Miracle-dz/UniFAR-FTUs huggingface dataset:
Stable calcium-free myocilin olfactomedin domain variants reveal challenges in differentiating between benign and glaucoma-causing mutations

Nonsynonymous gene mutations can be beneficial, neutral, or detrimental to the stability, structure, and biological function of the encoded protein, but the effects of these mutations are often not readily predictable. For example, the β-propeller olfactomedin domain of myocilin (mOLF) exhibits a complex interrelationship among structure(s), stability, and aggregation. Numerous mutations within mOLF are linked to glaucoma; the resulting variants are less stable, aggregation-prone, and sequestered intracellularly, causing cytotoxicity. Here, we report the first stable mOLF variants carrying substitutions in the calcium-binding site that exhibit solution characteristics indistinguishable from those of glaucoma variants. Crystal structures of these stable variants at 1.8–2.0-Å resolution revealed features that we could not predict by molecular dynamics simulations, including loss of loop structure, helix unwinding, and a blade shift. Double mutants that combined a stabilizing substitution and a selected glaucoma-causing single-point mutant rescued in vitro folding and stability defects. In the context of full-length myocilin, secretion of stable single variants was indistinguishable from that of the WT protein, and the double mutants were secreted to varying extents. In summary, our finding that mOLF can tolerate particular substitutions that render the protein stable despite a conformational switch emphasizes the complexities in differentiating between benign and glaucoma-causing variants and provides new insight into the possible biological function of myocilin.
Role of diet in type 2 diabetes incidence: umbrella review of meta-analyses of prospective observational studies

Abstract Objective To summarise the evidence of associations between dietary factors and incidence of type 2 diabetes and to evaluate the strength and validity of these associations. Design Umbrella review of systematic reviews with meta-analyses of prospective observational studies. Data sources PubMed, Web of Science, and Embase, searched up to August 2018. Eligibility criteria Systematic reviews with meta-analyses reporting summary risk estimates for the associations between incidence of type 2 diabetes and dietary behaviours or diet quality indices, food groups, foods, beverages, alcoholic beverages, macronutrients, and micronutrients. Results 53 publications were included, with 153 adjusted summary hazard ratios on dietary behaviours or diet quality indices (n=12), food groups and foods (n=56), beverages (n=10), alcoholic beverages (n=12), macronutrients (n=32), and micronutrients (n=31), regarding incidence of type 2 diabetes. Methodological quality was high for 75% (n=115) of meta-analyses, moderate for 23% (n=35), and low for 2% (n=3). Quality of evidence was rated high for an inverse association for type 2 diabetes incidence with increased intake of whole grains (for an increment of 30 g/day, adjusted summary hazard ratio 0.87 (95% confidence interval 0.82 to 0.93)) and cereal fibre (for an increment of 10 g/day, 0.75 (0.65 to 0.86)), as well as for moderate intake of total alcohol (for an intake of 12-24 g/day v no consumption, 0.75 (0.67 to 0.83)). Quality of evidence was also high for the association for increased incidence of type 2 diabetes with higher intake of red meat (for an increment of 100 g/day, 1.17 (1.08 to 1.26)), processed meat (for an increment of 50 g/day, 1.37 (1.22 to 1.54)), bacon (per two slices/day, 2.07 (1.40 to 3.05)), and sugar sweetened beverages (for an increase of one serving/day, 1.26 (1.11 to 1.43)). Conclusions Overall, the association between dietary factors and type 2 diabetes has been extensively studied, but few of the associations were graded as high quality of evidence. Further factors are likely to be important in type 2 diabetes prevention; thus, more well conducted research, with more detailed assessment of diet, is needed. Systematic review registration PROSPERO CRD42018088106.
The influence of temperature and pH on bacterial community composition of microbial mats in hot springs from Costa Rica

