Miracle-dz/UniFAR-FTUs huggingface dataset:
Intra-locked G-quadruplex structures formed by irregular DNA G-rich motifs

Abstract G-rich DNA sequences with tracts of three or more continuous guanines (G≥3) are known to have high propensity to adopt stable G-quadruplex (G4) structures. Bioinformatic analyses suggest high prevalence of G-rich sequences with short G-tracts (G≤2) in the human genome. However, due to limited structural studies, the folding principles of such sequences remain largely unexplored and hence poorly understood. Here, we present the solution NMR structure of a sequence named AT26 consisting of irregularly spaced G2 tracts and two isolated single guanines. The structure is a four-layered G4 featuring two bi-layered blocks, locked between themselves in an unprecedented fashion making it a stable scaffold. In addition to edgewise and propeller-type loops, AT26 also harbors two V-shaped loops: a 2-nt V-shaped loop spanning two G-tetrad layers and a 0-nt V-shaped loop spanning three G-tetrad layers, which are named as VS- and VR-loop respectively, based on their distinct structural features. The intra-lock motif can be a basis for extending the G-tetrad core and a very stable intra-locked G4 can be formed by a sequence with G-tracts of various lengths including several G2 tracts. Findings from this study will aid in understanding the folding of G4 topologies from sequences containing irregularly spaced multiple short G-tracts.
Embedding Mobile Health Technology into the Nurses' Health Study 3 to Study Behavioral Risk Factors for Cancer

Background: Physical activity and sleep are behavioral risk factors for cancer that may be influenced by environmental exposures, including built and natural environments. However, many studies in this area are limited by residence-based exposure assessment and/or self-reported, time-aggregated measures of behavior. Methods: The Nurses' Health Study 3 (NHS3) Mobile Health Substudy is a pilot study of 500 participants in the prospective NHS3 cohort who use a smartphone application and a Fitbit for seven-day periods, four times over a year, to measure minute-level location, physical activity, heart rate, and sleep. Results: We have collected data on 435 participants, comprising over 6 million participant-minutes of heart rate, step, sleep, and location. Over 90% of participants had five days of ≥600 minutes of Fitbit wear-time in their first sampling week, and this percentage dropped to 70% for weeks 2 to 4. Over 819 sampling weeks, we observed an average of 7,581 minutes of heart rate and step data [interquartile range (IQR): 6,651–9,645] per participant-week, and >2 million minutes of sleep in over 5,700 sleep bouts. We have recorded location data for 5,237 unique participant-days, averaging 104 location observations per participant-day (IQR: 103–107). Conclusions: This study describes a protocol to incorporate mobile health technology into a nationwide prospective cohort to measure high-resolution objective data on environment and behavior. Impact: This project could provide translational insights into interventions for urban planning to optimize opportunities for physical activity and healthy sleep patterns to reduce cancer risk. See all articles in this CEBP Focus section, “Modernizing Population Science. ”
CG200745, a Novel HDAC Inhibitor, Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome

Histone deacetylases have been a target of therapy for organ fibrosis. Here, we report the protective effect of CG200745 (CG), a novel histone deacetylase inhibitor, on tubulointerstitial fibrosis in Col4a3−/− mice, a murine model of Alport syndrome. Morphological analyses revealed CG treatment markedly alleviated kidney fibrosis in Col4a3−/− mice at the age of 7 weeks. CG prevented the activation of transforming growth factor β (TGFβ) and its downstream SMAD signaling in the kidney of Col4a3−/− mice. As critical upstream regulators of TGFβ signaling, immunoblotting of whole kidney lysate of Col4a3−/− mice reveled that intra-renal renin–angiotensin system (RAS) was activated with concurrent upregulation of inflammation and apoptosis, which were effectively suppressed by CG treatment. CG suppressed both activation of RAS and up-regulation of TGFβ signals in angiotensin II-stimulated HK-2 cells, a human kidney proximal tubular epithelial cell line. CG inhibited activation of TGFβ-driven signals and fibrosis in NRK-49F cells, a rat kidney fibroblast cell line, under angiotensin II-rich conditions. Collectively, CG was found to be effective both in proximal tubular epithelial cells by inhibiting local RAS and TGFβ signaling activation, as well as in fibroblasts by blocking their transition to myofibroblasts, attenuating renal fibrosis in a murine model of Alport syndrome.
Comparison of the performance of risk scoring systems for tumor bleeding in patients with inoperable gastric cancer

