bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19 transmission in a theme-park
Authors: Aruffo Elena , Athar Safia , Raad Angie , Ali Md Afsar , Althubyani Mohammed , Chow Christopher , Ruma Mahmuda , Liu Chao , Wu Jianhong , Asgary Ali , Kong Jude D. , Heffernan Jane M.
Published: April 2021

Background

As COVID-19 vaccination coverage increases, public health and industries are contemplating re-opening measures of public spaces, including theme-parks. To re-open, theme-parks must provide public health mitigation plans. Questions on implementation of public health mitigation strategies such as park cleaning, COVID-19 testing, and enforcement of social distancing and the wearing of personal protective equipment (PPE) in the park remain.

Methods

We have developed a mathematical model of COVID-19 transmission in a theme-park that considers direct human-human and indirect environment-human transmission of the virus. The model thus tracks the changing infection/disease landscape of all visitors, workers, and environmental reservoirs in a theme park setting.

Findings

Models results show that theme-park public health mitigation must include mechanisms that reduce virus contamination of the environment to ensure that workers and visitors are protected from COVID-19 transmission in the park. Thus, cleaning rates and mitigation of human-environment contact increases in importance.

Conclusion

Our findings have important practical implications in terms of public health as policy- and decision-makers are equipped with a mathematical tool that can guide theme-parks in developing public health mitigation strategies for a safe re-opening.
The relationship between human mobility measures and SAR-Cov-2 transmission varies by epidemic phase and urbanicity: results from the United States
Authors: Kishore Nishant , Taylor Aimee R. , Jacob Pierre E. , Vembar Navin , Cohen Ted , Buckee Caroline O. , Menzies Nicolas A.
Published: April 2021

Global efforts to prevent the spread of the SARS-COV-2 pandemic in early 2020 focused on non-pharmaceutical interventions like social distancing; policies that aim to reduce transmission by changing mixing patterns between people. As countries have implemented these interventions, aggregated location data from mobile phones have become an important source of real-time information about human mobility and behavioral changes on a population level. Human activity measured using mobile phones reflects the aggregate behavior of a subset of people, and although metrics of mobility are related to contact patterns between people that spread the coronavirus, they do not provide a direct measure. In this study, we use results from a nowcasting approach from 1,396 counties across the US between January 22nd, 2020 and July 9th, 2020 to determine the effective reproductive number (R(t)) along an urban/rural gradient. For each county, we compare the time series of R(t) values with mobility proxies from mobile phone data from Camber Systems, an aggregator of mobility data from various providers in the United States. We show that the reproduction number is most strongly associated with mobility proxies for change in the travel into counties compared to baseline, but that the relationship weakens considerably after the initial 15 weeks of the epidemic, consistent with the emergence of a more complex ecosystem of local policies and behaviors including masking. Importantly, we highlight potential issues in the data generation process, representativeness and equity of access which must be addressed to allow for general use of these data in public health.
Are epidemic growth rates more informative than reproduction numbers?
Authors: Parag Kris V , Thompson Robin N , Donnelly Christl A
Published: April 2021

Summary statistics, often derived from simplified models of epidemic spread, inform public health policy in real time. The instantaneous reproduction number,Rt, is predominant among these statistics, measuring the average ability of an infection to multiply. However,Rtencodes no temporal information and is sensitive to modelling assumptions. Consequently, some have proposed the epidemic growth rate,rt, i.e., the rate of change of the log-transformed case incidence, as a more temporally meaningful and model-agnostic policy guide. We examine this assertion, identifying if and when estimates ofrtare more informative than those ofRt. We assess their relative strengths both for learning about pathogen transmission mechanisms and for guiding public health interventions in real time.
Amerind ancestry predicts the impact of FADS genetic variation on omega-3 PUFA deficiency, cardiometabolic and inflammatory risk in Hispanic populations
Authors: Yang Chaojie , Hallmark Brian , Chai Jin Choul , O’Connor Timothy D. , Reynolds Lindsay M , Wood Alexis C , Seeds Michael , Chen Yii-Der Ida , Steffen Lyn M , Tsai Michael Y , Kaplan Robert C. , Daviglus Martha L. , Mandarino Lawrence J. , Fretts Amanda M. , Lemaitre Rozenn N , Coletta Dawn K. , Blomquist Sarah A. , Johnstone Laurel M. , Tontsch Chandra , Qi Qibin , Ruczinski Ingo , Rich Stephen S , Mathias Rasika A , Chilton Floyd H , Manichaikul Ani
Published: April 2021

