Miracle-dz/UniFAR-FTUs huggingface dataset:
miRNA-Mediated Knockdown of ATXN3 Alleviates Molecular Disease Hallmarks in a Mouse Model for Spinocerebellar Ataxia Type 3

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by the expansion of a CAG repeat in the ATXN3 gene. This mutation leads to a toxic gain of function of the ataxin-3 protein, resulting in neuronal dysfunction and atrophy of specific brain regions over time. As ataxin-3 is a dispensable protein in rodents, ataxin-3 knockdown by gene therapy may be a powerful approach for the treatment of SCA3. In this study, we tested the feasibility of an adeno-associated viral (AAV) vector carrying a previously described artificial microRNA against ATXN3 in a striatal mouse model of SCA3. Striatal injection of the AAV resulted in good distribution throughout the striatum, with strong dose-dependent ataxin-3 knockdown. The hallmark intracellular ataxin-3 inclusions were almost completely alleviated by the microRNA-induced ATXN3 knockdown. In addition, the striatal lesion of dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) in the SCA3 mice was rescued by ATXN3 knockdown, indicating functional rescue of neuronal signaling and health upon AAV treatment. Together, these data suggest that microRNA-induced ataxin-3 knockdown is a promising therapeutic strategy in the treatment of SCA3.
Guidelines for Spacing between Freeway Ramps

Existing geometric design guidance related to interchange ramp spacing in the Texas Roadway Design Manual and AASHTO's Policy on Geometric Design of Highways and Streets is not speed dependent even though intuition indicates that spacing and speed are related. Understanding the relationship between interchange ramp spacing, speed, and freeway operations is important, especially in developing potential design values for higher speeds (e.g., 85 to 100 mph). The objectives of this Texas Department of Transportation project were (a) to investigate relationships between weaving length, speed, and overall vehicle operations for successive ramps on Texas freeways and (b) to propose updates to current guidance on recommended distances between ramps. Several methods were used to assist in developing guidance on ramp spacing lengths. The methods and resources used to generate potential lengths included (a) guidance provided in the Design Manual for Roads and Bridges published by the Highways Agency in England, (b) minimum deceleration and acceleration lengths for freeway conditions, (c) decision sight distance, (d) sign spacing needs, (e) NCHRP Project 3–75 findings, (f) findings from field studies at seven sites in Texas, (g) findings from simulation conducted as part of this research, and (h) safety relationships identified in the literature. Suggested ramp spacings were developed for the entrance–exit and exit–exit ramp scenarios.
A single intranasal dose of a live-attenuated parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in hamsters

Significance Pediatric SARS-CoV-2 infections, though generally mild, are associated with substantial morbidity and contribute to transmission dynamics. No SARS-CoV-2 vaccines are available for young children. Bovine/human parainfluenza virus 3 (B/HPIV3) vectors for intranasal immunization of children were evaluated previously in phase 1/2 studies and were well-tolerated in children as young as 2 mo of age. This manuscript describes a B/HPIV3 vector expressing a prefusion-stabilized version of the SARS-CoV-2 S protein (S-2P), and shows that a single intranasal dose is highly immunogenic and protective against SARS-CoV-2 challenge in the hamster model, the most robust SARS-CoV-2 challenge model available. Based on these results, B/HPIV3/S-2P represents a promising vaccine candidate for clinical evaluation as a pediatric vaccine for intranasal immunization against HPIV3 and SARS-CoV-2. Single-dose vaccines with the ability to restrict SARS-CoV-2 replication in the respiratory tract are needed for all age groups, aiding efforts toward control of COVID-19. We developed a live intranasal vector vaccine for infants and children against COVID-19 based on replication-competent chimeric bovine/human parainfluenza virus type 3 (B/HPIV3) that express the native (S) or prefusion-stabilized (S-2P) SARS-CoV-2 S spike protein, the major protective and neutralization antigen of SARS-CoV-2. B/HPIV3/S and B/HPIV3/S-2P replicated as efficiently as B/HPIV3 in vitro and stably expressed SARS-CoV-2 S. Prefusion stabilization increased S expression by B/HPIV3 in vitro. In hamsters, a single intranasal dose of B/HPIV3/S-2P induced significantly higher titers compared to B/HPIV3/S of serum SARS-CoV-2–neutralizing antibodies (12-fold higher), serum IgA and IgG to SARS-CoV-2 S protein (5-fold and 13-fold), and IgG to the receptor binding domain (10-fold). Antibodies exhibited broad neutralizing activity against SARS-CoV-2 of lineages A, B.1. 1.7, and B.1. 351. Four weeks after immunization, hamsters were challenged intranasally with 104.5 50% tissue-culture infectious-dose (TCID50) of SARS-CoV-2. In B/HPIV3 empty vector-immunized hamsters, SARS-CoV-2 replicated to mean titers of 106.6 TCID50/g in lungs and 107 TCID50/g in nasal tissues and induced moderate weight loss. In B/HPIV3/S-immunized hamsters, SARS-CoV-2 challenge virus was reduced 20-fold in nasal tissues and undetectable in lungs. In B/HPIV3/S-2P–immunized hamsters, infectious challenge virus was undetectable in nasal tissues and lungs; B/HPIV3/S and B/HPIV3/S-2P completely protected against weight loss after SARS-CoV-2 challenge. B/HPIV3/S-2P is a promising vaccine candidate to protect infants and young children against HPIV3 and SARS-CoV-2.
Pilot Trial of Neuromuscular Stimulation in Human Subjects with Chronic Venous Disease