We used the 16S rRNA gene pyrosequencing approach to investigate the microbial diversity and community composition in several Costa Rican hot springs alongside the latitudinal axis of the country, with a range of temperatures (37–63°C), pH (6–7.5) and other geochemical conditions. A principal component analyses of the physicochemical parameters showed the samples were separated into three geochemically distinct habitats associated with the location (North, Central, and South). Cyanobacteria and Chloroflexi comprised 93% of the classified community, the former being the most abundant phylum in all samples except for Rocas Calientes 1, (63°C, pH 6), where Chloroflexi and Deinococcus‐Thermus represented 84% of the OTUs. Chloroflexi were more abundant as temperature increased. Proteobacteria, Bacteriodetes and Deinococcus‐Thermus comprised 5% of the OTUs represented. Other Phyla were present in very small percentages (<1%). A LINKTREE analysis showed that the community structure of the mats was shaped primarily by pH, separating samples with pH > 6.6 from samples with pH < 6.4. Thus, both pH and temperature were relevant for community composition even within the moderate ranges of variables studied. These results provide a basis for an understanding of the physicochemical influences in moderately thermophilic microbial mats.
Acute neurocognitive deficits in active duty service members following subconcussive blast exposure

Abstract Military service members are frequently subjected to subconcussive blast events during training and deployment. Emerging evidence suggests blast exposures of these magnitudes may have long-term consequences for dimensions of cognitive function. Less is known about cognitive sequelae acutely following deployment-related subconcussive blast events. The current study addressed this knowledge gap by assessing the extent to which subconcussive blast exposure affected performance on the Automated Neuropsychological Assessment Metrics 4 TBI-MIL (ANAM). Baseline-referenced and normative comparisons of archival ANAM data were analyzed for a cohort of personnel who were exposed to blast (blast group; n = 27) and personnel who were not exposed to blast (no-blast group; n = 36) that were otherwise asymptomatic for a concussion. The blast group exhibited statistically significant lower scores compared to the no-blast group (between-subjects), baseline assessments (within-subjects), and an age-matched normative population. Normative comparisons revealed that the scores for the reaction time subtests (i.e., procedural and both simple reaction time tasks) were outside the range of normal functioning (1 SD) and reliable change indices revealed clinically meaningful change only for simple reaction time. The results highlight covert effects of subconcussive blast exposure that may warrant further monitoring in the immediate aftermath of a blast event.
An improved method for circular RNA purification using RNase R that efficiently removes linear RNAs containing G-quadruplexes or structured 3′ ends

Abstract Thousands of eukaryotic protein-coding genes generate circular RNAs that have covalently linked ends and are resistant to degradation by exonucleases. To prove their circularity as well as biochemically enrich these transcripts, it has become standard in the field to use the 3′-5′ exonuclease RNase R. Here, we demonstrate that standard protocols involving RNase R can fail to digest >20% of all highly expressed linear RNAs, but these shortcomings can largely be overcome. RNAs with highly structured 3′ ends, including snRNAs and histone mRNAs, are naturally resistant to RNase R, but can be efficiently degraded once a poly(A) tail has been added to their ends. In addition, RNase R stalls in the body of many polyadenylated mRNAs, especially at G-rich sequences that have been previously annotated as G-quadruplex (G4) structures. Upon replacing K+ (which stabilizes G4s) with Li+ in the reaction buffer, we find that RNase R is now able to proceed through these sequences and fully degrade the mRNAs in their entirety. In total, our results provide important improvements to the current methods used to isolate circular RNAs as well as a way to reveal RNA structures that may naturally inhibit degradation by cellular exonucleases.
The relationship between B7 homologous 1 with interleukin-4, interleukin-17 and interferon gamma in patients with allergic rhinitis

ABSTRACT Background: The etiology of allergic rhinitis includes an increase in cytokine levels, including IL- 4, IL-13, IL-17, and reduction in B7 homologous 1 (B7-H1) or programmed cell death-1 ligand-1 (PD-L1), a new member of the CD28: B7 stimulant molecule family. The aim of this study was to determine the relationship between cytokines and PD-L1. Methods: In this experimental study, 80 patients with allergic rhinitis were enrolled according to inclusion and exclusion criteria. The severity and stage of the disease were determined by a specialist physician. A 5 cc venous blood sample was collected from the patients. IL-4, IL-17, INFγ and PD-L1 were measured using ELISA technique. Results: There was a significant correlation between SPD-L1 and INFγ, IL-4 and IL-17 in allergic rhinitis patients (P < 0.05). Statistical analysis based on the severity of the disease (Mild, Moderate and Severe) showed a significant positive correlation between the SPD-L1 and INFγ in all three levels (P < 0.001). There was also a significant negative correlation between SPD-L1 and two cytokines IL-4 and IL-17 (P < 0.001). Conclusion: PD-L1 may have a protective role against allergic rhinitis, although the precise mechanism requires further detailed studies.
Achieving Infrared Detection by All-Si Plasmonic Hot-Electron Detectors with High Detectivity.

