bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling and Simulation of Neocortical Micro- and Mesocircuitry. Part I: Anatomy
Authors: Reimann Michael W. , Bolaños-Puchet Sirio , Courcol Jean-Denis , Egas Santander Daniela , Arnaudon Alexis , Coste Benoît , Delalondre Fabien , Delemontex Thomas , Devresse Adrien , Dictus Hugo , Dietz Alexander , Ecker András , Favreau Cyrille , Ficarelli Gianluca , Gevaert Mike , Herttuainen Joni , Isbister James B. , Kanari Lida , Keller Daniel , King James , Kumbhar Pramod , Lapere Samuel , Lazovskis Jᾱnis , Lu Huanxiang , Ninin Nicolas , Pereira Fernando , Planas Judit , Pokorny Christoph , Riquelme Juan Luis , Romani Armando , Shi Ying , Smith Jason P. , Sood Vishal , Srivastava Mohit , Van Geit Werner , Vanherpe Liesbeth , Wolf Matthias , Levi Ran , Hess Kathryn , Schürmann Felix , Muller Eilif B. , Markram Henry , Ramaswamy Srikanth 
Published: August 2022

AbstractThe function of the neocortex is fundamentally determined by its repeating microcircuit motif, but also by its rich, interregional connectivity. We present a data-driven computational model of the anatomy of non-barrel primary somatosensory cortex of juvenile rat, integrating whole-brain scale data while providing cellular and subcellular specificity. The model consists of 4.2 million morphologically detailed neurons, placed in a digital brain atlas. They are connected by 14.2 billion synapses, comprising local, mid-range and extrinsic connectivity. We delineated the limits of determining connectivity from neuron morphology and placement, finding that it reproduces targeting by Sst+ neurons, but requires additional specificity to reproduce targeting by PV+ and VIP+ interneurons. Globally, connectivity was characterized by local clusters tied together through hub neurons in layer 5, demonstrating how local and interegional connectivity are complicit, inseparable networks. The model is suitable for simulation-based studies, and a 211,712 neuron subvolume is made openly available to the community.
Comparative analysis of drug-salt-polymer interactions by experiment and molecular simulation improves biopharmaceutical performance
Authors: Mukesh Sumit , Mukherjee Goutam , Singh Ridhima , Steenbuck Nathan , Demidova Carolina , Joshi Prachi , Sangamwar Abhay T. , Wade Rebecca C. 
Published: August 2022

AbstractThe propensity of poorly water-soluble drugs to aggregate at supersaturation impedes their bioavailability. The emergence of supersaturated amorphous drug-salt-polymer systems provides a new approach to this problem. However, the effects of polymers on drug-drug interactions in aqueous phase are largely unexplored and it is unclear how to choose an optimal salt-polymer combination for a particular drug. We describe a comparative experimental and computational characterization of amorphous solid dispersions containing the drug celecoxib, and PVP-VA or HPMCAS polymers with or without Na+/K+salts. Classical models for drug-polymer interactions fail to identify the best drug-salt-polymer combination. In contrast, more stable drug-polymer interaction energies computed from molecular dynamics simulations correlate with prolonged stability of supersaturated amorphous drug-salt-polymer systems, along with better dissolution and pharmacokinetic profiles. The celecoxib-salt-PVP-VA formulations exhibit excellent biopharmaceutical performance, offering the prospect of less frequent administration and lower doses of this widely used anti-inflammatory, thereby increasing cost-effectiveness, and reducing side-effects.
A stimulus-contingent positive feedback loop enables IFN-β dose-dependent activation of pro-inflammatory genes
Authors: Wilder Catera L. , Lefaudeux Diane , Mathenge Raisa , Kishimoto Kensei , Munoz Alma Zuniga , Nguyen Minh A. , Meyer Aaron S. , Cheng Quen J. , Hoffmann Alexander 
Published: August 2022

