bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure, function and inhibition of critical protein–protein interactions involving mixed lineage leukemia 1 and its fusion oncoproteins
Authors: Li Xin , Song Yongcheng 
Published: April 2021

AbstractMixed lineage leukemia 1 (MLL1, also known as MLL or KMT2A) is an important transcription factor and histone-H3 lysine-4 (H3K4) methyltransferase. It is a master regulator for transcription of important genes (e.g., Hox genes) for embryonic development and hematopoiesis. However, it is largely dispensable in matured cells. Dysregulation of MLL1 leads to overexpression of certain Hox genes and eventually leukemia initiation. Chromosome translocations involving MLL1 cause ~ 75% of acute leukemia in infants and 5–10% in children and adults with a poor prognosis. Targeted therapeutics against oncogenic fusion MLL1 (onco-MLL1) are therefore needed. Onco-MLL1 consists of the N-terminal DNA-interacting domains of MLL1 fused with one of > 70 fusion partners, among which transcription cofactors AF4, AF9 and its paralog ENL, and ELL are the most frequent. Wild-type (WT)- and onco-MLL1 involve numerous protein–protein interactions (PPI), which play critical roles in regulating gene expression in normal physiology and leukemia. Moreover, WT-MLL1 has been found to be essential for MLL1-rearranged (MLL1-r) leukemia. Rigorous studies of such PPIs have been performed and much progress has been achieved in understanding their structures, structure–function relationships and the mechanisms for activating gene transcription as well as leukemic transformation. Inhibition of several critical PPIs by peptides, peptidomimetic or small-molecule compounds has been explored as a therapeutic approach for MLL1-r leukemia. This review summarizes the biological functions, biochemistry, structure and inhibition of the critical PPIs involving MLL1 and its fusion partner proteins. In addition, challenges and perspectives of drug discovery targeting these PPIs for the treatment of MLL1-r leukemia are discussed.
Magnitude and associated factors of virological failure among children on ART in Bahir Dar Town public health facilities, Northwest Ethiopia: a facility based cross-sectional study
Authors: Gelaw Belete , Mulatu Getasew , Tesfa Getasew , Marew Chalie , Chekole Bogale , Alebel Animut 
Published: April 2021

Abstract
Background
Despite the rapid scale-up of antiretroviral therapy, virologic failure has become global public health concern and challenge, especially in developing countries. Viral load monitoring is an important approach to identify treatment failure and develop public health interventions in children receiving antiretroviral therapy. Thus, this study aims to assess the magnitude and associated factors of virological failure among children on antiretroviral therapy.

Methods
A facility-based cross-sectional study was conducted among 399 HIV-positive children on antiretroviral therapy from 2016 to 2019 in Bahir Dar Town public health facilities. Data were extracted from children’s charts using a standardized data extraction tool, adapted from ART intake and follow-up forms. Data were entered using Epi-Data Version 3.1, and analyzed using SPSS Version 25. Bivariable and multivariable binary logistic regression models were done to identify factors associated with virological failure. Variables with p-values < 0.25 were fitted into the multivariable analysis. Finally, variables with p-values <0.05 were considered as statistically significant factors.

Results
The period prevalence of virological failure was found to be 14.8% (95% CI: 11.5–19.3%). Opportunistic infections (AOR = 2.19, CI: 1.13–4.25), history of treatment interruption and restart (AOR = 2.21, CI: 1.09–4.54), younger age (AOR = 2.42, CI: 1.02–5.74), poor/fair ART adherence (AOR = 2.19, CI: 1.05–4.57), and advanced baseline WHO clinical staging (AOR = 2.32, CI: 1.14–4.74) were found to be factors significantly associated with virological failure.

