bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methylation as a key regulator of Tau aggregation and neuronal health in Alzheimer’s disease
Authors: Balmik Abhishek Ankur , Chinnathambi Subashchandrabose 
Published: May 2021

AbstractNeurodegenerative diseases like Alzheimer’s, Parkinson’s and Huntington’s disease involves abnormal aggregation and accumulation of toxic proteins aggregates. Post-translational modifications (PTMs) of the causative proteins play an important role in the etiology of disease as they could either slow down or accelerate the disease progression. Alzheimer disease is associated with the aggregation and accumulation of two major protein aggregates—intracellular neurofibrillary tangles made up of microtubule-associated protein Tau and extracellular Amyloid-β plaques. Post-translational modifications are important for the regulation of Tau`s function but an imbalance in PTMs may lead to abnormal Tau function and aggregation. Tau methylation is one of the important PTM of Tau in its physiological state. However, the methylation signature on Tau lysine changes once it acquires pathological aggregated form. Tau methylation can compete with other PTMs such as acetylation and ubiquitination. The state of PTM at these sites determines the fate of Tau protein in terms of its function and stability. The global methylation in neurons, microglia and astrocytes are involved in multiple cellular functions involving their role in epigenetic regulation of gene expression via DNA methylation. Here, we have discussed the effect of methylation on Tau function in a site-specific manner and their cross-talk with other lysine modifications. We have also elaborated the role of methylation in epigenetic aspects and neurodegenerative conditions associated with the imbalance in methylation metabolism affecting global methylation state of cells.
Suicide mortality data from the Italian police during the COVID-19 pandemic
Authors: Garbarino Sergio , Fornaro Michele , Messina Rita , Pompili Maurizio , Ciprani Fabrizio 
Published: May 2021

AbstractSuicide is a major public health issue worldwide, with about 880,000 dying annually for such a cause. The COVID-19 pandemic has led to severe social disruption both from health and economic standpoints. Law enforcement personnel have been significantly involved in helping to face the many difficulties due to the pandemic. Police officers have been subjected to further stress from managing social restrictions imposed by governments to contain the pandemic. The Italian State Police steadily approximate 100,000 people aged 25–65 years: 14 subjects (mean age 43.64 years) died by suicide in 2015, 7 (mean age 47.5 years) in 2016, 13 (mean age 45.62 years) in 2017, 10 (mean age 48.1 years) in 2018, 18 (mean age 46.78 years) in 2019, and 12 (mean age 52 years) in 2020. Our records excluded significant changes in suicide incidence rate within 2015–2020 (till December 2020). However, the COVID-19 pandemic spread faster in Italy than in other regions, meaning that the Italian State Police possibly faced prolonged, intense stress. Suicide prevention, therefore, remains a priority, especially during this difficult time.
Systematic review of experiences and perceptions of key actors and organisations at multiple levels within health systems internationally in responding to COVID-19
Authors: Turner Simon , Botero-Tovar Natalia , Herrera Maria Alejandra , Borda Kuhlmann Juan Pablo , Ortiz Francisco , Ramírez Jean Carlo , Maldonado Luisa Fernanda 
Published: May 2021

Abstract
Background
COVID-19 has presented challenges to healthcare systems and healthcare professionals internationally. After one year of the pandemic, the initial evidence on health system responses begins to consolidate, and there is a need to identify and synthesise experiences of responding to COVID-19 among healthcare professionals and other health system stakeholders. This systematic review of primary qualitative studies depicts the experiences and perceptions of organisations and actors at multiple levels of health systems internationally in responding to COVID-19.

Methods
Six main databases of biomedical information, public health and health administration research were searched over the period October 1, 2019, to October 21, 2020. Information extracted from included studies was analysed thematically.

Results
Thirty-four studies were eligible for data extraction. Nine of those studies, of lower methodological quality, were removed from the thematic analysis of study results. Considering the professional level experiences, predominant themes of the studies consisted of the new roles and responsibilities of healthcare workers, burnout and distress, recognition of ´unseen´ healthcare workers, and positive changes and emergent solutions amid the crisis. Organisational level findings of the studies included provision of psychological support, COVID-19 as "catalyst" for change, and exercise of more "open" leadership by managers and health authorities. Continuous training, regulation of working conditions, providing supportive resources, coordinating a diversity of actors, and reviewing and updating regulations were roles identified at the local health system level.

