Miracle-dz/UniFAR-FTUs huggingface dataset:
De-ubiquitination of ELK-1 by USP17 potentiates mitogenic gene expression and cell proliferation

Abstract ELK-1 is a transcription factor involved in ERK-induced cellular proliferation. Here, we show that its transcriptional activity is modulated by ubiquitination at lysine 35 (K35). The level of ubiquitinated ELK-1 rises in mitogen-deprived cells and falls upon mitogen stimulation or oncogene expression. Ectopic expression of USP17, a cell cycle-dependent deubiquitinase, decreases ELK-1 ubiquitination and up-regulates ELK-1 target-genes with a concomitant increase in cyclin D1 expression. In contrast, USP17 depletion attenuates ELK-1-dependent gene expression and slows cell proliferation. The reduced rate of proliferation upon USP17 depletion appears to be a direct effect of ELK-1 ubiquitination because it is rescued by an ELK-1(K35R) mutant refractory to ubiquitination. Overall, our results show that ubiquitination of ELK-1 at K35, and its reversal by USP17, are important mechanisms in the regulation of nuclear ERK signalling and cellular proliferation. Our findings will be relevant for tumours that exhibit elevated USP17 expression and suggest a new target for intervention.
AJICAP: Affinity Peptide Mediated Regiodivergent Functionalization of Native Antibodies.

The need for atom-precise biomolecule modification, and particularly the irreversible formation of covalent bonds to specific amino acids in proteins, has become an essential issue in the fields of pharmaceuticals and chemical biology. For example, antibody-drug conjugates (ADCs) are increasingly common entries into the clinical oncology pipeline. Herein, we report a new method of affinity peptide mediated regiodivergent functionalization (AJICAP™) that enables the synthesis of ADCs from native IgG antibodies. We succeeded in introducing thiol functional groups onto three lysine residues in IgGs using Fc affinity peptide reagents without antibody engineering. A cytotoxic molecule was then connected to the newly introduced thiol group, and both a surface plasmon resonance binding assay and in vivo xenograft mouse model results showed that the resulting ADC could selectively target and kill HER2-positive cells. Our strategy provides a new approach for constructing complex antibody-derived biomolecules.
Cost-effectiveness of ambulatory oxygen in improving quality of life in fibrotic lung disease: preliminary evidence from the AmbOx Trial

Fibrotic interstitial lung diseases (ILDs) are chronic and often progressive conditions resulting in substantial impact on morbidity, health-related quality of life (HRQoL), and health system costs. Ambulatory oxygen (AO) used during routine daily activities could lead to improved exercise performance, reduced symptoms and improved mobility in daily life. A UK prospective, multicentre, mixed method, randomised controlled crossover trial in patients with fibrotic ILD (AmbOx trial: NCT02286063), the first study on AO effects in daily life, reported improved HRQoL after 2 weeks of AO compared to no intervention, when measured by the King's Brief ILD (K-BILD) questionnaire [1–3]. Although AO is used in ILD, evidence supporting its health-economic impact is absent. Here, we evaluate the cost-effectiveness of AO in patients with ILD, using data collected alongside the AmbOx Trial. Ambulatory oxygen may be cost-effective in improving quality of life in fibrotic lung disease. To be more conclusive, we need to understand societal willingness to pay for quality of life improvements and whether improvements are sustained. http://bit.ly/2pAiBJi
Reply to letter: Does Parkinson’s disease increase the risk of cardiovascular events? A systematic review and meta‐analysis

We recognize that we were very conservative concerning the implications of our results for clinical practice. Following their comment and in order to better appraise the robustness of our results we applied the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) criteria adapted for prognostic studies.2,3 The GRADE approach was independently assessed by two investigators (MA and DC).
Importin-9 wraps around the H2A-H2B core to act as nuclear importer and histone chaperone

We report the crystal structure of nuclear import receptor Importin-9 bound to its cargo, the histones H2A-H2B. Importin-9 wraps around the core, globular region of H2A-H2B to form an extensive interface. The nature of this interface coupled with quantitative analysis of deletion mutants of H2A-H2B suggests that the NLS-like sequences in the H2A-H2B tails play a minor role in import. Importin-9•H2A-H2B is reminiscent of interactions between histones and histone chaperones in that it precludes H2A-H2B interactions with DNA and H3-H4 as seen in the nucleosome. Like many histone chaperones, which prevent inappropriate non-nucleosomal interactions, Importin-9 also sequesters H2A-H2B from DNA. Importin-9 appears to act as a storage chaperone for H2A-H2B while escorting it to the nucleus. Surprisingly, RanGTP does not dissociate Importin-9•H2A-H2B but assembles into a RanGTP•Importin-9•H2A-H2B complex. The presence of Ran in the complex, however, modulates Imp9-H2A-H2B interactions to facilitate its dissociation by DNA and assembly into a nucleosome.
Haploinsufficiency of the brain-derived neurotrophic factor gene is associated with reduced pain sensitivity

Abstract Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of A&dgr;- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity.
Association of Overt and Subclinical Hyperthyroidism During Weeks 4-8 with Adverse Pregnancy Outcomes.