Conclusion
The magnitude of virological failure among HIV-infected children remained high. Children with poor/fair ART adherence, history of treatment interruption, advanced baseline WHO clinical staging, younger age, and opportunistic infections were significantly associated with virologic failure. Thus, special attention should be given to children who had poor/fair ART adherence and presenting with opportunistic infections.
Effect of the combination of automated peripheral mechanical stimulation and physical exercise on aerobic functional capacity and cardiac autonomic control in patients with Parkinson’s disease: a randomized clinical trial protocol
Authors: Zelada-Astudillo Nicolle , Moreno Vinicius Christianini , Herrera-Santelices Andrea , Barbieri Fabio Augusto , Zamunér Antonio Roberto 
Published: April 2021

AbstractBackgroundAutomated peripheral mechanical stimulation (AMPS) has been proposed as a new complementary therapy with potential for improving motor and cardiovascular abnormalities in Parkinson’s disease (PD). However, AMPS long-term effects and its combination with physical exercise are unknown. Thus, this study aims to compare the effects of a program of 12 weeks of physical exercise with a 12-week intervention program combining physical exercise and AMPS on the aerobic capacity, cardiac autonomic control, and gait parameters in patients with PD.MethodsA randomized, controlled clinical trial will be conducted. Older volunteers with PD will be randomly assigned to one of the two groups studied: (1) exercise or (2) AMPS + exercise. Both groups will undergo an exercise program of 24 sessions, for 12 weeks, performed twice a week. Before exercise sessions, the group AMPS + exercise will receive a session of active AMPS, while the group exercise will receive an AMPS sham intervention. Shapiro-Wilk’s and Levene’s tests will be used to check for data normality and homogeneity, respectively. In case parametric assumptions are fulfilled, per-protocol and intention-to-treat analyses will be performed using a mixed model analysis of variance to check for group*time interaction. Significance level will be set at 5%.DiscussionSeveral non-pharmacological treatment modalities have been proposed for PD, focusing primarily on the reduction of motor and musculoskeletal disorders. Regular exercise and motor training have been shown to be effective in improving quality of life. However, treatment options in general remain limited given the high prevalence and adverse impact of these disorders. So, developing new strategies that can potentiate the improvement of motor disabilities and also improve non-motor symptoms in PD is relevant. It is expected that the participants from both groups will improve their quality of life, gait parameters, and their cardiac autonomic control, with greater improvements being observed in the group combining active AMPS and physical exercise.Trial registrationClinicalTrials.govNCT04251728. Registered on February 05, 2020.
Developing a complex intervention whilst considering implementation: the TANDEM (Tailored intervention for ANxiety and DEpression Management) intervention for patients with chronic obstructive pulmonary disease (COPD)
Authors: Steed Liz , Heslop-Marshall Karen , Sohanpal Ratna , Saqi-Waseem Sarah , Kelly Moira , Pinnock Hilary , Taylor Stephanie 
Published: April 2021

Abstract
Background
Guidelines now call for a thorough and comprehensive description of the development of healthcare interventions to aid evaluation and understanding of the processes of change. This was the primary aim of this study but we also recognised that effective interventions are commonly not implemented in clinical practice. It is suggested that insufficient attention is given to the implementation process at the development phase of interventions. This study outlines the 5 step iterative process we adopted for considering both implementation and effectiveness issues from the outset of intervention development. We use the development of a complex intervention Tailored intervention for ANxiety and DEpression Management (TANDEM) in patients with chronic obstructive pulmonary disease to illustrate this process.

Methods
Intervention development built upon the Medical Research Council framework for developing complex interventions and the person-based approach for development of behavioural interventions. Building an expert team, specifying theory, qualitative data collection and pre-piloting were all critical steps in our intervention development and are described here.

Results
Contact with experts in the field, and explicitly building on previous work, ensured efficiency of design. Qualitative work suggested guiding principles for the intervention such as introducing mood in relation to breathlessness, and providing flexible tailoring to patients’ needs, whilst implementation principles focused on training selected respiratory professionals and requiring supervision to ensure standards of care. Subsequent steps of intervention development, pre-piloting and intervention refinement led to an intervention that was deemed acceptable and if successful will be ready for implementation.

Conclusions
The TANDEM study was developed efficiently by building on previous work and considering implementation issues from the outset, with the aim that if shown to be effective it will have more rapid translation in to the health care system with accelerated patient benefits.