ABSTRACTType I interferons (IFN) induce powerful anti-viral and innate immune responses via the transcription factor, IFN-stimulated gene factor (ISGF3). However, in some pathological contexts type I IFNs are responsible for exacerbating inflammation. Here, we show that a high dose of IFN-β also activates an inflammatory gene expression program in contrast to IFN-λ3, a type III IFN, which elicits only the common anti-viral gene program. We show that the inflammatory gene program depends on a second, potentiated phase in ISGF3 activation. Iterating between mathematical modeling and experimental analysis we show that the ISGF3 activation network may engage a positive feedback loop with its subunits IRF9 and STAT2. This network motif mediates stimulus-specific ISGF3 dynamics that are dependent on ligand, dose, and duration of exposure, and when engaged activates the inflammatory gene expression program. Our results reveal a previously underappreciated dynamical control of the JAK-STAT/IRF signaling network that may produce distinct biological responses, and suggest that studies of type I IFN dysregulation, and in turn therapeutic remedies, may focus on feedback regulators within it.HIGHLIGHTSHigh dose IFN-β activates a pro-inflammatory gene program in epithelial cells.IFN-β, but not IFN-λ3, induces a second, potentiated phase in ISGF3 activity.ISGF3 induces its subunits to form a stimulus-contingent positive feedback loop.The positive feedback motif is required for the pro-inflammatory gene program.
DUnet: A deep learning guided protein-ligand binding pocket prediction
Authors: Wang Xinglong , Zhao Beichen , Yang Penghui , Tan Yameng , Ma Ruyi , Rao Shengqi , Du Jianhui , Chen Jian , Zhou Jingwen , Liu Song 
Published: August 2022

AbstractInvestigating protein-ligand binding sites is the key step in engineering protein/enzyme activity and selectivity. In this study, we developed a 3D convolutional neural network DUnet that derived from DenseNet and UNet for predicting the protein-ligand binding sites. To train DUnet, the features of protein 3D structure were extracted by describing the atomic physical characters, and the ligand binding sites were used as training labels. DUnet was trained using three dataset, the scPDB dataset (collecting of protein-ligand complexes from Protein Data Bank), scPDB and SC6K (collecting of protein-ligand complexes deposited after January 1st, 2018 from Protein Data Bank) datasets, and scPDB and its derived dataset by rotating the samples in the dataset. DUnet displayed better performance than the current state-of-art methods during the benchmark test using independent validation sets, and enlarging the training set contributed to better accuracy. We developed a small dataset contains commonly used industrial enzymes for testing DUnet and found that it was also accurate in predicting the substrate binding sites. We experimentally characterized the substrate binding sites of microbial transglutaminase according to the prediction and showed the significance of these sites. Finally, DUnet was used to predict the ligand binding sites of Swiss-Prot annotated proteins.
Proof of Concept: detection of cell free RNA from EDTA plasma in patients with lung cancer and non-cancer patients
Authors: Mullins Kristin E. , Seneviratne Chamindi , Shetty Amol C. , Jiang Feng , Christenson Robert , Stass Sanford 
Published: August 2022

ABSTRACTNucleic acid sequencing technologies have advanced significantly in recent years, allowing the development of liquid biopsies as new means to detect cancer biomarkers and cancer heterogenicity. Most of the assays available clinically focus on cell free DNA, however, cell free RNA (cfRNA) is also present and has the potential to complement and improve cancer detection especially in cancers like lung cancer, which are usually only diagnosed at late stages and therefore have poor long-term survival outcomes. Remnant EDTA plasma was collected from lung cancer patients and non-cancer individuals at the University of Maryland Medical Center. RNA was extracted and processed for next generation sequencing with a tagmentation-based library preparation approach. cfRNA was successfully extracted and sequenced from 52 EDTA-treated plasma samples with volumes as low as 1.5 mL. This quantity was sufficient to prepare libraries with the length of libraries averaging from 264bp to 381bp and resulted in over 2.2 to 3.6 million total sequence reads respectively. Sequential dilution of cfRNA samples from healthy individuals indicated that the starting cfRNA concentration influenced the detection of differentially expressed genes. This proof-of-concept study provides a framework for screening cfRNA for identifying biomarkers for early detection of lung cancer (and other cancers), using minimal amounts of samples (1.5 ml) from standard EDTA 3-mL collection tubes routinely used for patient care. Further studies in large populations are required to establish limit of detection and other parameters including precision, accuracy, sensitivity, and specificity, to standardize this method.
Unravelling habituation for COVID-19-related information: A panel data study in Japan
Authors: Fukui Shinya 
Published: August 2022