Conclusions
The experiences of frontline healthcare workers have been the focus of attention of the majority of primary qualitative studies as of October 2020. However, organisational and wider system level studies indicate that some responses to COVID-19 have been characterised by increased emphasis on coordination activities by local health system actors, making service adaptations at pace, and reliance on expanded roles of front-line workers. The need for theory-informed qualitative studies was identified at the organisational level.

Trial registration
CRD42020202875
Blocking circ-CNST suppresses malignant behaviors of osteosarcoma cells and inhibits glycolysis through circ-CNST-miR-578-LDHA/PDK1 ceRNA networks
Authors: Hu Rui , Chen Shan , Yan Jianxin 
Published: May 2021

Abstract
Background
CircRNA CNST (circ-CNST) is a newly identified biomarker for prognosis of osteosarcoma (OS). However, its role in OS progression remains to be well documented.

Methods
Expression of circ-CNST, microRNA (miR)-578, lactate dehydrogenase A (LDHA), and pyruvate dehydrogenase kinase 1 (PDK1) was detected by quantitative real-time polymerase chain reaction and Western blotting. The physical interaction was confirmed by dual-luciferase reporter assay. Cell behaviors and glycolysis were measured by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay, colony formation assay, flow cytometry, transwell assays, xenograft experiment, and commercial kits.

Results
Circ-CNST was upregulated in human OS tissues and cells, accompanied with downregulation of miR-578 and upregulation of LDHA and PDK1. There were negative correlations between miR-578 expression and circ-CNST or LDHA/PDK1 in OS tissues. Moreover, high circ-CNST/LDHA/PDK1 or low miR-578 might predict shorter overall survival, advanced TNM stages, and lymph node metastasis. Physically, miR-578 was targeted by circ-CNST, and miR-578 could target LDHA/PDK1. Functionally, blocking circ-CNST and restoring miR-578 enhanced apoptosis rate and suppressed cell proliferation, colony formation, migration, and invasion in 143B and U2OS cells, accompanied with decreased glucose consumption, lactate production, and adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratio. Furthermore, in vivo growth of U2OS cells was retarded by silencing circ-CNST. Depletion of miR-578 could counteract the suppressive role of circ-CNST deficiency in 143B and U2OS cells, and restoring LDHA or PDK1 partially reversed the role of miR-578 inhibition as well.

Conclusion
Circ-CNST knockdown could antagonize malignant behaviors and glycolysis of OS cells by regulating miR-578-LDHA/PDK1 axes.
The effect of sacrificing the posterior cruciate ligament on total knee arthroplasty with cruciate retaining highly congruent rotating platform prosthesis
Authors: Chen Long , Xu Jie , Lin Yuan , Luo Fen Qi , Yu Yu Guo 
Published: May 2021

Abstract
Objective
To analyze the effect of sacrificing the posterior cruciate ligament (PCL) on the early postoperative outcome of cruciate retaining (CR) highly congruent rotating platform TKA.

Methods
From May 2018 to September 2019, 105 cases of total knee arthroplasty (TKA) with CR highly congruent rotating platform prosthesis were retrospectively analyzed. According to the tension of posterior cruciate ligament, they were divided into sacrifice group (29 cases, 27.6%) and retention group (76 cases, 72.4%). Preoperative and postoperative The Hospital for Special Surgery (HSS) score, range of motion (ROM) were compared between the two groups. In addition, postoperative infection, prosthesis loosening, bearing dislocation, and other complications were also compared.

Results
All patients were followed up for 11~24 months (mean 18.14 ± 3.52) months. There was no significant difference in general data, preoperative HSS score, and ROM between the two groups (P > 0.05). At the last follow-up, HSS score and ROM of the two groups were better than those before operation (P < 0.05). However, there was no significant difference between the two groups (P > 0.05). Moreover, there were no complications such as infection, loosening of prosthesis, and bearing dislocation in all cases.

