bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita
Authors: Shukla Siddharth , Jeong Ho-Chang , Sturgeon Christopher M. , Parker Roy , Batista Luis Francisco Zirnberger 
Published: June 2020

Abstract
Dyskeratosis congenita (DC) is a pediatric bone marrow failure syndrome caused by germline mutations in telomere biology genes. Mutations in DKC1 (the most commonly mutated gene in DC), the 3′ region of TERC, and poly(A)-specific ribonuclease (PARN) cause reduced levels of the telomerase RNA component (TERC) by reducing its stability and accelerating TERC degradation. We have previously shown that depleting wild-type DKC1 levels by RNA interference or expression of the disease-associated A353V mutation in the DKC1 gene leads to decay of TERC, modulated by 3′-end oligoadenylation by noncanonical poly(A) polymerase 5 (PAPD5) followed by 3′ to 5′ degradation by EXOSC10. Furthermore, the constitutive genetic silencing of PAPD5 is sufficient to rescue TERC levels, restore telomerase function, and elongate telomeres in DKC1_A353V mutant human embryonic stem cells (hESCs). Here, we tested a novel PAPD5/7 inhibitor (RG7834), which was originally discovered in screens against hepatitis B viral loads in hepatic cells. We found that treatment with RG7834 rescues TERC levels, restores correct telomerase localization in DKC1 and PARN-depleted cells, and is sufficient to elongate telomeres in DKC1_A353V hESCs. Finally, treatment with RG7834 significantly improved definitive hematopoietic potential from DKC1_A353V hESCs, indicating that the chemical inhibition of PAPD5 is a potential therapy for patients with DC and reduced TERC levels.
The neuro-pathophysiology of temporomandibular disorders-related pain: a systematic review of structural and functional MRI studies
Authors: Yin Yuanyuan , He Shushu , Xu Jingchen , You Wanfang , Li Qian , Long Jingyi , Luo Lekai , Kemp Graham J. , Sweeney John A. , Li Fei , Chen Song , Gong Qiyong 
Published: June 2020

AbstractChronic pain surrounding the temporomandibular joints and masticatory muscles is often the primary chief complaint of patients with temporomandibular disorders (TMD) seeking treatment. Yet, the neuro-pathophysiological basis underlying it remains to be clarified. Neuroimaging techniques have provided a deeper understanding of what happens to brain structure and function in TMD patients with chronic pain. Therefore, we performed a systematic review of magnetic resonance imaging (MRI) studies investigating structural and functional brain alterations in TMD patients to further unravel the neurobiological underpinnings of TMD-related pain. Online databases (PubMed, EMBASE, and Web of Science) were searched up to August 3, 2019, as complemented by a hand search in reference lists. A total of 622 papers were initially identified after duplicates removed and 25 studies met inclusion criteria for this review. Notably, the variations of MRI techniques used and study design among included studies preclude a meta-analysis and we discussed the findings qualitatively according to the specific neural system or network the brain regions were involved in. Brain changes were found in pathways responsible for abnormal pain perception, including the classic trigemino-thalamo-cortical system and the lateral and medial pain systems. Dysfunction and maladaptive changes were also identified in the default mode network, the top-down antinociceptive periaqueductal gray-raphe magnus pathway, as well as the motor system. TMD patients displayed altered brain activations in response to both innocuous and painful stimuli compared with healthy controls. Additionally, evidence indicates that splint therapy can alleviate TMD-related symptoms by inducing functional brain changes. In summary, MRI research provides important novel insights into the altered neural manifestations underlying chronic pain in TMD.
Conjunctival structure of glaucomatous eyes treated with anti-glaucoma eye drops: a cross-sectional study using anterior segment optical coherence tomography
Authors: Gozawa Makoto , Takamura Yoshihiro , Iwasaki Kentaro , Arimura Shogo , Inatani Masaru 
Published: June 2020

Abstract
Background
To determine the effect of various factors to the preservation rate of the conjunctival layer borderlines of glaucomatous eyes treated with anti-glaucoma eye drops.

Methods
Anterior segment optical coherence tomography (AS-OCT) images of the bulbar conjunctiva of 328 eyes were analyzed with and without anti-glaucoma eye drops to quantify the preservation rates of the conjunctival layer borderlines.