AbstractThis study examines people’s habituation to COVID-19-related information over almost three years. Using publicly available data from 47 Japanese prefectures, we analyse how human mobility responded to COVID-19-related information, such as the number of COVID-19-infected cases and the declaration of a state of emergency (DSE), using an interactive effects model, which is a type of panel data regression. The results show that Japanese citizens were generally fearful and cautious in the first wave of an unknown infection; however, they gradually became habituated to similar infection information during subsequent waves. Nevertheless, the level of habituation decreased in response to different types of infections, such as new variants. By contrast, regarding the DSE, it is more plausible to consider that human mobility responds to varying requests rather than habituate them. We also find spatial spillovers of infection information on human mobility using a spatial weight matrix included in the regression model. The implementation of flexible human mobility control policies by closely monitoring human mobility can prevent excessive or insufficient mobility control requests. Such a flexible policy can efficiently suppress infection spread and prevent economic activity reduction more than necessary. These implications are useful for evidence-based policymaking during future pandemics.
Efficacy of ultra-short, response-guided sofosbuvir and daclatasvir therapy for Hepatitis C: a single arm mechanistic pilot study
Authors: Flower Barnaby , Hung Le Manh , McCabe Leanne , Ansari M. Azim , Le Ngoc Chau , Vo Thi Thu , Vu Thi Kim Hang , Nguyen Thi Ngoc Phuong , Phuong Le Thanh , Quang Vo Minh , Trong Thuan Dang , Le Thi Thao , Bao Tran Nguyen , Kingsley Cherry , Smith David , Hoglund Richard M. , Tarning Joel , Kestelyn Evelyne , Pett Sarah L , van Doorn Rogier , van Nuil Jennifer Ilo , Turner Hugo , Thwaites Guy , Barnes Eleanor , Rahman Motiur , Walker Ann Sarah , Day Jeremy , Van Vinh Chau Nguyen , Cooke Graham S 
Published: August 2022

ABSTRACTBackgroundWHO has called for research into predictive factors for selecting persons who could be successfully treated with shorter durations of direct acting antiviral (DAA) therapy for Hepatitis C. We evaluated early virological response as a means of shortening treatment and explored host, viral and pharmacokinetic contributors to treatment outcome.MethodsDuration of sofosbuvir and daclatasvir (SOF/DCV) was determined according to day 2 (D2) virologic response for HCV genotype (gt) 1- or 6-infected adults in Vietnam with mild liver disease. Participants received 4 or 8 weeks treatment according to whether D2 HCV RNA was above or below 500 IU/ml (standard duration is 12 weeks). Primary endpoint was sustained virological response (SVR12). Those failing therapy were retreated with 12 weeks SOF/DCV. Host IFNL4 genotype and viral sequencing was performed at baseline, with repeat viral sequencing if virological rebound was observed. Levels of SOF, its inactive metabolite GS-331007 and DCV were measured on day 0 and 28.ResultsOf 52 adults enrolled, 34 received 4 weeks SOF/DCV, 17 got 8 weeks and one withdrew. SVR12 was achieved in 21/34 (62%) treated for 4 weeks, and 17/17 (100%) treated for 8 weeks. Overall 38/51 (75%) were cured with first-line treatment (mean duration 37 days). Despite a high prevalence of putative NS5A-inhibitor resistance associated substitutions (RAS), all first-line treatment failures cured after retreatment (13/13). We found no evidence treatment failure was associated with host IFNL4 genotype, viral subtype, baseline RAS or DCV levels. SOF metabolite levels were higher in those failing 4-week therapy.ConclusionsShortened SOF/DCV therapy, with retreatment if needed, reduces DAA use while maintaining high cure rates. D2 virologic response alone does not adequately predict SVR12 with 4 weeks treatment.FundingFunded by the Medical Research Council (grant MR/P025064/1) and The Global Challenges Research Fund (Wellcome Trust Grant 206/296/Z/17/Z).)Clinical trial numberISRCTN17100273
The role of vaccination and public awareness in medium-term forecasts of monkeypox incidence in the United Kingdom
Authors: Brand SPC , Cavallaro M , Hilton J , Guzman-Rincon LM , House T , Keeling MJ , Nokes DJ 
Published: August 2022

