Miracle-dz/UniFAR-FTUs huggingface dataset:
Polyprotein processing and intermolecular interactions within the viral replication complex spatially and temporally control norovirus protease activity

Norovirus infections are a major cause of acute viral gastroenteritis and a significant burden on global human health. A vital process for norovirus replication is the processing of the nonstructural polyprotein by a viral protease into the viral components required to form the viral replication complex. This cleavage occurs at different rates, resulting in the accumulation of stable precursor forms. Here, we characterized how precursor forms of the norovirus protease accumulate during infection. Using stable forms of the protease precursors, we demonstrated that all of them are proteolytically active in vitro, but that when expressed in cells, their activities are determined by both substrate and protease localization. Although all precursors could cleave a replication complex-associated substrate, only a subset of precursors lacking the NS4 protein were capable of efficiently cleaving a cytoplasmic substrate. By mapping the full range of protein–protein interactions among murine and human norovirus proteins with the LUMIER assay, we uncovered conserved interactions between replication complex members that modify the localization of a protease precursor subset. Finally, we demonstrate that fusion to the membrane-bound replication complex components permits efficient cleavage of a fused substrate when active polyprotein-derived protease is provided in trans. These findings offer a model for how norovirus can regulate the timing of substrate cleavage throughout the replication cycle. Because the norovirus protease represents a key target in antiviral therapies, an improved understanding of its function and regulation, as well as identification of interactions among the other nonstructural proteins, offers new avenues for antiviral drug design.
Healthcare Workers Occupationally Exposed to Ionizing Radiation Exhibit Altered Levels of Inflammatory Cytokines and Redox Parameters

Studies have shown an increased risk for a variety of cancers, specifically brain cancer, in healthcare workers occupationally exposed to ionizing radiation. Although the mechanisms mediating these phenomena are not fully understood, ionizing radiation-mediated elevated levels of reactive oxygen species (ROS), oxidative DNA damage, and immune modulation are likely involved. A group of 20 radiation exposed workers and 40 sex- and age-matched non-exposed control subjects were recruited for the study. We measured superoxide (O2•−) levels in whole blood of healthcare workers and all other measurements of cytokines, oxidative DNA damage, extracellular superoxide dismutase (EcSOD) activity and reduced/oxidized glutathione ratio (GSH/GSSG) in plasma. Levels of O2•− were significantly higher in radiation exposed workers compared to control. Similarly, a significant increase in the levels of interleukin (IL)-6, IL-1α and macrophage inflammatory protein (MIP)-1α in radiation exposed workers compared to control was observed, while there was no significance difference in the other 27 screened cytokines. A significant positive correlation was found between MIP-1α and O2•− levels with no correlation in either IL-6 or IL-1α. Further, a dose-dependent relationship with significant O2•− production and immune alterations in radiation exposed workers was demonstrated. There was no statistical difference between the groups in terms of oxidative DNA damage, GSH/GSSG levels, or EcSOD activity. Although the biologic significance of cytokines alterations in radiation exposed workers is unclear, further studies are needed for determining the underlying mechanism of their elevation.
MORPHOLOGICAL CHARACTERISTICS AND VISUAL ACUITY OF HIGHLY MYOPIC EYES WITH DIFFERENT SEVERITIES OF MYOPIC MACULOPATHY.