Introduction Neuromuscular stimulation (NMES) has been shown to improve peripheral blood flow in healthy people. We investigated the effect of bilateral leg NMES on the symptoms of chronic venous disease. Methods Forty subjects were recruited from four groups: healthy, superficial insufficiency, deep insufficiency, and deep obstruction. Haemodynamic venous measurements were taken from the right femoral vein with ultrasound, laser Doppler fluximetry from the left hand and foot. Devices were then worn for 4–6 hours per day, for 6 weeks. Haemodynamic measurements were repeated at week 6. Quality of life questionnaires were taken at week 0, 6 and 8. Results The mean age was 48.7, BMI 28.6kg/m2, and maximum calf circumference 39.0 cm. Twenty-four subjects were men. NMES increased femoral vein peak velocity, TAMV and volume flow by 55%, 20%, 36% at 20 minutes (all p<0.05), which was enhanced at week 6 (PV and TAMV p<0.05). Mean increases in arm and leg fluximetry were 71% and 194% (both p<0.01). Leg swelling was reduced by mean 252.7 mL (13%, p<0.05) overall; 338.9 mL (16%, p<0.05) in venous disease. For those with venous pathology, scores for disease specific and generic quality of life questionnaires improved. Those with C4-6 disease benefitted the most, with improvements in VDS score of 1, AVVQ of 6, and SF-12 of 10. Conclusion NMES improves venous haemodynamic parameters in chronic venous disease, which is enhanced by regular use. NMES reduces leg oedema, improves blood supply to the skin of the foot, and may positively affect quality of life. Clinical Trials This trial was registered with www.clinicaltrials. org.uk (NCT02137499).
Effect of Periodic Voluntary Interventions on Trapezius Activation and Fatigue During Light Upper Limb Activity

Objective The effects of diverse periodic interventions on trapezius muscle fatigue and activity during a full day of computer work were investigated. Background Musculoskeletal disorders, including trapezius myalgia, may be associated with repeated exposure to prolonged low-level activity, even during light upper-extremity tasks including computer work. Methods Thirty healthy adults participated in a study that simulated two 6-hour workdays of computer work. One workday involved imposed periodic passive and active interventions aimed at disrupting trapezius contraction monotony (Intervention day), whereas the other workday did not (Control day). Trapezius muscle activity was quantified by the 3-dimensional acceleration of the jolt movement of the acromion produced by electrically induced muscle twitches. The spatio-temporal distribution of trapezius activity was measured through high-density surface electromyography (HD-EMG). Results The twitch acceleration magnitude in one direction was significantly different across measurement periods (p = 0.0156) on Control day, whereas no significant differences in any direction were observed (p > 0.05) on Intervention day. The HD-EMG from Intervention day showed that only significant voluntary muscle contractions (swing arms, Jacobson maneuver) induced a decrease in the muscle activation time and an increase in the spatial muscle activation areas (p < 0.01). Conclusion Disruption of trapezius monotonous activity via brief voluntary contractions effectively modified the ensuing contraction pattern (twitch acceleration along one axis, active epochs reduction, and larger spatial distribution). The observed changes support an associated reduction of muscle fatigue. Application This study suggests that disruptive intervention activity is efficient in reducing the impact of trapezius muscle fatigue.
Plasma levels of sirtuin and adiponectin in patients with primary open-angle glaucoma, exfoliative glaucoma, and healthy controls