AbstractMonkeypox virus (MPXV) is spreading rapidly through close human-to-human contact primarily amongst communities of men-who-have-sex-with-men (MSM). Behavioural change arising from increased knowledge and health warnings may decelerate the rate of transmission and Vaccinia-based vaccination is likely to be an effective longer-term intervention. Here we investigate the current epidemic within the UK population and simulate control options over a 12 week projection using a stochastic discrete-population transmission model which includes MSM status, rate of formation of new sexual partners, and an underlying random sized metapopulation structure. We find that the virus may have already infected a significant proportion of the MSM group with the highest sexual activity (32.5%; 15.9% - 44.9% prediction IQR); the associated immunity, albeit among groups that form a small but sexually active part of the MSM community in the UK, coupled to behavioural driven decrease in the transmission rate of individuals infected with monkeypox, leads to case incidence flattening and then declining over the projection period (12 weeks). Vaccination is most beneficial when targeted to MSM with highest activity if delivered in the near term to further interrupt transmission amongst those driving the epidemic.
Cannabis, identity, and attitudes: a qualitative study in adolescents who do and do not use cannabis
Authors: Karashiali Christiana , Lawn Will , Petrilli Kat , Mokrysz Claire , Black Georgia 
Published: August 2022

AbstractBackground and objectiveCannabis use during adolescence is common. Cannabis use and identity are thought to influence one another. This study aimed to examine what London-based adolescents (aged 16-17 years) think about cannabis use, its relationships with identity, and its benefits and harms.MethodThree semi-structured focus groups interviews were conducted, two with adolescents who use cannabis (n=3 and n=5) and one with adolescents who do not use cannabis (n=6). Participants also completed a drug-use questionnaire.ResultsThematic analysis (TA) revealed four identities. Two identities emerged from both groups: ‘The person who uses cannabis is chilled’ and ‘The person who uses cannabis is sometimes ostracised’. Two identities emerged from the group of adolescents who used cannabis: ‘The person who uses cannabis is an expert in risky things’ and ‘The person who uses cannabis is not addicted’. Skunk was identified as potentially more harmful than hash, but more powerful and pleasurable.ConclusionThe findings provide insight into how cannabis use shape personal and social identity amongst teenagers in London in the late 2010s. Those who use cannabis described the benefits of cannabis, including socialising and for relaxation, and emphasised they are not addicted. Stigmatising and devaluing attitudes were held by some non-users about adolescents who use cannabis. Stereotypes seem to still exist, despite cannabis normalisation. Implications for research and policy are outlined.
Comparison of Structural Diagnosis and Management (SDM) approach and Myofascial Release (MFR) for improving planter heel pain, ankle range of motion and disability: A Randomized Clinical Trial
Authors: Akter Sapia , Hossain Mohammad Shahadat , Hossain K M Amran , Uddin Zakir , Hossain Mohammad Anwar , Alom Foisal , Kabir Md. Feroz , Walton Lori Maria , Raigangar Veena 
Published: August 2022

AbstractPurposeThis study compared the effect of Structural Diagnosis and Management (SDM) approach over Myofascial Release (MFR) on gastrocnemii, soleus and plantar fascia in patients with plantar heel pain.SubjectsSixty-four (n=64) subjects, aged 30-60 years, with a diagnosis of plantar heel pain, plantar fasciitis or calcaneal spur by a physician and according to ICD-10. Participants were equally allocated to MFR (n=32) and SDM (n=32) group by hospital randomization and concealed allocation.MethodsIn this assessor blinded randomized clinical trial, the control group performed MFR (three tissue specific stretching techniques) and the experimental group performed 2 tissue-specific interventions utilizing the Structural Diagnosis and Management (SDM) concept for 12 sessions over a 4-week period. In addition, both groups received strengthening exercises and other conventional treatments. Pain, activity limitations and disability were assessed as primary outcomes utilizing the foot function index (FFI) and range of motion (ROM) of the ankle dorsiflexors and plantar flexors were measured with a universal goniometer. Secondary outcomes were measured using the Foot Ankle Disability Index (FADI) and 10-point manual muscle testing process for the ankle dorsiflexors and plantar flexors.ResultBoth MFR and SDM groups exhibited significant improvements from baseline in all outcome variables, including: pain, activity level, disability, range of motion and function after the 12-week intervention period (p<.05), The SDM group showed more significant improvements than MFR for FFI pain (p=.001), FFI activity (p=.009), FFI (p= .001) and FADI (p=.002).ConclusionMFR and SDM approaches are both effective to reduce pain, improving function, ankle range of motion, and reduce disability in plantar heel pain. However, the SDM approach is significantly superior (for reducing pain, improving function and reducing disability (p<.05).
Revealing geographic transmission pattern of COVID-19 using neighborhood-level simulation with human mobility data and SEIR model: A Case Study of South Carolina
Authors: Ning Huan , Li Zhenlong , Qiao Shan , Zeng Chengbo , Zhang Jiajia , Olatosi Bankole , Li Xiaoming 
Published: August 2022