PURPOSE To investigate the morphological feature, visual acuity, and prevalence of macular complications in highly myopic eyes with different categories of myopic maculopathy (MM) according to the META-PM classification system. METHODS The clinical records of 1,132 consecutive patients (1,841 eyes) with high myopia (refractive error ≤ -6D and axial length ≥26.5 mm), who visited the High Myopia Clinic at the Zhongshan Ophthalmic Center from January 2014 to July 2017, were reviewed. Fundus photograph, optical coherence tomography, axial length, refractive error, and best-corrected visual acuity were measured in each patient. Myopic maculopathy was graded from fundus photographs according to the META-PM classification, including tessellated fundus (C1), diffuse chorioretinal atrophy (C2), patchy atrophy (C3), and macular atrophy (C4). Other macular complications, including foveoschisis, extrafoveal schisis, full-thickness macular hole, epiretinal membrane, lacquer cracks, Fuchs spot, choroidal neovascularization, macular hemorrhage, and dome-shaped macula, were also investigated. RESULTS Among the 1,841 eyes, 58 (3.15%) had no MM (C0), 779 (42.31%) had tessellated fundus only (C1), 524 (28.46%) had diffuse chorioretinal atrophy (C2), 352 (19.12%) had patchy chorioretinal atrophy (C3), and 128 (6.95%) had macular atrophy (C4). Age increased and best-corrected visual acuity became worse with the severity of MM (P < 0.01). Axial length was significantly longer with the severity of MM from C0 to C3 (P < 0.01), and spherical equivalent was greater with the severity of MM from C0 to C3 (P < 0.01) but was not different between C3 and C4 (P > 0.05). Subfoveal and parafoveal choroidal thicknesses were significantly thinner from C0 to C3 (P < 0.01). However, no significant difference was found between C3 and C4 in parafoveal choroidal thickness (P > 0.05). The complications were different among C0 to C4 correlated with MM (P < 0.01). The complications of foveoschisis, choroidal neovascularization, hemorrhage, lacquer cracks, Fuchs spot, dome-shaped macula, and epiretinal membrane were different between C1 and C2 (P < 0.01), but none of the complications were different between C3 and C4 (P > 0.05) except Fuchs spot (P = 0.009). CONCLUSION The morphological and functional characteristics in eyes with high myopia were positively correlated with the severity of C0 to C3 MM. However, no morphological difference was found between C3 and C4. The absence of the progressive relationship between C3 and C4 might be determined.
Examining work-to-rest ratios to optimize upper body sprint interval training

The objective was to compare the metabolic influence of varying work-to-rest ratios during upper body sprint interval training (SIT). Forty-two recreationally-trained men were randomized into a training group [10 s work - 2 min of rest (10:2) or 4 min of rest (10:4), or 30 s work - 4 min of rest (30:4)] or a control group (CON). Participants underwent six training sessions over two weeks. Assessments consisted of a graded exercise test [maximal oxygen consumption (VO2peak) and peak power output (PPO)], four constant-work rate trials [critical power, anaerobic working capacity, and electromyographic fatigue threshold], and an upper body Wingate test (mean/peak power and total work). Post-training absolute and relative VO2peak was greater than pre-training for 30:4 (p = .005 and p = .009, respectively), but lower for CON (p = .001 and p = .006, respectively). Post-training PPO was greater in 30:4 (p < .001). No differences were observed during the constant-work rate trials or Wingate test. Traditional SIT appears to have enhanced VO2peak in the upper body over a short-term two-week intervention.
Hsp90 Heterocomplexes Regulate Steroid Hormone Receptors: From Stress Response to Psychiatric Disease

The hypothalamus-pituitary-adrenal (HPA) axis directly controls the stress response. Dysregulation of this neuroendocrine system is a common feature among psychiatric disorders. Steroid hormone receptors, like glucocorticoid receptor (GR), function as transcription factors of a diverse set of genes upon activation. This activity is regulated by molecular chaperone heterocomplexes. Much is known about the structure and function of these GR/heterocomplexes. There is strong evidence suggesting altered regulation of steroid receptor hormones by chaperones, particularly the 51 kDa FK506-binding protein (FKBP51), may work with environmental factors to increase susceptibility to various psychiatric illnesses including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), and anxiety. This review highlights the regulation of steroid receptor dynamics by the 90kDa heat shock protein (Hsp90)/cochaperone heterocomplexes with an in depth look at how the structural regulation and imbalances in cochaperones can cause functional effects on GR activity. Links between the stress response and circadian systems and the development of novel chaperone-targeting therapeutics are also discussed.
Drivers of Irrational Use of Antibiotics in Europe