Conclusion
In CR, highly congruent rotating platform TKA with or without tension of the PCL can achieve satisfactory outcomes. Tension-free PCL do not cause joint instability.
Model organisms contribute to diagnosis and discovery in the undiagnosed diseases network: current state and a future vision
Authors:   Undiagnosed Diseases Network, Baldridge Dustin , Wangler Michael F. , Bowman Angela N. , Yamamoto Shinya , Schedl Tim , Pak Stephen C. , Postlethwait John H. , Shin Jimann , Solnica-Krezel Lilianna , Bellen Hugo J. , Westerfield Monte 
Published: May 2021

AbstractDecreased sequencing costs have led to an explosion of genetic and genomic data. These data have revealed thousands of candidate human disease variants. Establishing which variants cause phenotypes and diseases, however, has remained challenging. Significant progress has been made, including advances by the National Institutes of Health (NIH)-funded Undiagnosed Diseases Network (UDN). However, 6000–13,000 additional disease genes remain to be identified. The continued discovery of rare diseases and their genetic underpinnings provides benefits to affected patients, of whom there are more than 400 million worldwide, and also advances understanding the mechanisms of more common diseases. Platforms employing model organisms enable discovery of novel gene-disease relationships, help establish variant pathogenicity, and often lead to the exploration of underlying mechanisms of pathophysiology that suggest new therapies. The Model Organism Screening Center (MOSC) of the UDN is a unique resource dedicated to utilizing informatics and functional studies in model organisms, including worm (Caenorhabditis elegans), fly (Drosophila melanogaster), and zebrafish (Danio rerio), to aid in diagnosis. The MOSC has directly contributed to the diagnosis of challenging cases, including multiple patients with complex, multi-organ phenotypes. In addition, the MOSC provides a framework for how basic scientists and clinicians can collaborate to drive diagnoses. Customized experimental plans take into account patient presentations, specific genes and variant(s), and appropriateness of each model organism for analysis. The MOSC also generates bioinformatic and experimental tools and reagents for the wider scientific community. Two elements of the MOSC that have been instrumental in its success are (1) multidisciplinary teams with expertise in variant bioinformatics and in human and model organism genetics, and (2) mechanisms for ongoing communication with clinical teams. Here we provide a position statement regarding the central role of model organisms for continued discovery of disease genes, and we advocate for the continuation and expansion of MOSC-type research entities as a Model Organisms Network (MON) to be funded through grant applications submitted to the NIH, family groups focused on specific rare diseases, other philanthropic organizations, industry partnerships, and other sources of support.
Violence against healthcare in conflict: a systematic review of the literature and agenda for future research
Authors: Haar Rohini J. , Read Róisín , Fast Larissa , Blanchet Karl , Rinaldi Stephanie , Taithe Bertrand , Wille Christina , Rubenstein Leonard S. 
Published: May 2021

Abstract
Background
Attacks on health care in armed conflict, including those on health workers, facilities, patients and transports, represent serious violations of human rights and international humanitarian law. Information about these incidents and their characteristics are available in myriad forms: as published research or commentary, investigative reports, and within online data collection initiatives. We review the research on attacks on health to understand what data they rely on, what subjects they cover and what gaps exist in order to develop a research agenda going forward.

Methods and findings
This study utilizes a systematic review of peer-reviewed to identify and understand relevant data about attacks on health in situations of conflict. We identified 1479 papers published before January 1, 2020 using systematic and hand-searching and chose 45 articles for review that matched our inclusion criteria. We extracted data on geographical and conflict foci, methodology, objectives and major themes. Among the included articles, 26 focused on assessment of evidence of attacks, 15 on analyzing their impacts, three on the legal and human rights principles and one on the methods of documentation. We analyzed article data to answer questions about where and when attacks occur and are investigated, what types of attacks occur, who is perpetrating them, and how and why they are studied. We synthesized cross-cutting themes on the impacts of these attacks, mitigation efforts, and gaps in existing data.