Purpose To compare plasma levels of sirtuin 1 (SIRT1) and adiponectin (APN) in patients with primary open-angle glaucoma (POAG), exfoliative glaucoma (XFG), and healthy control subjects. Methods This prospective case-control study collected plasma samples from 118 participants. All subjects underwent a comprehensive ophthalmologic examination before the acquisition of a plasma sample. Plasma samples were obtained from 40 POAG, 38 XFG, and 40 healthy control subjects without any evidence of systemic or ocular disease. Serum SIRT1 and APN levels were estimated by an enzyme-linked immunosorbent assay, ELISA (Elabscience, Houston, USA) method. Statistical analysis of results relied on Kolmogorov-Smirnov, Kruskal-Wallis, Chi-square, analysis of variance (ANOVA) tests, and linear regression analysis, where appropriate. Results A significant decrease in SIRT1 levels was observed in POAG patients compared to healthy controls (p = 0.004, Dunn's test). In contrast, no difference was detected between XFG and POAG patients or healthy controls (p = 0.32 and p = 0.34, respectively, Dunn's test). There was no significant difference in plasma APN levels between the three groups under investigation (p = 0.59, ANOVA). Conclusion Alterations in serum level of SIRT1 may suggest a possible role in POAG via potential effects in neuroprotection and oxidative stress.
Preoperative MRI PI‐RADS scores are associated with prostate cancer upstaging on surgical pathology

Prostate Imaging Reporting and Data System (PI‐RADS) scores can help identify clinically significant prostate cancer and improve patient selection for prostate biopsies. However, the role of PI‐RADS scores in patients already diagnosed with prostate cancer remains unclear. The purpose of this study was to evaluate the association of PI‐RADS scores with prostate cancer upstaging. Upstaging on final pathology harbors a higher risk for biochemical recurrence with important implications for additional treatments, morbidity, and mortality.
Are smokers scared by COVID-19 risk? How fear and comparative optimism influence smokers’ intentions to take measures to quit smoking

Research suggests that smoking may compound the risk of serious health problems to smokers who contract COVID-19. This study examines whether and how exposure to news stories reporting the severe COVID-19 risk to smokers may influence smokers’ emotional responses (fear, anxiety, and sadness) and intentions to take measures to quit smoking. Current smokers in the US participated in an online experiment (N = 495) and were randomized to read smoking risk news stories or news stories reporting the combined risk of smoking and COVID-19. We found that combined risk news stories lead to participants feeling more fearful and sadder than when they viewed smoking risk news stories (M = 5.74; SD = 2.57 vs. M = 5.20; SD = 2.74; p < .05). Fear fully mediated the effect of news exposure on intentions to take measures to quit smoking (ß = .09; SE = 05; 95% CI [.010, .200]). Moreover, moderated-mediation analyses revealed that the mediating effect of fear was conditioned on the levels of comparative optimism, such that the association between fear and intentions to take measures to quit smoking was only significant among smokers whose comparative optimism was at the mean score (ß = .16; SE = 05; 95% CI [.071, .250]), and for those whose comparative optimism was high (ß = .27; SE = .06; 95% CI [.146, .395]). These results suggest that fear of the pandemic and optimism might play important roles in predicting and explaining the association between exposure to news stories and intentions to take measures to quit smoking. Messages about heightened risk of COVID-19 complications for smokers that increase fear might be an effective strategy to motivate smokers to quit. Such messages should be used to turn the adversity of COVID-19 pandemic into an intervention opportunity to reduce tobacco-related disease.
Association Between Charlson Comorbidity Index and Community-Acquired Pressure Injury in Older Acute Inpatients in a Chinese Tertiary Hospital