The unnecessary use of antibiotics and concomitant rapid growth of antibiotic resistance (ABR) is a widely acknowledged threat to global health, development, and sustainability. While the underlying cause of ABR is undoubtedly the overall volume of antibiotic use in general, irrational antibiotic use, which is influenced by several interrelated factors, is a major contributory factor. Here, we aimed to present and describe selected main drivers of irrational use of antibiotics in Europe. We performed a broad search of the current literature in databases such as PubMed, Google Scholar, Cochrane, as well as various institutional websites (World Health Organization, European Observatory, European Commission) to provide a new perspective on selected drivers of irrational antibiotic use in Europe. We also searched for relevant literature using snowballing, i.e., using reference lists of papers to identify additional papers. In this narrative review, we present that major factors among the general public driving antibiotic resistance are lack of public knowledge and awareness, access to antibiotics without prescription and leftover antibiotics, and knowledge attitude and perception of prescribers and dispensers, inadequate medical training, pharmaceutical promotion, lack of rapid and sufficient diagnostic tests, and patient–doctor interaction as major factors among healthcare providers. We further discuss initiatives that, if taken and implemented, can have an impact on and improve the current situation in Europe.
Mutagenesis of putative ciliary genes with the CRISPR/Cas9 system in zebrafish identifies genes required for retinal development

Cilia are conserved microtubule‐based organelles that function as mechanical and chemical sensors in various cell types. By bioinformatic, genomic, and proteomic studies, more than 2000 proteins have been identified as cilium‐associated proteins or putative ciliary proteins; these proteins are referred to as the ciliary proteome or the ciliome. However, little is known about the function of these numerous putative ciliary proteins in cilia. To identify the possible new functional proteins or pathways in cilia, we carried out a small‐scale genetic screen targeting 54 putative ciliary genes by using the clustered regularly interspaced short palindromic repeats/CRISPR‐associated protein 9 (CRISPR/Cas9) system. We successfully constructed 54 zebrafish mutants, and 8 of them displayed microphthalmias. Three of these 8 genes encode proteins for protein transport, suggesting the important roles of protein transport in retinal development. In situ hybridization revealed that all these genes are expressed in zebrafish eyes. Furthermore, polo‐like kinase 1 was required for ciliogenesis in neural tube. We uncovered the potential function of the ciliary genes for the retinal development of zebrafish. —Hu, R. , Huang, W. , Liu, J., Jin, M. , Wu, Y. , Li, J., Wang, J., Yu, Z. , Wang, H. , Cao, Y. Mutagenesis of putative ciliary genes with the CRISPR/Cas9 system in zebrafish identifies genes required for retinal development. FASEB J. 33, 5248–5256 (2019). www.fasebj. org
Massive Pulmonary Embolism as the Initial Presentation of Acromegaly: Is Acromegaly a Hypercoagulable Condition?

Patient: Male, 21 Final Diagnosis: Massive pulmonary embolism and acromegaly Symptoms: Chest pain and syncope Medication: Thrombolysis and Anticoagulation Clinical Procedure: Computerized tomography pulmonary angiogram and magnetic resonance imaging of pituitary Specialty: Endocrinology and Pulmonology Objective: Unusual clinical course Background: The clinical presentation in acromegaly is usually insidious, with headaches or visual disturbances being the most common symptoms. Previous studies have shown higher fibrinogen levels, lower protein C and S activity values, and enhanced platelet function in patients with acromegaly compared to a normal population. Nevertheless, the link between hypercoagulability and acromegaly is often overlooked and rarely reported in the literature. Case Report: We report a case of a young man with a massive pulmonary embolism as the initial presentation of acromegaly. Extensive workup excluded other causes of thrombophilia. Furthermore, the diagnosis of acromegaly was confirmed by the patient’s clinical features as well as laboratory and radiological testing. A literature review on the link between hypercoagulability and acromegaly was performed. Conclusions: This case report shed light on hypercoagulability as an under-recognized serious complication of acromegaly and paves the road for future studies on this topic.
Indulgent Foods Can Paradoxically Promote Disciplined Dietary Choices