Abstract Background The Glasgow – Blatchford bleeding score (GBS) and admission and full Rockall scores are widely used risk scoring systems to stratify risk and determine the need for intervention in patients with upper gastrointestinal bleeding. We evaluated the performance of these risk scoring systems in patients with gastric cancer and tumor bleeding. Methods This retrospective study included patients with inoperable gastric cancer who presented with tumor bleeding at the National Cancer Center, Korea, between 2001 and 2015. The GBS, and admission and full Rockall scores were calculated. Primary outcome was the performance of the risk scoring systems in predicting the need for urgent interventions (endoscopic therapy, transarterial embolization, and surgery). The risk factors associated with urgent intervention were analyzed. Results Of 357 patients with tumor bleeding, 118 (33.1 %; 116 endoscopic therapy, 2 trans-arterial embolization) required urgent intervention. The full Rockall score was better at predicting the need for urgent intervention (area under the receiver operating characteristic curve = 0.78; P < 0.001) than the GBS (0.56) and admission Rockall score (0.56). Hemostatic intervention was not performed in patients with a full Rockall score ≤ 6 (103 patients, 28.9 %). On multivariate analysis, endoscopic stigmata of recent hemorrhage of Forrest classes Ia – IIb were significant factors associated with urgent intervention. Conclusions The full Rockall score was superior to the GBS and admission Rockall score in predicting the need for urgent intervention for tumor bleeding. Thus, endoscopic evaluation is required to determine the need for urgent intervention in patients with gastric cancer and tumor bleeding.
PLA–PCL–PEG–PCL–PLA based micelles for improving the ocular permeability of dexamethasone: development, characterization, and in vitro evaluation

Abstract The aim of the present research was to investigate the feasibility of developing polylactide–polycaprolactone–polyethylene glycol–polycaprolactone–polylactide (PLA–PCL–PEG–PCL–PLA) based micelles to improve ocular permeability of dexamethasone (DEX). PLA–PCL–PEG–PCL–PLA copolymers were synthesized by a ring-opening polymerization method. DEX was loaded into the developed copolymers. The DEX-loaded micelles were characterized using transmission electron microscopy (TEM) and dynamic light scattering (DLS) methods. Cytotoxicity of the micelles obtained was investigated on L929 cell line. Cellular uptake was followed by fluorescence microscopy and flow cytometry analyses. The release behavior of DEX from the micelles as well as the drug release kinetics was studied. Corneal permeability was also evaluated using an ex vivo bovine model. The pentablock copolymers were successfully synthesized. The TEM results verified the formation of spherical micelles, the sizes of which was approximately 65 nm. The micelles exhibited suitable compatibility on L929 cells. The release profile showed an initial burst release phase followed by a sustained release phase, the kinetic of which was close to the Weibull’s distribution model. The micelles showed higher corneal permeability in comparison to a marketed DEX eye drop. Taken together, the results indicated that the PLA–PCL–PEG–PCL–PLA micelles could be appropriate candidates for the ocular delivery of DEX, and probably other hydrophobic drugs.
Association between Neighborhood Environment and Quality of Sleep in Older Adult Residents Living in Japan: The JAGES 2010 Cross-Sectional Study