Background: Although increasing data suggest that hyperthyroidism is associated with adverse pregnancy outcomes, there are only a few reports with different conclusions on whether the mild transient reduction in thyrotropin (TSH) with or without free thyroxine (FT4) elevation during the early stage of pregnancy also causes adverse pregnancy outcomes. Subjects and Methods: We analyzed data from 3,783 women in this study from August 2011 to December 2013. Participants completed a questionnaire survey. Samples of blood were obtained in the 4th-8th week of pregnancy and their TSH, FT4, thyroid peroxidase antibody, and thyroglobulin antibody were measured. We divided the participants into overt hyperthyroidism group (OHG), subclinical hyperthyroidism group (SHG), and control group based on their blood results and followed up on their pregnancy outcomes. Results: (1) The serum level of FT4 in the SHG was much higher than the control group (p < 0.05). No difference was found in the TSH between the OHG and SHG. The positive rate of autoimmune thyroid antibodies in the OHG (25.6%) was significantly higher than that in the SHG (14.2%) and control group (13.9%) (p < 0.05), whereas there was no difference between the SHG and control group. (2) The SHG had a lower incidence of miscarriage (1.7% vs. 7.2%; OR = 0.218, p = 0.016) than the control group, and the OHG had a higher incidence of placenta previa (3.3% vs. 0.8%; OR = 4.366, p = 0.039) than the control group. (3). We used a binary logistic regression to take other factors into consideration and found that subclinical hyperthyroidism was associated with a lower risk of abortion (OR = 0.206; 95% CI = 0.050-0.840; p = 0.028) but higher risk of preeclampsia (OR = 5.143; 95% CI = 1.463-18.076; p = 0.011) and placental abruption (OR = 4.676; 95% CI = 1.017-21.509; p = 0.048), and overt hyperthyroidism may increase the incidence of placenta previa (OR = 4.193; 95% CI = 1.222-14.382; p = 0.023). Conclusions: Subclinical hyperthyroidism during weeks 4-8 of pregnancy may be associated with the decreased incidence of abortion but might be a risk factor for preeclampsia and placental abruption. Meanwhile, pregnancy with overt hyperthyroidism may be an independent risk factor for placenta previa.
Alanine Aminotransferase Results Differ by Analyzer Manufacturer in a National Integrated Health Setting, 2012-2017.

CONTEXT. — Disease guidelines specify universal alanine aminotransferase (ALT) thresholds for clinical decision-making, yet the effect of variability among ALT analyzers remains unclear. OBJECTIVE. — To compare ALT results from different analyzers from 2012-2017. DESIGN. — Veterans Health Administration (VHA) laboratories perform external ALT proficiency testing using standardized College of American Pathologists (CAP) samples in analyzers by 5 manufacturers. In this operational analysis, we evaluated 22 950 ALT values from 80 independent CAP samples tested at 223 laboratories. Using mixed effects modeling, we estimated the association between analyzer manufacturer and CAP outcome, adjusting for manufacturer, facility, and calendar year. We performed subgroup analyses on CAP samples with overall means near clinical guideline-specified thresholds, including less than 50 U/L (n = 10) and less than 35 U/L (n = 5). RESULTS. — The VHA used Abbott Laboratories (n = 3175; 14%), Beckman Coulter Diagnostics (n = 8723; 38%), Roche Diagnostics (n = 2595; 11%), Siemens Healthineers USA (n = 5713; 25%), and Vitros/Ortho Clinical Diagnostics (n = 2744; 12%) analyzers. The CAP samples (n = 80 samples, n = 22 950 tests) covered a wide range of mean ALT values (21-268 U/L). The average difference in mean ALT value per sample between the highest-reading and lowest-reading manufacturers was 15.4 U/L (SD = 1.8) for the 10 samples with mean ALT less than 50 U/L, and it was 10.4 U/L (SD = 3.6) overall (n = 80). In linear mixed effects modeling, we found statistically significant differences in ALT values between the different manufacturers in each year. CONCLUSIONS. — We found statistically and clinically meaningful differences between analyzers across the ALT spectrum in each year, including at ALT levels lower than 50 U/L and lower than 35 U/L. Universal ALT thresholds should be avoided as a trigger for clinical action until differences between analyzers can be resolved.
Assessing the Impact of Animal Husbandry and Capture on Anemia among Women and Children in Low- and Middle-Income Countries: A Systematic Review