Results
More anti-glaucoma eye drops and a longer duration of administration were associated with lower preservation rates of the borderlines between both the conjunctival stroma/Tenon’s capsule (P < 0.001 and P < 0.001, respectively) and Tenon’s capsule/sclera (P < 0.001 and P < 0.001, respectively). Prostaglandin analogs and fixed combinations of β-blockers/prostaglandin analogs were prognostic factors for lower preservation rates of the borderlines between both the conjunctival stroma/Tenon’s capsule (P < 0.001 and P = 0.009, respectively) and Tenon’s capsule/sclera (P < 0.001 and P = 0.008, respectively).

Conclusions
Numerous anti-glaucoma eye drops and their long-term administration are associated with the disruption of the bulbar conjunctival borderlines detected by AS-OCT.
Validity, reliability and feasibility of a new observation rating tool and a post encounter rating tool for the assessment of clinical reasoning skills of medical students during their internal medicine clerkship: a pilot study
Authors: Haring Catharina M. , Klaarwater Claudia C. R. , Bouwmans Geert A. , Cools Bernadette M. , van Gurp Petra J. M. , van der Meer Jos W. M. , Postma Cornelis T. 
Published: June 2020

Abstract
Background
Systematic assessment of clinical reasoning skills of medical students in clinical practice is very difficult. This is partly caused by the lack of understanding of the fundamental mechanisms underlying the process of clinical reasoning.

Methods
We previously developed an observation tool to assess the clinical reasoning skills of medical students during clinical practice. This observation tool consists of an 11-item observation rating form (ORT). In the present study we verified the validity, reliability and feasibility of this tool and of an already existing post-encounter rating tool (PERT) in clinical practice among medical students during the internal medicine clerkship.

Results
Six raters each assessed the same 15 student-patient encounters. The internal consistency (Cronbach’s alfa) for the (ORT) was 0.87 (0.71–0.84) and the 5-item (PERT) was 0.81 (0.71–0.87). The intraclass-correlation coefficient for single measurements was poor for both the ORT; 0.32 (p < 0.001) as well as the PERT; 0.36 (p < 0.001). The Generalizability study (G-study) and decision study (D-study) showed that 6 raters are required to achieve a G-coefficient of > 0.7 for the ORT and 7 raters for the PERT. The largest sources of variance are the interaction between raters and students. There was a consistent correlation between the ORT and PERT of 0.53 (p = 0.04).

Conclusions
The ORT and PERT are both feasible, valid and reliable instruments to assess students’ clinical reasoning skills in clinical practice.
T2 and T17 cytokines alter the cargo and function of airway epithelium-derived extracellular vesicles
Authors: Ax Elisabeth , Jevnikar Zala , Cvjetkovic Aleksander , Malmhäll Carina , Olsson Henric , Rådinger Madeleine , Lässer Cecilia 
Published: June 2020

Abstract
Background
Asthma is a common and heterogeneous disease that includes subgroups characterized by type 2 (T2) or type 17 (T17) immune responses for which there is a need to identify the underlying mechanisms and biomarkers in order to develop specific therapies. These subgroups can be defined by airway epithelium gene signatures and the airway epithelium has also been implicated to play a significant role in asthma pathology. Extracellular vesicles (EVs) carry functional biomolecules and participate in cell-to-cell communication in both health and disease, properties that are likely to be involved in airway diseases such as asthma. The aim of this study was to identify stimulus-specific proteins and functionality of bronchial epithelium-derived EVs following stimulation with T2 or T17 cytokines.

Methods
EVs from cytokine-stimulated (T2: IL-4 + IL-13 or T17: IL-17A + TNFα) human bronchial epithelial cells cultured at air-liquid interface (HBEC-ALI) were isolated by density cushion centrifugation and size exclusion chromatography and characterized with Western blotting and electron microscopy. Transcriptomic (cells) and proteomic (EVs) profiling was also performed.

Results
Our data shows that EVs are secreted and can be isolated from the apical side of HBEC-ALI and that cytokine stimulation increases EV release. Genes upregulated in cells stimulated with T2 or T17 cytokines were increased also on protein level in the EVs. Proteins found in T17-derived EVs were suggested to be involved in pathways related to neutrophil movement which was supported by assessing neutrophil chemotaxis ex vivo.