Poor sleep is associated with lifestyle, however, few studies have addressed the association between sleep quality and the neighborhood environment. This study aimed to investigate the associations between living environment factors and sleep quality in older people. Participants were community-dwelling people aged ≥65 years who participated in the 2010 Japanese Gerontological Evaluation Study. The data of 16,650 people (8102 men, 8548 women) were analyzed. Sleep quality (good or poor) was evaluated using a self-administered questionnaire. Multilevel Poisson regression analysis stratified by depressive status (measured by the Geriatric Depression Scale-15 [GDS]) was conducted with sleep quality as the dependent variable and social and physical environmental factors as explanatory variables. The 12,469 non-depressive respondents and 4181 depressive respondents were evaluated. The regression analysis indicated that non-depressive participants slept better if they lived in environments with few hills or steps (prevalence ratio [PR] = 0.75, 95% CI: 0.56–0.9) and with places where they felt free to drop in (PR = 0.51, 95% CI: 0.26–0.98). For depressive participants, these associations were not evident. Living alone, poor self-rated health, low income, and unemployment were associated with poor sleep quality. In addition to support with these individual factors, improving environmental factors at the neighborhood level may improve the sleep quality of community-dwelling older adults.
Nitrate sources and the effect of land cover on the isotopic composition of nitrate in the catchment of the Rhône River

ABSTRACT The Rhône River originates in the high Alps and drains an intensely cultivated and industrialised catchment before it discharges to the Gulf of Lion. We investigated the interaction of catchment geomorphology with nitrate sources (atmosphere, agriculture, and nitrification of soil organic matter) and removal processes in large and diverse watersheds on the basis of dual nitrate isotope signatures in river water. In March 2015, we took surface water samples along the Rhône River, including its main tributaries, and measured nutrient concentrations and the stable isotopic composition of nitrate (δ15N, δ18O and Δ17O), and water (δ18O-H2O). Results show that high altitude regions are dominated by nitrate from nitrification in pristine soils and atmospheric deposition, while nitrate in the downstream Rhône River originates mainly from nitrification of agricultural/urban sources. Parallel increases in δ15N and δ18O reflect the influence of primary production. Previous studies suggested robust correlations between land use and . Based on our observation that nitrate δ15N values at higher altitudes are lower than expected, we assume that lower nitrate δ15N values likely reflect limited nitrate consumption and lower soil nitrogen turnover rates. We propose that correlation between land use and nitrate δ15N is sensitive to slope and geomorphology.
Prevalence and Factors Associated With Low-Value Preoperative Testing for Patients Undergoing Carpal Tunnel Release at an Academic Medical Center

Background: Routine preoperative screening tests before low-risk surgery cannot be justified if the risks to patients are not outweighed by benefits. Several studies and professional guidelines suggest avoiding screening tests prior to minor operations. We aimed to assess the prevalence and patient characteristics associated with low-value preoperative tests (LVTs) prior to carpal tunnel release (CTR) at an academic medical center. Methods: From electronic medical records, we identified patients aged ≥18 who underwent CTR from 2015 to 2017. We determined the occurrence of 9 common LVTs, such as complete blood count (CBC), basic metabolic profile (BMP), and electrocardiogram (ECG), in the 30 days prior to CTR. Multivariable logistic and Poisson regression were used to identify factors associated with receiving any LVT and the number of LVTs, respectively. Results: Among 572 patients, 248 (43.4%) had at least 1 LVT. The most common tests were ECG (31.3% of CTRs), CBC (27.3% of CTRs), and BMP (23.6% of CTRs). Patient factors associated with higher odds of receiving LVT included older age, higher Elixhauser comorbidity score, and general or regional anesthesia (vs monitored anesthesia care). Conclusions: Low-value preoperative tests were frequently received by patients undergoing CTR and were associated with anesthesia type, age, and number of comorbidities. Although our study focused on CTR, these results likely have implications for other commonly performed low-risk procedures. These findings can help guide efforts to improve the quality and value of surgery for carpal tunnel syndrome and facilitate the development of strategies to reduce LVT, such as audit feedback and provider education.
Embodiment Is Related to Better Performance on a Brain–Computer Interface in Immersive Virtual Reality: A Pilot Study