Conclusion
Recognizing limitations in the review, we find there have been comparatively few studies over the past four decades but the literature is growing. To deepen the discussions of the scope of attacks and to enable cross-context comparisons, documentation of attacks on health must be enhanced to make the data more consistent, more thorough, more accessible, include diverse perspectives, and clarify taxonomy. As the research on attacks on health expands, practical questions on how the data is utilized for advocacy, protection and accountability must be prioritized.
circPVT1 regulates medullary thyroid cancer growth and metastasis by targeting miR-455-5p to activate CXCL12/CXCR4 signaling
Authors: Zheng Xun , Rui Shu , Wang Xiao-Fei , Zou Xiu-He , Gong Yan-Ping , Li Zhi-Hui 
Published: May 2021

Abstract
Background
Medullary thyroid cancer (MTC) represents 13.4 % of all thyroid cancers-related deaths. The treatments for MTC are very limited especially for patients with distal metastasis. Therefore, it is critical to understand the mechanisms of MTC to pursue novel therapeutic avenues. Here, we studied the function of circPVT1/miR-455-5p in MTC.

Methods
Human MTC tissues and cell lines were used. qRT-PCR and Western blotting were employed to measure expression levels of miR-455-5p, circPVT1, CXCL12, and epithelial mesenchymal transformation (EMT)-related proteins. Colony formation assay, flow cytometry, transwell assay, and scratch wound healing assay were used to assess the abilities of cell proliferation, apoptosis, migration and invasion, respectively. Dual luciferase assay and RNA immunoprecipitation were employed to validate interactions of circPVT1/miR-455-5p and miR-455-5p/CXCL12. Nude mouse xenograft model was used to evaluate the effects of shcircPVT1 and miR-455-5p mimics on tumor growth and metastasis in vivo.

Results
miR-455-5p was reduced in MTC tissues and cells while circPVT1 was elevated. Their levels were correlated with prognosis of MTC. Overexpression of miR-455-5p or sh-circPVT1 suppressed EMT and MTC cell proliferation, migration and invasion. miR-455-5p targeted CXCL12 while circPVT1 sponged miR-455-5p. Knockdown of CXCL12 or CXCL12/CXCR4 signaling inhibitor reversed the effects of circPVT1 overexpression or miR-455-5p inhibitor on EMT and MTC cell proliferation, migration and invasion. Knockdown of circPVT1 or miR-455-5p overexpression repressed MTC tumor growth and lung metastasis in vivo.

Conclusions
miR-455-5p suppresses MTC growth and metastasis by targeting CXCL12/CXCR4 signaling pathway while circPVT1 promotes MTC by sponging miR-455-5p. Our study sheds light on the mechanisms of MTC growth and metastasis.
Monitoring of patients with microdialysis following pancreaticoduodenectomy—the MINIMUM study: study protocol for a randomized controlled trial
Authors: Lindholm Espen , Ekiz Nil , Tønnessen Tor Inge 
Published: May 2021

Abstract
Background
Postoperative pancreatic fistula after pancreatoduodenectomy is a much-feared complication associated with substantial mortality and morbidity. The current standard for diagnosing postoperative pancreatic fistula, besides routine clinical examination, include radiological examinations, analysis of pancreatic drain amylase activity, and routine blood samples. Another promising method is by intraperitoneal microdialysis to monitor intraperitoneal metabolites measured at the pancreaticojejunostomy, thereby detecting what occurs locally, before chemical events can be reflected as measurable changes in systemic blood levels.

Methods
The MINIMUM study is a prospective, randomized, controlled, single center enrolling 200 patients scheduled for open pancreatoduodenectomy comparing the microdialysis method to the “standard of care.” Half of the included patients will be randomized to receive an intraperitoneal microdialysis catheter implanted at the end of surgery and will be monitored by microdialysis as an additional monitoring tool. The other half of the patients will not receive a microdialysis catheter and will be monitored according to the current standard of care. The primary objective is to evaluate if the microdialysis method can reduce the total length of stay at the hospital. Secondary endpoints are the frequency of complications, length of stay at the hospital at our institution, catheter malfunction, number of infections and bleeding episodes caused by the microdialysis catheter, patient-reported quality of life and pain, and cost per patient undergoing pancreatoduodenectomy. The patients will be randomized in a 1:1 ratio.

Discussion
Intraabdominal microdialysis could potentially reduce morbidity and mortality after pancreatoduodenectomy. Furthermore, there is a great potential for shortening the in-hospital length of stay and reducing the financial aspect considerably. This study may potentially open the possibility for using microdialysis as standard monitoring in patients undergoing pancreatoduodenectomy. The hypothesis is that the microdialysis method compared to “standard care” will reduce the total length of hospital stay.