Trial registration
ISRCTN ISRCTN59537391. Registered on 20 March 2017. Protocol version 6.0, 22 April 2018.
GSK3β rephosphorylation rescues ALPL deficiency-induced impairment of odontoblastic differentiation of DPSCs
Authors: Zhang Liqiang , Zhao Jiangdong , Dong Jiayi , Liu Yuting , Xuan Kun , Liu Wenjia 
Published: April 2021

Abstract
Background
Premature exfoliation of the deciduous teeth is a common manifestation in childhood patients with hypophosphatasia (HPP), which is an autosomal inherited disease caused by ALPL mutations. Dysplasia of the cementum, dentin, and alveolar bone has been proposed to be the main reasons for the exfoliation of teeth, while the extraordinarily complex intracellular mechanisms remain elusive. Dental pulp stem cells (DPSCs) have been demonstrated to successfully regenerate functional pulp-dentin-like tissue. Dental pulp cells derived from HPP patients impaired mineralization; however, insight into the deeper mechanism is still unclear.

Methods
The effects of ALPL on odontoblastic differentiation of DPSCs from HPP patient were assessed by Alizarin Red staining, immunofluorescent staining, Western blot and RT-PCR, and micro-CT assays.

Result
Here, we found DPSCs from HPP patient exhibited low ALP activity and impaired odontoblastic differentiation. Meanwhile, we found that loss of function of ALPL reduced phosphorylation of GSK3β in DPSCs. While GSK3β rephosphorylation improved odontoblastic differentiation of HPP DPSCs with LiCl treatment. Finally, we demonstrated systemic LiCl injection ameliorated tooth-associated defects in ALPL+/− mice by enhanced phosphorylation of GSK3β in the teeth.

Conclusions
Our study indicates that ALPL regulates odontoblastic differentiation of DPSCs and provides useful information for understanding how ALPL deficiency led to tooth dysplasia and, ultimately, may inform efforts at improvement tooth defects in HPP patients.
Mesenchymal stromal/stem cells and their exosomes for restoration of spermatogenesis in non-obstructive azoospermia: a systemic review
Authors: Zhankina Rano , Baghban Neda , Askarov Manarbek , Saipiyeva Dana , Ibragimov Almaz , Kadirova Bakhyt , Khoradmehr Arezoo , Nabipour Iraj , Shirazi Reza , Zhanbyrbekuly Ulanbek , Tamadon Amin 
Published: April 2021

AbstractStem cells have been introduced as new promising therapeutic agents in treatment of degenerative diseases because of having high differentiation potential while maintaining the ability to self-replicate and retaining features of their source cells. Among different type of cell therapies, mesenchymal stromal/stem cell (MSC) therapy is being increasingly developed as a new way to treat structural defects that need to be repaired and regenerated. Non-obstructive azoospermia (NOA) is a reproductive disease in men that causes infertility in 10% of infertile men. Based on in vitro studies, MSCs from different tissue sources have been differentiated into germ cells or gamete progenitor cells by simple methods in both male and female. On the other hand, the therapeutic effects of MSCs have been evaluated for the treatment of NOA animal models created by chemical or surgical compounds. The results of these studies confirmed successful allotransplantation or xenotransplantation of MSCs in the seminiferous tubules. As well, it has been reported that exosomes secreted by MSCs are able to induce the process of spermatogenesis in the testes of infertile animal models. Despite numerous advances in the treatment of reproductive diseases in men and women with the help of MSCs or their exosomes, no clinical trial has been terminated on the treatment of NOA. This systematic review attempts to investigate the possibility of MSC therapy for NOA in men.
Synthetic speech detection through short-term and long-term prediction traces
Authors: Borrelli Clara , Bestagini Paolo , Antonacci Fabio , Sarti Augusto , Tubaro Stefano 
Published: April 2021

AbstractSeveral methods for synthetic audio speech generation have been developed in the literature through the years. With the great technological advances brought by deep learning, many novel synthetic speech techniques achieving incredible realistic results have been recently proposed. As these methods generate convincing fake human voices, they can be used in a malicious way to negatively impact on today’s society (e.g., people impersonation, fake news spreading, opinion formation). For this reason, the ability of detecting whether a speech recording is synthetic or pristine is becoming an urgent necessity. In this work, we develop a synthetic speech detector. This takes as input an audio recording, extracts a series of hand-crafted features motivated by the speech-processing literature, and classify them in either closed-set or open-set. The proposed detector is validated on a publicly available dataset consisting of 17 synthetic speech generation algorithms ranging from old fashioned vocoders to modern deep learning solutions. Results show that the proposed method outperforms recently proposed detectors in the forensics literature.
Reporting quality of clinical practice guidelines regarding gout and hyperuricemia according to the RIGHT checklist: systematic review
Authors: Wang Can , Luo Xufei , Li Maichao , Cui Lingling , Li Xinde , Han Lin , Wang Xuefeng , Ren Wei , He Yuwei , Sun Wenyan , Li Changgui , Chen Yaolong , Liu Zhen 
Published: April 2021