ABSTRACT Animal husbandry and capture (AHC) may mitigate anemia among women and children by supplying a source of micronutrient-rich animal source foods (ASF), yet may concurrently increase exposure to anemia-inducing pathogens such as Plasmodium spp. , helminths, and enteropathogens. We conducted a systematic literature review to assess the relation between AHC and anemia among women of reproductive age, school-aged children, and children aged <5 y in low- and middle-income countries (LMICs). We used a 2-stage screening process, in which 1 reviewer searched 4 databases (PubMed, Web of Science, EMBASE, and Global Health) with predetermined search terms for relevant articles. Two reviewers then independently screened studies using a priori exclusion criteria, yielding a total of 23 articles included in the final review. We evaluated evidence from observational studies assessing animal-dependent livelihoods and livestock ownership, and interventions that promoted livestock and fish production. We found little consistency in anemia outcomes across the several AHC exposures and population groups. Poultry production interventions had modest benefits on anemia among women and children, although whether these improvements were a result of increased ASF consumption, or a result of the combined treatment study design could not be determined. Observational studies identified chicken ownership, and no other livestock species, as a risk factor for anemia among young children. However, there was limited evidence to evaluate pathways underlying these associations. Studies tended to rely on self-reported fever and diarrhea to assess illness, and no study directly assessed linkages between AHC, pathogen burden, and anemia. Thus, there is insufficient evidence to conclude whether AHC improves or worsens anemia among women and children in LMICs. Given the current interest in promoting animal production among low-income households, future studies with robust measures of livestock ownership, ASF consumption, pathogen burden, and anemia status are needed to understand the nuances of this complex and potentially contradictory relation.
Executive Summary

Following the September 11, 2001, attacks on New York City’s World Trade Center (WTC), the Federal Emergency Management Agency (FEMA) and the Structural Engineering Institute of the American Society of Civil Engineers (SEI/ASCE), in association with New York City and several other Federal agencies and professional organizations, deployed a team of civil, structural, and fire protection engineers to study the performance of buildings at the WTC site.
Effectiveness of telerehabilitation in the management of adults with stroke: A systematic review

Background Stroke is a leading cause of mortality and morbidity and access to timely rehabilitation can reduce morbidity and help patients to return to normal life. Telerehabilitation can deliver rehabilitation services with the use of technology to increase patient options, deliver services more efficiently and overcome geographical barriers to healthcare access. Despite its popularity, there is conflicting evidence for its effectiveness. Therefore, the aim of this systematic review was to update the current evidence base on the effectiveness of telerehabilitation for stroke. Methods A systematic search of databases (Medline Ovid; Embase; Emcare; Scopus; The Cochrane Library; PEDro; OTSeeker) was conducted in April 2018 (updated in October 2018). This review was conducted and reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and methodology registered with PROSPERO (CRD42018090445). A modified McMaster critical appraisal tool for quantitative studies was used to assess the methodological quality of the included studies. Given the heterogeneity of the included studies, a descriptive synthesis was conducted. Results Out of 1868 studies, 13 randomised controlled trials met the inclusion criteria. A diverse range of interventions were delivered through a variety of telerehabilitation systems and the effectiveness measured through a myriad of outcome measures. Summarised findings from the heterogeneous evidence base indicate that telerehabilitation may have a positive impact on a range of primary and secondary outcomes. However, despite these positive findings, the current evidence lacks clarity and uniformity in terms of intervention parameters and measurement of outcomes, which limits broader application of these results. Discussion Telerehabilitation, as an alternate form of rehabilitation for people with stroke, shows potential. However, due to methodological and practical concerns, an unequivocal recommendation cannot be made. Findings from this review may inform future policies and practices regarding the use of telerehabilitation for stroke patients.
Progestins for the Treatment of Endometriosis: An Update

Endometriosis is a gynecological condition that affects approximately 10% of women of reproductive age, including 25-40% of infertile women. Dysmenorrhea, dyspareunia and chronic pelvic pain are the most common symptoms. Currently available medical therapies for endometriosis do not cure the disease, but are directed at symptom relief, typically utilizing the hormone responsiveness of endometriotic tissue to induce lesion atrophy. Unfortunately, pain relapse after treatment suspension is a common event. Treatment with pharmacological therapies for endometriosis should be conceived in terms of years, thus agents that must be withdrawn after a few months due to poor tolerability or severe metabolic side effects do not greatly benefit women with symptomatic endometriosis. The characteristics of progestins render this class an ideal pharmacological choice for administration over extended periods. The present paper will review the rationale for using progestins and their mechanism of action in endometriosis. Thereafter, the results obtained by various progestins in the treatment of endometriosis will be evaluated (danazol, gestrinone, norethisterone acetate, desogestrel, cyproterone acetate, megestrol acetate, medroxyprogesterone acetate, and levonorgestrel). A progestin called dienogest, recently introduced for the treatment of endometriosis, will be given special focus, describing its mechanism of action and clinical results.
Does the presence of maxillary central incisor edge asymmetry influence the perception of dentofacial esthetics in video analysis?