As obesity rates continue to rise, interventions promoting healthful choices will become increasingly important. Here, participants (N = 79) made binary choices between familiar foods; some trials contained a common consequence that had a constant probability of receipt regardless of the participant’s choice. We theorized—on the basis of simulations using a value-normalization model—that indulgent common consequences potentiated disciplined choices by shaping other options’ perceived healthfulness and tastiness. Our experimental results confirmed these predictions: An indulgent common consequence more than doubled the rate of disciplined choices. We used eye-gaze data to provide insights into the underlying mechanisms, finding that an indulgent common consequence biased eye gaze toward healthful foods. Furthermore, attention toward the common consequence predicted individual differences in behavioral bias. Results were replicated across two independent samples receiving distinct goal primes. These results demonstrate that introducing an irrelevant indulgent food can alter processing of healthier items—and thus promote disciplined choices.
Biosynthetic Conversion of Ag+ to highly Stable Ag0 Nanoparticles by Wild Type and Cell Wall Deficient Strains of Chlamydomonas reinhardtii

In the current study, two different strains of the green, freshwater microalga Chlamydomonas reinhardtii bioreduced Ag+ to silver nanoparticles (AgNPs), which have applications in biosensors, biomaterials, and therapeutic and diagnostic tools. The bioreduction takes place in cell cultures of C. reinhardtii at ambient temperature and atmospheric pressure, thus eliminating the need for specialized equipment, harmful reducing agents or the generation of toxic byproducts. In addition to the visual changes in the cell culture, the production of AgNPs was confirmed by the characteristic surface plasmon resonance (SPR) band in the range of 415–425 nm using UV-Vis spectrophotometry and further evolution of the SPR peaks were studied by comparing the peak intensity at maximum absorbance over time. X-ray diffraction (XRD) determined that the NPs were Ag0. Micrographs from transmission electron microscopy (TEM) revealed that 97 ± 2% AgNPs were <10 nm in diameter. Ag+ to AgNP conversion was determined by inductively coupled plasma atomic emission spectroscopy (ICP-AES). The AgNPs were stable over time in the cell culture media, acetone, NaCl and reagent alcohol solutions. This was verified by a negligible change in the features of the SPR band after t > 300 days of storage at 4 °C.
Vitamin D testing and treatment: a narrative review of current evidence

Vitamin D testing and treatment is a subject of controversial scientific discussions, and it is challenging to navigate through the expanding vitamin D literature with heterogeneous and partially opposed opinions and recommendations. In this narrative review, we aim to provide an update on vitamin D guidelines and the current evidence on the role of vitamin D for human health with its subsequent implications for patient care and public health issues. Vitamin D is critical for bone and mineral metabolism, and it is established that vitamin D deficiency can cause rickets and osteomalacia. While many guidelines recommend target serum 25-hydroxyvitamin D (25[OH]D) concentrations of ≥50 nmol/L (20 ng/mL), the minimum consensus in the scientific community is that serum 25(OH)D concentrations below 25–30 nmol/L (10–12 ng/mL) must be prevented and treated. Using this latter threshold of serum 25(OH)D concentrations, it has been documented that there is a high worldwide prevalence of vitamin D deficiency that may require public health actions such as vitamin D food fortification. On the other hand, there is also reason for concern that an exploding rate of vitamin D testing and supplementation increases costs and might potentially be harmful. In the scientific debate on vitamin D, we should consider that nutrient trials differ from drug trials and that apart from the opposed positions regarding indications for vitamin D treatment we still have to better characterize the precise role of vitamin D for human health.
Reply to: Generalized Periodic Discharges With and Without Triphasic Morophology.

1. Hirsch LJ, LaRoche SM, Gaspard N, et al. American clinical Neurophysiology society’s standardized critical care EEG terminology: 2012 version. J Clin Neurophysiol 2013;30:1e27. 2. Rodriguez Ruiz A, Vlachy J, Lee J, et al. Association of periodic and rhythmic electroencephalographic patterns with seizures in critically ill patients. JAMA Neurol 2017;74:181e188. 3. Foreman B, Mahulikar A, Tadi P, et al. Generalized periodic discharges and “triphasic waves”: a blinded evaluation of inter-rater agreement and clinical significance. Clin Neurophysiol 2016;127: 1073e1080. 4. Claassen J, Mayer SA, Kowalski RG, et al. Detection of electrographic seizures with continuous EEG monitoring in critically ill patients. Neurology 2004;62:1743e1748. 5. Leitinger M, Trinka E, Gardella E, et al. Diagnostic accuracy of the Salzburg EEG criteria for nonconvulsive status epilepticus: a retrospective study. Lancet Neurol 2016;15:1054e1062.
Differences in Kidney Function Estimates Based on Creatinine and/or Cystatin C in Non-Traumatic Amputation Patients and Their Impact on Drug Prescribing