Purpose To explore the correlation between community-acquired pressure injury (CAPI) and comorbidities in elderly patients with emergency admission. Patients and Methods Patients aged 65 years or above were enrolled from multiple departments, such as Internal Medicine, Surgery, Geriatrics, and Intensive Care Unit of Wuhan Third Hospital, which is affiliated to Wuhan University, from January to December 2020. Comorbidity data were extracted using the 10th edition of the International Classification of Diseases (ICD-10) from the hospital electronic medical record system, and the Charlson Comorbidity Index (CCI) was calculated using these data. Participants were divided into two groups according to whether pressure injury was present at admission. The baseline characteristics of the two groups were compared using Student’s t-tests, Mann–Whitney U-tests, and chi-square tests. Univariate and multivariate logistic regression models were constructed to explore the relationship between CAPI and the CCI. Smooth curve fitting was used to show the relationship between the CCI and CAPI. By drawing the receiver operating characteristic curve, the CCI was used to predict CAPI. Results A total of 5759 participants with an average age of 75.1 ± 7.6 were included in this population-based study. The prevalence of CAPI was 4.3%. In logistic regression analysis, there was a positive relationship between the CCI and CAPI after adjustment for sex, age, hypoproteinemia, and anemia (OR = 1.37, 95% CI = 1.29–1.45, p < 0.001, trend test p < 0.001). The area under the receiver operating characteristic curve was 0.75, and the maximum value of the Youden index was 0.35, with a critical value of 5.5. Conclusion The development of CAPI was positively correlated with the CCI. The risk of developing pressure injury increases with the number and severity of comorbidities. This study shows that the CCI has certain reference value in predicting CAPI.
Using Transverse Profile Data to Compute Plastic Deformation Parameters for Asphalt Concrete Pavements

Previous studies have shown that the performance of in-service pavements may deviate significantly from that predicted by use of laboratory-calibrated performance models. Therefore calibration of performance prediction models with data from in-service pavements is important. Calibration of mechanistic rutting models by use of transverse profile data is explored. A well-known family of mechanistic rutting prediction models uses plastic deformation parameters [slope of elastic or plastic strain (or both) and load hardening factor] for quantification of the amount of permanent deformation resulting from each load application. For the purpose of obtaining these parameters, two traditional methods have been used: repeated load testing in the laboratory and calibration by use of time-series data from in-service pavements. Although the first suffers from the lack of compatibility between laboratory-predicted and actual performance, the second requires collection of field data for an extended period of time (years of monitoring) and may be interrupted by rehabilitation activities. The transverse profile contains valuable information that can be used for determining the contribution of each pavement layer to the observed rutting and the plastic deformation parameters. Transverse profile data were used for calibration of rutting prediction models. The stability and sensitivity of the computed parameters were also investigated.
University of Birmingham Trust and relationship development among users in Dark Web child sexual exploitation and abuse networks: A literature review from a psychological and criminological perspective

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Investigating barriers to accident precursor reporting in East Azerbaijan Province Gas Company from the perspective of HSE officers: a qualitative study

Objectives. Investigating the root causes of under-reporting near misses is very important. The aim of this study was investigating barriers to near-miss reporting in East Azerbaijan Province Gas Company from the perspective of health, safety and environment (HSE) officers. Methods. Semi-structured individual interviews were used and 21 interviews were conducted with HSE officers. Inductive content analysis was used for analyzing interviews. After analyzing the interviews, the codes in the interviews were categorized. Results. In general, two categories of code were created: reasons for non-reporting of accident precursors; and suggested solutions to improve the reporting system of accident precursors. However, two main categories were found for not reporting: individual reasons such as lack of commitment to the job, lack of attention to social responsibility, forgetfulness and laches in reporting, etc.; and organizational reasons such as job instability among employees, lack of sufficient training, failure of the organization to provide feedback, etc. Conclusion. This study found that the opinions of people working in the organization can be very effective in promoting reporting, so any organization can choose the appropriate strategy to increase the number and quality of reports by examining the opinions of managers, HSE officers and workers in the organization.
Sensory neuron transcriptomes reveal complex neuron-specific function and regulation of mec-2/Stomatin splicing