Conclusions
Together, the results suggest that epithelial EVs are involved in airway inflammation and that the EV proteome may be used for discovery of disease-specific mechanisms and signatures which may enable a precision medicine approach to the treatment of asthma.
Non-optimal effectiveness of convalescent plasma transfusion and hydroxychloroquine in treating COVID-19: a case report
Authors: Xu Tian-min , Lin Bin , Chen Cong , Liu Long-gen , Xue Yuan 
Published: June 2020

Abstract
Background
Convalescent plasma (CP) transfusion was reported to be effective in treating critically ill patients with COVID-19, and hydroxychloroquine could potently inhibit SARS-CoV-2 in vitro. Herein, we reported a case receiving combination therapy with CP transfusion and hydroxychloroquine for the first time.

Case presentation
Laboratory findings showed high lactic acid level (2.1 mmol/L) and C-reactive protein (CRP, 48.8 mg/L), and low white blood cell count (1.96 × 109/L) in a 65-year-old Chinese man, who was diagnosed with severe COVID-19. CP was intravenously given twice, and hydroxychloroquine was orally administrated for a week (0.2 g, three times a day). The lactic acid and C-reactive protein levels remained high (2.1 mmol/L and 73.23 mg/L, respectively), while the arterial oxyhemoglobin saturation decreased to 86% with a low oxygenation index (OI, 76 mmHg) on day 4 after CP transfusion. His temperature returned to normal and the OI ascended above 300 on day 11. Moreover, the RNA test remained positive in throat swab, and computed tomography revealed severe pulmonary lesions on day 11 after admission.

Conclusion
These findings suggested that the effectiveness of combination therapy with CP and hydroxychloroquine may be non-optimal, and specific therapy needs to be explored.
Audit and feedback to improve laboratory test and transfusion ordering in critical care: a systematic review
Authors: Foster Madison , Presseau Justin , McCleary Nicola , Carroll Kelly , McIntyre Lauralyn , Hutton Brian , Brehaut Jamie 
Published: June 2020

AbstractBackgroundLaboratory tests and transfusions are sometimes ordered inappropriately, particularly in the critical care setting, which sees frequent use of both. Audit and Feedback (A&F) is a potentially useful intervention for modifying healthcare provider behaviors, but its application to the complex, team-based environment of critical care is not well understood. We conducted a systematic review of the literature on A&F interventions for improving test or transfusion ordering in the critical care setting.MethodsFive databases, two registries, and the bibliographies of relevant articles were searched. We included critical care studies that assessed the use of A&F targeting healthcare provider behaviors, alone or in combination with other interventions to improve test and transfusion ordering, as compared to historical practice, no intervention, or another healthcare behaviour change intervention. Studies were included only if they reported laboratory test or transfusion orders, or the appropriateness of orders, as outcomes. There were no restrictions based on study design, date of publication, or follow-up time. Intervention characteristics and absolute differences in outcomes were summarized. The quality of individual studies was assessed using a modified version of the Effective Practice and Organisation of Care Cochrane Review Group’s criteria.ResultsWe identified 16 studies, including 13 uncontrolled before-after studies, one randomized controlled trial, one controlled before-after study, and one controlled clinical trial (quasi-experimental). These studies described 17 interventions, mostly (88%) multifaceted interventions with an A&F component. Feedback was most often provided in a written format only (41%), more than once (53%), and most often only provided data aggregated to the group-level (41%). Most studies saw a change in the hypothesized direction, but not all studies provided statistical analyses to formally test improvement. Overall study quality was low, with studies often lacking a concurrent control group.ConclusionsOur review summarizes characteristics of A&F interventions implemented in the critical care context, points to some mechanisms by which A&F might be made more effective in this setting, and provides an overview of how the appropriateness of orders was reported. Our findings suggest that A&F can be effective in the context of critical care; however, further research is required to characterize approaches that optimize the effectiveness in this setting alongside more rigorous evaluation methods.Trial registrationPROSPEROCRD42016051941.
Predictors of postoperative complication and prolonged intensive care unit stay after complete pericardiectomy in tuberculous constrictive pericarditis
Authors: Fang Likui , Yu Guocan , Huang Jinpeng , Zhao Wuchen , Ye Bo 
Published: June 2020

Abstract
Background
The risk factors of postoperative outcomes after pericardiectomy in tuberculous constrictive pericarditis have still been unclear. This study aimed to investigate the predictors of postoperative complication and prolonged intensive care unit (ICU) stay in the patients with tuberculous constrictive pericarditis undergoing pericardiectomy.