AbstractDirect human physical contact accelerates COVID-19 transmission. Smartphone mobility data has been an emerging data source to reveal fine-grained human mobility, which can be used to estimate the intensity of physical contact surrounding different locations. Our study applied smartphone mobility data to simulate the second wave spreading of COVID-19 in January 2021 in three major metropolitan statistical areas (Columbia, Greenville, and Charleston) in South Carolina, United States. Based on the simulation, the number of historical county-level COVID-19 cases was allocated to neighborhoods (Census blockgroups) and points of interest (POIs), and the transmission rate of each allocated place was estimated. The result reveals that the COVID-19 infections during the study period mainly occurred in neighborhoods (86%), and the number is approximately proportional to the neighborhood’s population. Restaurants and elementary and secondary schools contributed more COVID-19 infections than other POI categories. The simulation results for the coastal tourism Charleston area show high transmission rates in POIs related to travel and leisure activities. The results suggest that the neighborhood-level infectious controlling measures are critical in reducing COVID-19 infections. We also found that the households of lower socioeconomic status may be an umbrella against infection due to fewer visits to places such as malls and restaurants associated with their low financial status. Control measures should be tailored to different geographic locations since transmission rates and infection counts of POI categories vary among metropolitan areas.
Epidemiology of leprosy identified through active case detection in six districts of Nepal
Authors: Mahato Ram Kumar , Ghimire Uttam , Lamsal Madhav , Bajracharya Bijay , Poudel Mukesh , Naapit Prashanna , Lama Krishna , Dahal Gokarna , Hayman David TS , Karna Ajit Kumar , Pandey Basudev , Das Chuman Lal , Paudel Krishna Prasad 
Published: August 2022

AbstractBackgroundNepal has achieved and sustained elimination of leprosy as a public health problem since 2009, but 17 districts and 3 provinces have yet to eliminate the disease. Pediatric cases and grade-2 disabilities (G2D) indicate recent transmission and late diagnosis respectively, which necessitate active and early case detection. This operational research was performed to identify approaches best suited for early case detection, determine community-based leprosy epidemiology, and identify hidden leprosy cases early and respond with prompt treatment.MethodsActive case detection was performed by: house-to-house visits among vulnerable populations (n=26,469), contact examination and tracing (n=7,608) and screening prison populations (n=4,428) in Siraha, Bardiya, Rautahat, Banke, Lalitpur and Kathmandu districts of Nepal.ResultsNew case detection rates were highest for contact tracing (250), followed by house-to-house visits (102) and prison screening (45) per 100,000 population screened. However, cost per case identified was cheapest for house-to-house visits (Nepalese rupee (NPR) 76,500/case), then contact tracing (NPR90,286/case) and prison screening (NPR298,300/case). House-to-house and contact tracing case paucibacillary/multibacillary (PB:MB) ratios were 59:41 and 68:32; female/male ratios 63:37 and 57:43; pediatric cases 11% in both approaches; and G2D 11% and 5% respectively. Developing leprosy was similar among household and neighbor contacts (Odds ratios (OR)=1.4, 95% confidence interval (CI), 0.24-5.85) and for contacts of MB versus PB cases (OR=0.7, 0.26-2.0). Attack rates were similar among household contacts of MB cases (0.32%, 0.07-0.94%) and PB cases (0.13%, 0.03-0.73) and neighbor contacts of MB cases (0.23%, 0.1-0.46) and PB cases (0.48%, 0.19-0.98). BCG vaccination with scar presence had a significant protective effect against leprosy (OR=0.42, 0.22-0.81).ConclusionsThe most effective case identification approach here is contact tracing, followed by house-to-house visits in vulnerable populations and screening in prisons, though house-to-house visits were cheaper. The findings suggest hidden cases, recent transmission, and late diagnosis in the community exist and highlight the importance of early case detection.