Abstract
Background
The Reporting Items for Practice Guidelines in Healthcare (RIGHT) checklist was used to assess the reporting quality of 2009–2019 clinical practice guidelines (CPGs) regarding gout and hyperuricemia, aimed to improve the reporting quality of future guidelines.

Methods
We searched PubMed, the Chinese Biomedical Literature database, the Wanfang Database, and the China National Knowledge Infrastructure from January 2009 to June 2019 for guidelines regarding gout and hyperuricemia. We also searched the websites of guideline development organizations (the Guidelines International Network, the National Institute for Health and Clinical Excellence, the American College of Rheumatology, and the European League Against Rheumatism (EULAR)). Furthermore, supplementary guidelines reported in included articles were systematically searched, as well as Google Scholar.

Results
Seventeen guidelines were included, of which one was in Chinese and 16 were in English. The mean reporting rate of the 35 items specified was 14.9 (42.5%); only five CPGs (29.4%) had a reporting rate >50%. Of the 35 items, three were very frequently reported. The reporting proportion of the seven domains (basic information, background, evidence, recommendations, review and quality assurance, funding and declaration and management of interests, and other information) were 64.7%, 36.8%, 50.6%, 42.9%, 8.82%, 33.8%, and 31.4%, respectively.

Conclusion
The reporting quality of the present guidelines for gout and hyperuricemia is relatively poor. We suggest that the RIGHT reporting checklist should be used by CPG developers to ensure higher reporting quality of future guidelines.
Evaluation of a multimodal intervention to promote rational antibiotic use in primary care
Authors:   RAI Study Group, Petruschke Inga , Salm Florian , Kaufmann Michelle , Freytag Antje , Gensichen Jochen , Behnke Michael , Kramer Tobias Siegfried , Hanke Regina , Gastmeier Petra , Schneider Sandra 
Published: April 2021

AbstractBackgroundIncreasing antimicrobial resistance is a serious societal challenge affecting outpatient, inpatient and veterinary care. The GermanOne-Healthproject, RAI (Rational use of Antibiotics via Information and Communication) addresses all three sectors. In the outpatient sector, General Practitioners (GPs) are the main prescribers of antibiotics and were therefore, targeted for this study. A multimodal intervention focusing on Acute Respiratory Tract infections (ARI) was designed and implemented. The aim of this study was to evaluate acceptance, rating and the self-reported impact of the intervention among GPs.MethodsThe intervention offered six tools: a GP training on rational antibiotic use, an app for self-monitoring, a leaflet and a set of posters (both for use as information materials in waiting rooms) and both digital and printed information prescriptions (material for ‘prescribing’ information instead of an antibiotic to the patient). The tools could be used according to individual preferences. The intervention was conducted between August 2016 and July 2017. Following the intervention, a three pages anonymous questionnaire was sent to all 271 participants. Items covered socio-demographic and professional background, use and judgement of the intervention tools (6 point Likert scale), impact of the intervention tools (4 point Likert scale).ResultsThe response rate was 39% (n = 107). On average, respondents used 3.1 of the six available tools, with printed information prescriptions used most frequently (79%). Digital information prescriptions were used more frequently by men than by women (OR 2.8; 95% CI 1.16–7.24;p = 0.02). Eighty-seven percent of respondents stated that information prescriptions supported doctor-patient communication. In a comparison of the overall impression of the different intervention tools the GP training on rational antibiotic use was rated best (1.67 on a 6 point scale with 1 = highest, 6 = lowest) and most often noted as having had a “strong” or “very strong” impact on personal antibiotic prescribing behavior.ConclusionsThe multimodal intervention addressing education and communication was well accepted among GPs and could help in fostering rational use of antibiotics in primary care.
Role of oregano and Citrus species-based essential oil preparation for the control of coccidiosis in broiler chickens
Authors: Gordillo Jaramillo Francisco Xavier , Kim Da-Hye , Lee Sang Hyeok , Kwon Sun-Kwan , Jha Rajesh , Lee Kyung-Woo 
Published: April 2021

Abstract
Background
Due to presence of drug-resistant Eimeria strains and raised public health safety concerns about drug residues in the meat, there is renewed interest in the search for natural alternatives to the coccidiosis control agents. This study was conducted to test the anticoccidial efficacy of oregano and Citrus spp.-based essential oils for broilers.