Methods
A total of 88 patients with tuberculous constrictive pericarditis undergoing pericardiectomy were retrospectively enrolled. Logistic regression and Cox regression analysis were performed to identify the predictors of postoperative complication and prolonged ICU stay, respectively.

Results
All patients underwent complete pericardiectomy and 35 (39.8%) had postoperative complication with no mortality within 30 days after surgery and no in-hospital deaths. Postoperative complication prolonged postoperative ICU stay (P < 0.001), duration of chest drainage (P < 0.001) and postoperative hospital stay (P < 0.001). Preoperative NYHA functional class (P = 0.004, OR 4.051, 95%CI 1.558–10.533) and preoperative central venous pressure (CVP) (P = 0.031, OR 1.151, 95%CI 1.013–1.309) were independent risk factors of postoperative complication. Postoperative complication (P < 0.001, HR 4.132, 95%CI 2.217–7.692) was the independent risk factor for prolonged ICU stay.

Conclusion
Complete pericardiectomy was associated with high risk of postoperative complication in tuberculous constrictive pericarditis. Poor preoperative NYHA functional class and high preoperative CVP were shown to predict postoperative complication which was the predictor of prolonged ICU stay.
Selective inhibition of neuronal Cav3.3 T-type calcium channels by TAT-based channel peptide
Authors: Cmarko Leos , Weiss Norbert 
Published: June 2020

AbstractLow-voltage-activated Cav3 calcium channels (T-type) play an essential role in the functioning of the nervous system where they support oscillatory activities that relie on several channel molecular determinants that shape their unique gating properties. In a previous study, we documented the important role of the carboxy proximal region in the functioning of Cav3.3 channels. Here, we explore the ability of a TAT-based cell penetrating peptide containing this carboxy proximal region (TAT-C3P) to modulate the activity of Cav3 channels. We show that chronic application of TAT-C3P on tsA-201 cells expressing Cav3 channels selectively inhibits Cav3.3 channels without affecting Cav3.1 and Cav3.2 channels. Therefore, the TAT-C3P peptide described in this study represents a new tool to address the specific physiological role of Cav3.3 channels, and to potentially enhance our understanding of Cav3.3 in disease.
Enhanced Integrated Gradients: improving interpretability of deep learning models using splicing codes as a case study
Authors: Jha Anupama , K. Aicher Joseph , R. Gazzara Matthew , Singh Deependra , Barash Yoseph 
Published: June 2020

AbstractDespite the success and fast adaptation of deep learning models in biomedical domains, their lack of interpretability remains an issue. Here, we introduce Enhanced Integrated Gradients (EIG), a method to identify significant features associated with a specific prediction task. Using RNA splicing prediction as well as digit classification as case studies, we demonstrate that EIG improves upon the original Integrated Gradients method and produces sets of informative features. We then apply EIG to identify A1CF as a key regulator of liver-specific alternative splicing, supporting this finding with subsequent analysis of relevant A1CF functional (RNA-seq) and binding data (PAR-CLIP).
Characterization of exosome-like vesicles derived from Taenia pisiformis cysticercus and their immunoregulatory role on macrophages
Authors: Wang Li-Qun , Liu Ting-Li , Liang Pan-Hong , Zhang Shao-Hua , Li Tao-Shan , Li Yan-Ping , Liu Guang-Xue , Mao Li , Luo Xue-Nong 
Published: June 2020

Abstract
Background
Taenia pisiformis is one of the most common intestinal parasites in canines, and leads to serious economic losses in the rabbit breeding industry. Exosome-like vesicles from parasites play crucial roles in host-parasite interactions by transferring cargo from parasites to host cells and by modulating host immunological response through inducing production of host-derived cytokines. Nevertheless, the mechanism by which exosome-like vesicles from T. pisiformis cysticercus regulate the macrophage immune response remains unknown.

