authors: Arun Kumar Pramukh , Patel Boskey , Dasari Mahati , Bhattad Pradnya Brijmohan , Prabhu Sushmita , Hadley Michelle 
Published: May 2023

Abstract
Background
Coronary artery anomalies are characterized by an abnormality in the course or origin of three main coronary arteries. There needs to be more scientific evidence to promptly treat coronary artery anomalies with poorly understood prognostic implications, especially anomalous aortic origin of the right coronary artery from the left coronary cusp.

Case presentation
A 58-year-old Caucasian female presented multiple times over 6 months with atypical chest discomfort and palpitations. The treadmill exercise test demonstrated exercise-induced non-sustained ventricular tachycardia. A coronary angiogram revealed no obstructive coronary artery disease and an anomalous aortic origin of the right coronary artery from the left coronary cusp with an interarterial course. She was managed conservatively with medications, despite persistent recurrent symptoms.

Conclusion
It is essential to identify subtle symptoms and insidious onset of anomalous aortic origin of the right coronary artery symptoms as seen in our patient, which can contribute to significant morbidity. There are discrepancies in existing guidelines between different cardiovascular societies in managing selected subgroups of patients with anomalous aortic origin of the right coronary artery who do not have high-risk features, but continue to remain symptomatic.
Unexpected presentation of accessory breast: vulvar accessory breast tissue: a case report
Authors: Mansouri Ghazal , Alkatout Ibrahim , Iranpour Maryam , Pourkhandani Elham , Allahqoli Leila 
Published: May 2023

AbstractBackgroundThe accessory breast is composed of residual glandular mammary tissue that persists after normal embryonic development. The entity is so rare that it is easily neglected in the diagnosis of disease.Case presentationWe report a 24-year-old virgin Persian woman with a left-sided vulvar mass and no pain or discomfort until shortly before her presentation at our department. Ectopic breast tissue in the vulva was diagnosed. We performed wide local resection of the lesion. Pathological investigation of the lesion confirmed the presence of ectopic breast tissue with secretory changes. She had no specific developmental abnormalities and had no relevant family history. She was followed up for 10 months and had recovered fully by this time.ConclusionAccessory breast tissue should be considered as a diagnosis when a mass is seen along the embryonic milk line, especially if the clinical findings reveal changes in the mass accompanied by changes in sex hormones.
NAD+ metabolism-based immunoregulation and therapeutic potential
Authors: Fang Jiankai , Chen Wangwang , Hou Pengbo , Liu Zhanhong , Zuo Muqiu , Liu Shisong , Feng Chao , Han Yuyi , Li Peishan , Shi Yufang , Shao Changshun 
Published: May 2023

AbstractNicotinamide adenine dinucleotide (NAD+) is a critical metabolite that acts as a cofactor in energy metabolism, and serves as a cosubstrate for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+metabolism can regulate functionality attributes of innate and adaptive immune cells and contribute to inflammatory responses. Thus, the manipulation of NAD+bioavailability can reshape the courses of immunological diseases. Here, we review the basics of NAD+biochemistry and its roles in the immune response, and discuss current challenges and the future translational potential of NAD+research in the development of therapeutics for inflammatory diseases, such as COVID-19.