OBJECTIVE: To investigate the influence of incisal edge asymmetry of the maxillary central incisors on dentofacial esthetics among orthodontists, prosthodontists, and laypersons using video analysis. MATERIALS AND METHODS: Full-face films of a 52-year-old afro-descendant woman displaying various levels of incisal wear in the esthetic zone were captured. An acrylic resin mockup was made of the maxillary anterior region, enabling the reproduction of an attractive smile and restoring tooth wear. Four different levels of incisal asymmetry between the upper central incisors in 0.5 mm increments were prepared from this mockup. A film was made for each level of asymmetry (0.5, 1.0, 1.5, and 2.0) and one with no asymmetry, with the patient repeating a sentence, totaling five films. After a pilot study and sample calculation, the films were evaluated by 138 examiners: 46 orthodontists, 46 laypeople, and 46 prosthodontists. Each examiner evaluated the dentofacial esthetics of each film using visual analog scales. Data collected were statistically analyzed. RESULTS: Highest scores were awarded to the film with no asymmetry between upper centrals and the one with 0.5 mm of asymmetry. The asymmetries of 1.5 mm and 2.0 mm had the lowest scores from all three groups. CONCLUSIONS: The results of this video analysis indicate that asymmetries equal to or greater than 1.0 mm between the upper central incisors edges jeopardize dentofacial esthetics.
N-glycomic Complexity in Anatomical Simplicity: Caenorhabditis elegans as a Non-model Nematode?

Caenorhabditis elegans is a genetically well-studied model nematode or “worm”; however, its N-glycomic complexity is actually baffling and still not completely unraveled. Some features of its N-glycans are, to date, unique and include bisecting galactose and up to five fucose residues associated with the asparagine-linked Man2−3GlcNAc2 core; the substitutions include galactosylation of fucose, fucosylation of galactose and methylation of mannose or fucose residues as well as phosphorylcholine on antennal (non-reducing) N-acetylglucosamine. Only some of these modifications are shared with various other nematodes, while others have yet to be detected in any other species. Thus, C. elegans can be used as a model for some aspects of N-glycan function, but its glycome is far from identical to those of other organisms and is actually far from simple. Possibly the challenges of its native environment, which differ from those of parasitic or necromenic species, led to an anatomically simple worm possessing a complex glycome.
A randomized study on the effect of sequential acupoint stimulation on pulmonary function of patients with spontaneous pneumothorax during VATS perioperative period

Abstract This study aims to explore the effect of sequential acupoint stimulation on the postoperative pulmonary function of patients with spontaneous pneumothorax who underwent video-assisted thoracoscopic surgery (VATS). Using a random number table, the patients were randomly divided into 2 groups: routine nursing group and sequential acupoint stimulation group. Patients in the routine nursing group received standard nursing care of thoracic surgery, while patients in the acupoint group received sequential acupoint stimulation on Shenshu (BL23), Gaohuang (BL43), Feishu (BL13), and Tiantu (CV22). Then, the maximal ventilatory volume (MVV), oxygen saturation (SpO2), postoperative drainage volume, postoperative drainage time, postoperative hospitalization days, and procalcitonin (PCT) were observed on the first, third, fifth and 30th day after VATS operation. On the fifth day after spontaneous pneumothorax was treated with VATS, MVV, and SpO2 of the sequential acupoint stimulation group were significantly higher than those of the routine nursing group (P < .05). On both the third day and fifth day after VATS, PCT of the sequential acupoint stimulation group was significantly lower than that of the routine nursing group (P < .01). Furthermore, the difference in postoperative drainage volume between the 2 groups was not statistically significant (P > .05), while chest tube drainage time (P < .01) and postoperative hospitalization days (P < .05) of the sequential acupoint stimulation group were significantly lower than those of the routine nursing group. In spontaneous pneumothorax patients who underwent VATS, sequential acupoint stimulation nursing was significantly more effective than routine postoperative nursing in promoting postoperative recovery of lung function, alleviating inflammatory response and shortening hospitalization days.