Abstract The function and identity of a cell is shaped by transcription factors controlling transcriptional networks, and further shaped by RNA binding proteins controlling post-transcriptional networks. To overcome limitations inherent to analysis of sparse single-cell post-transcriptional data, we leverage the invariant Caenorhabditis elegans cell lineage, isolating thousands of identical neuron types from thousands of isogenic individuals. The resulting deep transcriptomes facilitate splicing network analysis due to increased sequencing depth and uniformity. We focus on mechanosensory touch-neuron splicing regulated by MEC-8/RBPMS. We identify a small MEC-8-regulated network, where MEC-8 establishes touch-neuron isoforms differing from default isoforms found in other cells. MEC-8 establishes the canonical long mec-2/Stomatin isoform in touch neurons, but surprisingly the non-canonical short isoform predominates in other neurons, including olfactory neurons, and mec-2 is required for olfaction. Forced endogenous isoform-specific expression reveals that the short isoform functions in olfaction but not mechanosensation. The long isoform is functional in both processes. Remarkably, restoring the long isoform completely rescues mec-8 mutant mechanosensation, indicating a single MEC-8 touch-neuron target is phenotypically relevant. Within the long isoform we identify a cassette exon further diversifying mec-2 into long/extra-long isoforms. Neither is sufficient for mechanosensation. Both are simultaneously required, likely functioning as heteromers to mediate mechanosensation.
Symmetry Perception by Deep Networks: Inadequacy of Feed-Forward Architectures and Improvements with Recurrent Connections

Symmetry is omnipresent in nature and perceived by the visual system of many species, as it facilitates detecting ecologically important classes of objects in our environment. Symmetry perception requires abstraction of long-range spatial dependencies between image regions, and its underlying neural mechanisms remain elusive. In this paper, we evaluate Deep Neural Network (DNN) architectures on the task of learning symmetry perception from examples. We demonstrate that feed-forward DNNs that excel at modelling human performance on object recognition tasks, are unable to acquire a general notion of symmetry. This is the case even when the DNNs are architected to capture long-range spatial dependencies, such as through `dilated' convolutions and the recently introduced `transformers' design. By contrast, we find that recurrent architectures are capable of learning to perceive symmetry by decomposing the long-range spatial dependencies into a sequence of local operations, that are reusable for novel images. These results suggest that recurrent connections likely play an important role in symmetry perception in artificial systems, and possibly, biological ones too.
Ionized Carbon around IRC+10216

Asymptotic giant branch stars create a rich inventory of molecules in their envelopes as they lose mass during later stages of their evolution. These molecules cannot survive the conditions in interstellar space, where they are exposed to ultraviolet photons of the interstellar radiation field. As a result, daughter molecules are the ones injected into space, and a halo of those molecules is predicted to exist around cool evolved stars. The most abundant molecule in the envelopes other than H2 is CO, which dissociates into C that is rapidly ionized into C+ in a halo around the star that is optically thin to the interstellar radiation field. We develop the specific predictions of the ionized carbon halo size and column density for the well-studied, nearby star IRC+10216. We compare those models to observations of the [C ii] 157.7 μm far-infrared fine structure line using the Stratospheric Observatory for Infrared Astronomy and Herschel. The combination of bright emission toward the star and upper limits to extended [C ii] is inconsistent with any standard model. The presence of [C ii] toward the star requires some dissociation and ionization in the inner part of the outflow, possibly due to a hot companion star. The lack of extended [C ii] emission requires that daughter products from CO photodissociation in the outer envelope remain cold. The [C ii] profile toward the star is asymmetric, with the blueshifted absorption due to the cold outer envelope.