An improved architecture for all-Si based photoelectronic detectors has been developed, consisting of a specially designed metasurface as antennas integrated into a Si nanowire array on insulator by an electron beam lithography based self-alignment process. Simulation using Finite Difference Time Domain (FDTD) method was carried out to ensure perfect absorption of light by the detector. Optic measurement shows a 90% absorption at 1.05 µm. Photo-electronic characterization demonstrates the responsivity and detectivity as high as 94.5 mA/W and 4.38×10^11 cm Hz^(1/2) /W, respectively, at 1.15 µm with the bandwidth of 480 nm, which is comparable to that of III-V/II-VI compound detectors. It is understood that the outstanding performances over other reported all-Si based detectors originate from the enhanced quantum efficiency in one-dimensional conduction channels with high density of states which efficiently accommodate the emitted plasmonic hot electrons for high conduction in the Si nanowires, enabling the near infrared detection by all-Si based detectors.
PUEGM: A Method of User Revenue Selection Based on a Publisher-User Evolutionary Game Model for Mobile Crowdsensing

Mobile crowdsensing (MCS) is a way to use social resources to solve high-precision environmental awareness problems in real time. Publishers hope to collect as much sensed data as possible at a relatively low cost, while users want to earn more revenue at a low cost. Low-quality data will reduce the efficiency of MCS and lead to a loss of revenue. However, existing work lacks research on the selection of user revenue under the premise of ensuring data quality. In this paper, we propose a Publisher-User Evolutionary Game Model (PUEGM) and a revenue selection method to solve the evolutionary stable equilibrium problem based on non-cooperative evolutionary game theory. Firstly, the choice of user revenue is modeled as a Publisher-User Evolutionary Game Model. Secondly, based on the error-elimination decision theory, we combine a data quality assessment algorithm in the PUEGM, which aims to remove low-quality data and improve the overall quality of user data. Finally, the optimal user revenue strategy under different conditions is obtained from the evolutionary stability strategy (ESS) solution and stability analysis. In order to verify the efficiency of the proposed solutions, extensive experiments using some real data sets are conducted. The experimental results demonstrate that our proposed method has high accuracy of data quality assessment and a reasonable selection of user revenue.
Detection and Characterization of Invertebrate Iridoviruses Found in Reptiles and Prey Insects in Europe over the Past Two Decades

Invertebrate iridoviruses (IIVs), while mostly described in a wide range of invertebrate hosts, have also been repeatedly detected in diagnostic samples from poikilothermic vertebrates including reptiles and amphibians. Since iridoviruses from invertebrate and vertebrate hosts differ strongly from one another based not only on host range but also on molecular characteristics, a series of molecular studies and bioassays were performed to characterize and compare IIVs from various hosts and evaluate their ability to infect a vertebrate host. Eight IIV isolates from reptilian and orthopteran hosts collected over a period of six years were partially sequenced. Comparison of eight genome portions (total over 14 kbp) showed that these were all very similar to one another and to an earlier described cricket IIV isolate, thus they were given the collective name lizard–cricket IV (Liz–CrIV). One isolate from a chameleon was also subjected to Illumina sequencing and almost the entire genomic sequence was obtained. Comparison of this longer genome sequence showed several differences to the most closely related IIV, Invertebrate iridovirus 6 (IIV6), the type species of the genus Iridovirus, including several deletions and possible recombination sites, as well as insertions of genes of non-iridoviral origin. Three isolates from vertebrate and invertebrate hosts were also used for comparative studies on pathogenicity in crickets (Gryllus bimaculatus) at 20 and 30 °C. Finally, the chameleon isolate used for the genome sequencing studies was also used in a transmission study with bearded dragons. The transmission studies showed large variability in virus replication and pathogenicity of the three tested viruses in crickets at the two temperatures. In the infection study with bearded dragons, lizards inoculated with a Liz–CrIV did not become ill, but the virus was detected in numerous tissues by qPCR and was also isolated in cell culture from several tissues. Highest viral loads were measured in the gastro-intestinal organs and in the skin. These studies demonstrate that Liz–CrIV circulates in the pet trade in Europe. This virus is capable of infecting both invertebrates and poikilothermic vertebrates, although its involvement in disease in the latter has not been proven.
Anthropometric indicators associated with dementia in the elderly from florianópolis – sC , Brazil : epifloripa Ageing study