Electroencephalography (EEG)-based brain–computer interfaces (BCIs) for motor rehabilitation aim to “close the loop” between attempted motor commands and sensory feedback by providing supplemental information when individuals successfully achieve specific brain patterns. Existing EEG-based BCIs use various displays to provide feedback, ranging from displays considered more immersive (e.g., head-mounted display virtual reality (HMD-VR)) to displays considered less immersive (e.g., computer screens). However, it is not clear whether more immersive displays improve neurofeedback performance and whether there are individual performance differences in HMD-VR versus screen-based neurofeedback. In this pilot study, we compared neurofeedback performance in HMD-VR versus a computer screen in 12 healthy individuals and examined whether individual differences on two measures (i.e., presence, embodiment) were related to neurofeedback performance in either environment. We found that, while participants’ performance on the BCI was similar between display conditions, the participants’ reported levels of embodiment were significantly different. Specifically, participants experienced higher levels of embodiment in HMD-VR compared to a computer screen. We further found that reported levels of embodiment positively correlated with neurofeedback performance only in HMD-VR. Overall, these preliminary results suggest that embodiment may relate to better performance on EEG-based BCIs and that HMD-VR may increase embodiment compared to computer screens.
Severity of Villous Atrophy at Diagnosis in Childhood Does Not Predict Long-Term Outcomes in Celiac Disease.

OBJECTIVES Current pediatric guidelines allow non-invasive diagnosis of celiac disease in selected children. We investigated in a large cohort study whether the severity of villous atrophy at diagnosis is associated with clinical characteristics or long-term health outcomes, thus having a prognostic significance. METHODS Comprehensive medical data on 906 children with celiac disease were analyzed. Long-term health outcomes of 503 adult patients diagnosed in childhood were moreover assessed with a specific study questionnaire and validated Gastrointestinal Symptom Rating Scale (GSRS) and Psychological General Well-Being (PGWB) questionnaires. Patients were classified into three groups according to severity of villous atrophy at diagnosis and all variables were compared. RESULTS Altogether 34% of the patients had partial, 40% subtotal, and 26% total villous atrophy. Children with milder lesions were diagnosed more recently (median year 2007 vs. 2006 vs. 2001 respectively, p < 0.001), more often by screening (30% vs. 25% vs. 17%, p < 0.001) and they suffered less often from anemia (16% vs. 21% vs. 32%, p < 0.001) and growth disturbances (22% vs. 36% vs. 54%, p < 0.001) and had lower transglutaminase-2 antibody levels (median 64 U/l vs. 120 U/l vs. 120 U/l, p < 0.001). There was no difference in other disease features.Altogether 212 adults diagnosed in childhood completed the questionnaires. Severity of villous atrophy at childhood diagnosis did not predict presence of complications or comorbidities, persistent symptoms, and self-perceived health, quality of life or adherence to a gluten-free diet in adulthood. CONCLUSIONS Presence of advanced villous atrophy at diagnosis is associated with more severe clinical characteristics but not with poorer long-term health and treatment outcomes.
Experience shapes activity dynamics and stimulus coding of VIP inhibitory cells

Cortical circuits can flexibly change with experience and learning, but the effects on specific cell types, including distinct inhibitory types, are not well understood. Here we investigated how excitatory and VIP inhibitory cells in layer 2/3 of mouse visual cortex were impacted by visual experience in the context of a behavioral task. Mice learned a visual change detection task with a set of eight natural scene images. Subsequently, during 2-photon imaging experiments, mice performed the task with these familiar images and three sets of novel images. Strikingly, the temporal dynamics of VIP activity differed markedly between novel and familiar images: VIP cells were stimulus-driven by novel images but were suppressed by familiar stimuli and showed ramping activity when expected stimuli were omitted from a temporally predictable sequence. This prominent change in VIP activity suggests that these cells may adopt different modes of processing under novel versus familiar conditions.
Coinfinder: detecting significant associations and dissociations in pangenomes