Methods
A total of 280 7-day-old broiler chicks were fed a control diet or diets with salinomycin or essential oils for up to 35 d of age. On d 14, half of the control groups and the treated groups were orally challenged with a coccidiosis vaccine at 25 times higher than the recommended vaccine dose. Control diet-fed chickens that were gavaged with phosphate-buffered saline were considered non-challenged control group.

Results
Eimeria challenge or dietary additives failed to affect growth performance during the 7 to 20 d growth period although essential oil-fed chickens exhibited the lowest body wight gain (P = 0.332) and the highest feed conversion ratio (P = 0.062). Oocysts in the litter were detected in the challenged control diet group and the challenged/essential oil-fed groups at 21 and 35 d, respectively. Superoxide dismutase activity in the serum was elevated (P = 0.059) in the salinomycin-fed chickens compared to the challenged controls. Alpha-1-acid glycoprotein was decreased by 28.7% in the salinomycin-fed chickens but increased by 38.1% in the essential oil group compared with the challenged control group. Challenged control group exhibited a significantly higher cooking loss of the thigh meat, compared to the non-challenged control diet group, which was marginally mitigated by dietary supplementation with essential oils. Chickens fed essential oil-added diet had the highest branched-chain fatty acids contents in the cecum.

Conclusions
In conclusion, this study shows that oregano and Citrus-based essential oil preparation did not affect growth performance in broiler chickens challenged with the coccidiosis vaccine nor did Eimeria-specific duodenal lesion. However, dietary essential oil preparation lowered oocysts present in litter materials and altered branched-chain fatty acids in cecal digesta. Beneficial findings of the essential oil preparation on volatile fatty acids and oocysts output may warrant further research into assessing its effectiveness and its efficacy in pathogenic field-isolate Eimeria spp.-induced coccidiosis disease model.
Repetitive mild traumatic brain injury in mice triggers a slowly developing cascade of long-term and persistent behavioral deficits and pathological changes
Authors: Xu Xiaoyun , Cowan Matthew , Beraldo Flavio , Schranz Amy , McCunn Patrick , Geremia Nicole , Brown Zalman , Patel Maitray , Nygard Karen L. , Khazaee Reza , Lu Lihong , Liu Xingyu , Strong Michael J. , Dekaban Gregory A. , Menon Ravi , Bartha Robert , Daley Mark , Mao Haojie , Prado Vania , Prado Marco A. M. , Saksida Lisa , Bussey Tim , Brown Arthur 
Published: April 2021

AbstractWe have previously reported long-term changes in the brains of non-concussed varsity rugby players using magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI) and functional magnetic imaging (fMRI). Others have reported cognitive deficits in contact sport athletes that have not met the diagnostic criteria for concussion. These results suggest that repetitive mild traumatic brain injuries (rmTBIs) that are not severe enough to meet the diagnostic threshold for concussion, produce long-term consequences. We sought to characterize the neuroimaging, cognitive, pathological and metabolomic changes in a mouse model of rmTBI. Using a closed-skull model of mTBI that when scaled to human leads to rotational and linear accelerations far below what has been reported for sports concussion athletes, we found that 5 daily mTBIs triggered two temporally distinct types of pathological changes. First, during the first days and weeks after injury, the rmTBI produced diffuse axonal injury, a transient inflammatory response and changes in diffusion tensor imaging (DTI) that resolved with time. Second, the rmTBI led to pathological changes that were evident months after the injury including: changes in magnetic resonance spectroscopy (MRS), altered levels of synaptic proteins, behavioural deficits in attention and spatial memory, accumulations of pathologically phosphorylated tau, altered blood metabolomic profiles and white matter ultrastructural abnormalities. These results indicate that exceedingly mild rmTBI, in mice, triggers processes with pathological consequences observable months after the initial injury.