Objective: To investigate the association between dementia and anthropometric indicators in the elderly from Florianópolis. Method: This is a cross-sectional population-based survey performed with 1,197 elderly (≥ 60 years) in 2013/2014. Dementia was defined as the combined evidence of low MMSE (Mini-Mental State Examination) score and moderate/severe disability in the activities of daily living. The independent variables were body mass index (BMI), waist circumference (WC), conicity index and waist-to-height ratio (WHtR). Logistic regression (crude and adjusted) was performed to identify associated factors. Results: Dementia prevalence was estimated at 15.1%. After adjustment for sociodemographic characteristics, lifestyle and depressive symptoms, dementia was positively associated with the upper tertiles of the BMI (OR: 2.32; CI95%: 1.26-4.25), WC (OR: 2.22; CI95%: 1.20-4.11) and WHtR (OR: 2.30; CI95%: 1.194.43). Conclusion: Results have shown that both obesity and abdominal fat were associated with the outcome, suggesting that BMI, WC and WHtR should be considered in the investigation of this relationship.
Manipulation under anesthesia after primary knee arthroplasty in Sweden: incidence, patient characteristics and risk of revision

Background and purpose — The incidence of manipulation under anesthesia (MUA) after knee arthroplasty surgery has been reported to vary between 0.5% and 10%. We evaluated the incidence of MUA after primary knee arthroplasty in Sweden, the demographics of the patients and the risk of revision. Patients and methods — Between 2009 and 2013, 64,840 primary total and unicompartmental knee arthroplasties (TKA and UKA) were registered in the Swedish Knee Arthroplasty Register (SKAR). MUAs performed between 2009 and 2014 were identified through the in- and outpatient registers of the Swedish National Board of Health and Welfare. Pertinent data were verified through medical records and patient demographics and revisions were obtained from the SKAR. Results — 1,258 MUAs were identified. Of these, 1,078 were 1st-time MUAs, performed within 1 year after the primary knee arthroplasty. The incidence of MUA was 1.7% and the incidence varied between hospitals from 0% to 5%. The majority were performed after TKA (98%), in younger patients (65% < 65 years), women (64%), and relatively healthy persons (88% had ASA ≤ 2). The cumulative risk of revision at 10 years was 10% (95% CI 8.6–12), similar for men and women. Interpretation — In Sweden, MUA is a rather uncommon measure after knee arthroplasty, especially after UKA. The CRR at 10 years was doubled compared to the general knee arthroplasty population. The frequency of the procedure varies between hospitals but in general it is performed more frequently in healthier and younger patients.
TERT gene polymorphisms are associated with chronic obstructive pulmonary disease risk in the Chinese Li population

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide and is characterized by a partially reversible airflow limitation. Currently, many studies put forward that COPD is associated with both genetic and environmental factors. It has been reported that germline mutations in telomerase are risk factors for COPD susceptibility. In this study, we validated the association between TERT polymorphisms and COPD risk with a case–control study in the Chinese Li population.
Acute Recurrent and Chronic Pancreatitis as Initial Manifestations of Cystic Fibrosis and Cystic Fibrosis Transmembrane Conductance Regulator-Related Disorders.