The accessory genes of prokaryote and eukaryote pangenomes accumulate by horizontal gene transfer, differential gene loss, and the effects of selection and drift. We have developed Coinfinder, a software program that assesses whether sets of homologous genes (gene families) in pangenomes associate or dissociate with each other (i.e. are “coincident”) more often than would be expected by chance. Coinfinder employs a user-supplied phylogenetic tree in order to assess the lineage-dependence (i.e. the phylogenetic distribution) of each accessory gene, allowing Coinfinder to focus on coincident gene pairs whose joint presence is not simply because they happened to appear in the same clade, but rather that they tend to appear together more often than expected across the phylogeny. Coinfinder is implemented in C++, Python3, and R and is freely available under the GPU license from https://github.com/fwhelan/coinfinder. 3. Impact statement Coinfinder identifies genes that co-occur (associate) or avoid (dissociate) with each other across the accessory genomes of a pangenome of interest. Genes that associate or dissociate more often than expected by chance, suggests that those genes have a connection (attraction or repulsion) that is interesting to explore. Identification of these groups of genes will further the field’s understanding of the importance of accessory genes. Coinfinder is a freely available, open-source software which can identify gene patterns locally on a personal computer in a matter of hours. 4. Data summary Coinfinder is freely available at https://github.com/fwhelan/coinfinder. A list of the Identifiers of the genomes used within as well as all input/output files are available at https://github.com/fwhelan/coinfinder-manuscript. The authors confirm all supporting data, code and protocols have been provided within the article or through supplementary data files.
Optical and Nonlinear Properties of Photonic Polymer Nanocomposites and Holographic Gratings Modified with Noble Metal Nanoparticles

Nanocomposites based on transparent polymer matrices containing nanoparticles (NPs) of noble metals are modern-day materials that can be specially designed for photonics, linear and nonlinear optics, laser physics and sensing applications. We present the improved photosensitive nanocomposites doped with Au and Ag NPs allowing fabrication of high effective submicrometer dimensional diffraction structures using holographic method. A general approach for the fabrication of holographic structures using a two-component mixture of the monomers of different reactivity was developed. Two different methods, ex situ and in situ, were studied to introduce Au and Ag NPs in the polymer matrix. The diffusion model of the grating formation upon holographic exposure as well as the process of Ag NP synthesis in a polymer matrix is considered. The influence of the NP size on the polymerization process, material dynamic range and nonlinear properties were investigated. The mechanisms and characteristics of the nanocomposite nonlinear optical response are discussed.
Dog Ownership and Walking: Perceived and Audited Walkability and Activity Correlates

Few studies assess dog ownership and walking with both self-reported or perceived and audited or objective walkability and physical activity measures. Across two years, we examined both types of walkability and activity measures for residents living within 2km of a “complete street”—one renovated with light rails, bike lanes, and sidewalks. Audited walkability (Irvine–Minnesota Inventory) was more consistently related to dog ownership and walking groups than perceived walkability (Neighborhood Environment Walkability Scale—Abbreviated). Self-reported leisure walking was much higher (289–383 min per week) among dog walkers than among other groups (100–270 min per week), despite no difference in accelerometer-measured light or moderate-to-vigorous physical activity (MVPA). Furthermore, the most powerful difference between groups involved single-family detached home residence, which was much lower among non-dog-owners (44%) than among non-dog-walkers or dog walkers (81% and 70%, respectively). Given discrepancies across walkability and activity measures, we recommend future use of walkability audits and objectively measured physical activity over the current emphasis on self-report measures. We also urge greater attention to increased densities of housing, which may negatively affect dog ownership levels unless compensating supports for dog ownership and walking are created by public health messaging, dog-friendly policies, and dog-friendly housing and community design.