Trial registration
Clinicaltrials.gov (NCT03631173). Registered on 7 September 2018 under the name: “Monitoring of patients With Microdialysis Following Pancreaticoduodenectomy”. Based on protocol version 19-1, dated 15th January 2019.
Evaluation of two sexual-stage antigens as bivalent transmission-blocking vaccines in rodent malaria
Authors: Yang Fan , Liu Fei , Yu Xinxin , Zheng Wenqi , Wu Yudi , Qiu Yue , Jin Ying , Cui Liwang , Cao Yaming 
Published: May 2021

Abstract
Background
Transmission-blocking vaccine (TBV) is a promising strategy for malaria elimination. It is hypothesized that mixing or fusing two antigens targeting different stages of sexual development may provide higher transmission-blocking activity than these antigens used individually.

Methods
A chimeric protein composed of fragments of Pbg37 and PSOP25 was designed and expressed the recombinant protein in Escherichia coli Rosetta-gami B (DE3). After immunizing mice with individual recombinant proteins Pbg37 and PSOP25, mixed proteins (Pbg37+PSOP25), or the fusion protein (Pbg37-PSOP25), the antibody titers of individual sera were analyzed by ELISA. IFA and Western blot were performed to test the reactivity of the antisera with the native proteins in the parasite. The transmission-blocking activity of the different immunization schemes was assessed using in vitro and in vivo assays.

Results
When Pbg37 and PSOP25 were co-administered in a mixture or as a fusion protein, they elicited similar antibody responses in mice as single antigens without causing immunological interference with each other. Antibodies against the mixed or fused antigens recognized the target proteins in the gametocyte, gamete, zygote, and ookinete stages. The mixed proteins or the fusion protein induced antibodies with significantly stronger transmission-reducing activities in vitro and in vivo than individual antigens.

Conclusions
There was no immunological interference between Pbg37 and PSOP25. The bivalent vaccines, which expand the portion of the sexual development during which the transmission-blocking antibodies act, produced significantly stronger transmission-reducing activities than single antigens. Altogether, these data provide the theoretical basis for the development of combination TBVs targeting different sexual stages.

Graphical Abstract
Loss of EZH2-like or SU(VAR)3–9-like proteins causes simultaneous perturbations in H3K27 and H3K9 tri-methylation and associated developmental defects in the fungus Podospora anserina
Authors: Carlier F. , Li M. , Maroc L. , Debuchy R. , Souaid C. , Noordermeer D. , Grognet P. , Malagnac F. 
Published: May 2021

Abstract
Background
Selective gene silencing is key to development. It is generally accepted that H3K27me3-enriched heterochromatin maintains transcriptional repression established during early development and regulates cell fate. Conversely, H3K9me3-enriched heterochromatin prevents differentiation but constitutes protection against transposable elements. We exploited the fungus Podospora anserina, a valuable alternative to higher eukaryote models, to question the biological relevance and functional interplay of these two distinct heterochromatin conformations.

Results
We established genome-wide patterns of H3K27me3 and H3K9me3 modifications, and found these marks mutually exclusive within gene-rich regions but not within repeats. We generated the corresponding histone methyltransferase null mutants and showed an interdependence of H3K9me3 and H3K27me3 marks. Indeed, removal of the PaKmt6 EZH2-like enzyme resulted not only in loss of H3K27me3 but also in significant H3K9me3 reduction. Similarly, removal of PaKmt1 SU(VAR)3–9-like enzyme caused loss of H3K9me3 and substantial decrease of H3K27me3. Removal of the H3K9me binding protein PaHP1 provided further support to the notion that each type of heterochromatin requires the presence of the other. We also established that P. anserina developmental programs require H3K27me3-mediated silencing, since loss of the PaKmt6 EZH2-like enzyme caused severe defects in most aspects of the life cycle including growth, differentiation processes and sexual reproduction, whereas loss of the PaKmt1 SU(VAR)3–9-like enzyme resulted only in marginal defects, similar to loss of PaHP1.

Conclusions
Our findings support a conserved function of the PRC2 complex in fungal development. However, we uncovered an intriguing evolutionary fluidity in the repressive histone deposition machinery, which challenges canonical definitions of constitutive and facultative heterochromatin.