OBJECTIVES Recurrent pancreatitis is considered a rare manifestation of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction; this case series highlights that pancreatitis can be a presenting symptoms of cystic fibrosis (CF) or a CFTR-related disorder (CFTR-RD). METHODS Retrospective review of patients younger than 30 years diagnosed as having acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP) and subsequently diagnosed as having CF or CFTR-RD. RESULTS Among 18 patients, median time from diagnosis of ARP/CP to diagnosis of CF was 0.4 years (range, 0-33 years). Eight were classified as having CF by elevated sweat chloride testing (SCT). Five had intermediate SCT (30-59 mmol/L) with 2 pathogenic mutations. Five had CFTR-RD with intermediate SCT and 0 to 1 pathogenic mutations. Eight patients (44%) had exocrine pancreatic insufficiency, and pancreatic fluid collections were more common in this group. Based on the CFTR mutation, 6 patients were eligible for CFTR potentiator therapy, although none received it during the study period. Nine of the 18 had ≥1 other likely CF manifestations, including sinusitis (33%), nasal polyps (11%), pneumonia (22%), and gallbladder disease (22%). CONCLUSIONS Cystic fibrosis or CFTR-RD can present as ARP/CP. Complete diagnostic testing for CFTR-RD in patients with ARP/CP will broaden treatment options and help to identify comorbid illness.
FtsZ as an Antibacterial Target: Status and Guidelines for Progressing This Avenue.

The disturbing increase in the number of bacterial pathogens that are resistant to multiple, or sometimes all, current antibiotics highlights the desperate need to pursue the discovery and development of novel classes of antibacterials. The wealth of knowledge available about the bacterial cell division machinery has aided target-driven approaches to identify new inhibitor compounds. The main division target being pursued is the highly conserved and essential protein, FtsZ. Despite very active research on FtsZ inhibitors for several years, this protein is not yet targeted by any commercial antibiotic. Here we discuss the suitability of FtsZ as an antibacterial target for drug development, and review progress achieved in this area. We use hindsight to highlight the gaps that have slowed progress in FtsZ inhibitor development, and to suggest guidelines for concluding that FtsZ is actually the target of these molecules, a key missing link in several studies. In moving forward, a multidisciplinary and a communicative and collaborative process, with sharing of research expertise, is critical if we are to succeed.
Microtubule nucleation in the cytoplasm of developing cortical neurons and its regulation by brain‐derived neurotrophic factor

The centrosomes of neurons do not nucleate microtubules (MTs). It is not well known where MTs are nucleated in neurons. We performed MT regrowth experiments in primary cultured cortical neurons from mice. After cold‐nocodazole depolymerization of MTs in neurons at 3 days in vitro (DIV), we observed numerous short MTs that regenerated in the cytoplasm; they were roughly equal in length and randomly oriented. Gamma‐tubulin and MZT2 were detected at one end of these MTs, indicating that the short MTs were nucleated by γ‐tubulin‐ring complexes; the Golgi apparatus was not the origin site of their nucleation. The ratio of MT‐regenerating cells, the density of regenerated MTs, and their lengths decreased at 7 DIV. Pretreatment of neurons with protein‐kinase inhibitors, K‐252a, staurosporine, or H7 diminished the length of the regenerated MTs, while pretreatment of neurons with brain‐derived neurotrophic factor increased the length of regenerated MTs. These results support the idea that short MTs with mixed orientations are transiently generated in the cytoplasm of differentiating neurons, and that they are possibly transported into dendrites to provide seeds for MTs with mixed polarity.
Fundamental principles of rehabilitation and musculoskeletal tissue healing

Abstract Objective To review fundamental principles of tissue healing and physical rehabilitation as they apply to dogs recovering from cranial cruciate ligament (CCL) surgery. Study design Invited Review. Sample population None. Methods A multidisciplinary group of specialists in small animal surgery, rehabilitation/sports medicine, and human physical and occupational therapy reviewed the currently available evidence for rehabilitation post‐CCL surgery. Because current evidence is limited, this group proposes guidelines for rehabilitation after CCL surgery based on the fundamental principles of tissue healing and physical therapy. Results This Review proposes four fundamental principles of small animal physical rehabilitation based on the foundations of tissue healing and patient‐centric and goal‐oriented therapy. Postoperative rehabilitation programs should be designed such that patient progress is based on individual assessment according to the degree of tissue healing, strength, and achievement of functional goals. Therapists must fully understand phases of tissue healing, reassess the patient frequently, and use clinical reasoning skills to progress treatment appropriately for the individual patient. Conclusion Until more robust evidence is available to guide treatment protocols, fundamental principles of rehabilitation should ideally be adhered to when providing rehabilitation, including after CCL surgery. Clinical significance While this Review specifically addresses post‐CCL surgery rehabilitation, these fundamental principles should be applied broadly to animals enrolled in rehabilitation programs.