Methods
Using ultracentrifugation, we isolated exosome-like vesicles from excretory/secretory products (ESP) of T. pisiformis cysticercus. The morphology and size of purified vesicles were confirmed by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). The components of proteins and miRNAs within these vesicles were identified by proteomic analysis and high-throughput small RNA sequencing. The biological function of targets of exosomal miRNAs was predicted by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Moreover, the expression of Th1- and Th2-type immune response associated cytokines in RAW264.7 macrophages were evaluated by qPCR and ELISA. We found that exosome-like vesicles were typical cup-shaped vesicles with diameters from 30 to 150 nm. A total of 87 proteins were identified by proteomic analysis, including proteins prominently associated with exosome-like vesicles biogenesis and vesicle trafficking. 41 known miRNAs and 18 novel miRNAs were identified in the exosome-like vesicles. Eleven selected miRNAs, including 7 known miRNAs (miR-71-5p, miR-10a-5p, miR-let-7-5p, miR-745-3p, miR-219-5p, miR-124-3p and miR-4989-3p) and 4 novel miRNAs (novel-mir-3, novel-mir-7, novel-mir-8 and novel-mir-11) were validated to exist in metacestiodes and exosome-like vesicles of T. pisiformis cysticercus by qPCR. The functions of most targets of exosomal miRNAs were mainly associated with signal transduction and the immune system. Additionally, T. pisiformis cysticercus-derived vesicles induced the production of IL-4, IL-6, IL-10, IL-13 and Arg-1, but downregulated the expression of IL-12, IFN-γ and iNOS in RAW264.7 macrophages.

Conclusions
We demonstrated that proteins and miRNAs enclosed within exosome-like vesicles from T. pisiformis cysticercus have immunomodulatory functions. Furthermore, exosome-like vesicles were shown to induce the macrophage Th2-type immune response in vitro. Our study suggests that exosome-like vesicles play an important role in the interaction between cysticerci and their hosts.
Diverse proteins aggregate in mild cognitive impairment and Alzheimer’s disease brain
Authors: Kepchia Devin , Huang Ling , Dargusch Richard , Rissman Robert A. , Shokhirev Maxim N. , Fischer Wolfgang , Schubert David 
Published: June 2020

Abstract
Background
All cells accumulate insoluble protein aggregates throughout their lifespan. While many studies have characterized the canonical disease-associated protein aggregates, such as those associated with amyloid plaques, additional, undefined proteins aggregate in the brain and may be directly associated with disease and lifespan.

Methods
A proteomics approach was used to identify a large subset of insoluble proteins in the mild cognitively impaired (MCI) and Alzheimer’s disease (AD) human brain. Cortical samples from control, MCI, and AD patients were separated into detergent-soluble and detergent-insoluble fractions, and high-resolution LC/MS/MS technology was used to determine which proteins became more insoluble in the disease state. Bioinformatics analyses were used to determine if the alteration of protein aggregation between AD and control patients was associated with any specific biological process. Western blots were used to validate the proteomics data and to assess the levels of secondary protein modifications in MCI and AD.

Results
There was a stage-dependent increase in detergent-insoluble proteins, with more extreme changes occurring in the AD cohort. Glycolysis was the most significantly overrepresented gene ontology biological process associated with the alteration of protein aggregation between AD and control patients. It was further shown that many low molecular weight proteins that were enriched in the AD brain were also highly aggregated, migrating on SDS-PAGE far above their predicted molecular masses. Glucose-6-phosphate isomerase, ubiquitin carboxyl-terminal hydrolase isoenzyme L1 (UCHL1/PARK5), and the DNA damage repair enzyme KU70 were among the top insoluble proteins identified by proteomics and validated by Western blot to be increased in the insoluble fractions of both MCI and AD brain samples.

Conclusions
Diverse proteins became more detergent-insoluble in the brains of both MCI and AD patients compared to age-matched controls, suggesting that multiple proteins aggregate in these diseases, likely posing a direct toxic insult to neurons. Furthermore, detergent-insoluble proteins included those with important biological activities for critical cellular processes such as energetics, proteolysis, and DNA damage repair. Thus, reduced protein solubility likely promotes aggregation and limits functionality, reducing the efficiency of multiple aspects of cell physiology. Pharmaceutical interventions that increase autophagy may provide a useful therapeutic treatment to combat protein aggregation.