Accurate kidney function estimates are necessary when prescribing renally-eliminated medications. Our objectives were to investigate how amputation affects estimated glomerular filtration rate (eGFR) and to determine if dosing recommendations differ among different eGFR equations. In a cohort study of non-traumatic amputation patients, eGFR based on creatinine and/or cystatin C were measured before and after amputation. Prescribed, renally-eliminated medications were compared with dosing guidelines in Renbase®. Data from 38 patients with a median age of 75 years were analyzed. The median (range) eGFR was 65 (15–103), 38 (13–79), and 48 (13–86) mL/min/1.73 m2 before amputation and 80 (22–107), 51 (13–95), and 62 (16–100) mL/min/1.73 m2 after amputation for eGFRCreatinine, eGFRCystatinC, and eGFRCombined, respectively (p < 0.01). From before to after amputation, eGFR increased on average by 8.5, 6.1, and 7.4 mL/min/1.73 m2 for eGFRCreatinine, eGFRCystatinC, and eGFRCombined (all p < 0.01), respectively. At least one renally-eliminated medication was prescribed at a higher dose than recommended in 37.8% of patients using eGFRCystatinC, 17.6% using eGFRCombined and 10.8% using eGFRCreatinine. In conclusion, amputation affects eGFR regardless of the eGFR equations. The differences among equations would impact prescribing of renally-eliminated medications, particularly when switching from creatinine to cystatin C.
Therapeutic options for adult patients with previously treated immune thrombocytopenia – a systematic review and network meta-analysis

ABSTRACT Objectives: The great majority of adult patients with immune thrombocytopenia (ITP) who fail to respond to first-line medication or who relapse following response require additional treatment. Although broad guidelines currently exist for second-line and subsequent therapies, none to date have been prescriptive. The purpose of this systematic review and network meta-analysis was to establish a clinically relevant ranking of the efficacy and safety of medications for adults (≥18 years old) with previously treated ITP. Methods: Relevant publications from Medline, Embase, and the Cochrane database were searched from their inceptions through July 31, 2018. The primary outcome was the overall response (OR, defined as a platelet count ≥50 × 109/L at the end of treatment without rescue therapy), while the secondary endpoints included early response (ER; i.e. a platelet count ≥50 × 109/L at week 2 after initiation of treatment) and therapy-related severe adverse events (AEs). Results: Thirteen randomized controlled trials (1,202 patients) were included in this study. According to pooled results, romiplostim appears to be the most suitable treatment in terms of OR, followed by avatrombopag, eltrombopag, fostamatinib, and rituximab. Avatrombopag produced more satisfactory outcomes than romiplostim, eltrombopag, and rituximab in terms of ER; severe AEs profiles were similar across all treatment arms. Conclusion: Romiplostim appears to be the best option for patients who fail to respond to prior treatment or relapse thereafter, while avatrombopag and eltrombopag are reasonable alternatives. Rituximab monotherapy is not recommended, as it produces the lowest OR and ER rates.
Acute Exacerbation of Idiopathic Interstitial Pneumonia in a Patient with Hepatocellular Carcinoma after Transcatheter Arterial Therapy Using Miriplatin

A 76-year-old Japanese woman with recurrent hepatocellular carcinoma presented with acute exacerbation of idiopathic interstitial pneumonia (AE-IIP) after transcatheter arterial therapy using miriplatin. She had a history of preexisting IIP five years before presenting at our hospital. On day 4 after transcatheter arterial therapy, she complained of shortness of breath. Subsequently, she developed acute respiratory failure on day 11 after transcatheter arterial therapy. Chest computed tomography revealed extensive ground-glass opacity and traction bronchiectasis in bilateral lung fields; subsequently, she was diagnosed with AE-IIP triggered by transcatheter arterial therapy using miriplatin. Despite systemic administration of high-dose corticosteroid and cyclophosphamide, she died of respiratory failure on day 36.