Hispanic populations have higher rates of obesity, elevated triglycerides, and a greater prevalence of diabetes. Long chain polyunsaturated fatty acids (LC-PUFAs) and LC-PUFA metabolites have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS cluster accounts for a large part of the interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind (AI) ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation, plasma phospholipid levels of LC-PUFAs, anthropometric measures, and circulating metabolic and inflammatory biomarkers in 1,102 Hispanic American participants, representing six distinct ancestry populations from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between AI genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. We further replicated the association with circulating TGs in two additional Hispanic cohorts: the Hispanic Community Health Study/Study of Latinos and the Arizona Insulin Resistance Registry. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk.
Post-treatment downregulation of type III interferons in patients with acute Brucellosis
Authors: Shokri Mehran , Khonakdar Oreinab Ghaffari , Mohammadnia-Afrouzi Mousa , Sadeghi-Haddad-Zavareh Mahmoud , Hasanpour Amirhossein , Barary Mohammad , Ebrahimpour Soheil
Published: April 2021

There is a limited number of clinical studies on interferon (IFN) levels in human brucellosis. The novel group of interferons, type III interferons, consists of four IFN-λ (lambda) molecules called IFN-λ1 or Interleukin-29 (IL-29), IFN-λ2 or IL-28A, IFN-λ3 or IL-28B, and IFN-λ4, are not fully known. This study is one of the first studies of IL-28A and IL-29 levels in Brucellosis cases at the end of their treatment course. A total of 33 acute Brucellosis patients were included in this study. We considered changes in the levels of IL-28A and IL-29 in cases with acute brucellosis before and after treatment with standard therapy that referred to the Ayatollah Rohani Hospital in Babol, Northern Iran. Serum IL-29 and IL-28A (acute form: 56.4 ± 30.32 and 48.73 ± 27.72, respectively, and post-treatment: 40.15 ± 20.30 and 38.79 ± 22.66, respectively) levels were elevated significantly in acute brucellosis than after treatment (p ≤ 0.05). These findings indicate that considering biomarker levels in Brucellosis patients may be indicative of the chronicity of infection. In conclusion, we suggest that IL-29 and IL-28A levels may be valuable biomarkers for follow-up patients with brucellosis.
INTRANASAL APPLICATION OFLACTOCOCCUS LACTIS W 136BACTERIA EARLY IN SARS-Cov-2 INFECTION MAY HAVE A BENEFICIAL IMMUNOMODULATORY EFFECT: A PROOF-OF-CONCEPT STUDY
Authors: Endam Leandra Mfuna , Tremblay Cécile , Filali Ali , Desrosiers Martin Yvon
Published: April 2021

Justification

Stimulation of early innate anti-viral responses during the early phase of SARS-COV-2 infection oxygen may improve evolution of illness and late pulmonary complications. This may be possible using a TLR agonist such as a probiotic bacterium possessing desirable immunomodulatory properties.

Method

We performed a non-contact, open-label, prospective randomized clinical trial comparing intranasally appliedLactococcus lactis W136with saline irrigation alone in patients within 96 hours of diagnosis of SARS-COV-2 infection not requiring supplemental oxygen.

Results

Twenty-three of a planned forty participants aged 18-59 without comorbidities were recruited. Irrigation with intranasalL lactis W136twice-daily for fourteen days of was associated with a nasal response characterised by increase in the symptom of Facial and Throat pain/discomfort, and with a lesser severity in symptoms of i) Fatigue ii) Olfactory dysfunction and iii) Breathlessness. Safety and tolerability were good, with no acute infections or severe deteriorations.

Interpretation

Facial and throat pain may correspond to postulated mechanism of action corresponding to activation of innate defences with antiviral effects and may explain the potentially protective effects seen. IntranasalL lactis W136irrigations may thus represent a potentially inexpensive, safe, and easily scalable non-antigen based therapeutic for the continuing global SARS-COV-2 pandemic.

Data availability statement

Data is available on request from the senior author, Dr Desrosiers:martin-yvon.desrosiers.med@ssss.gouv.qc.ca

Funding

This work was supported with internal funds from the Desrosiers laboratory at the Centre de Recherche du Centre Hospitaller de l’Université de Montreal (CRCHUM).

Competing Interests

Dr Desrosiers holds equity in Probionase Therapies inc., Which commercialisesLactococcus lactis W136for chronic rhinosinusitis.
Study Pre-protocol for “BronchStart - The Impact of the COVID-19 Pandemic on the Timing, Age and Severity of Respiratory Syncytial Virus (RSV) Emergency Presentations; a Multi-Centre Prospective Observational Cohort Study”
Authors: Williams Thomas C. , Lyttle Mark D , Cunningham Steve , Sinha Ian , Swann Olivia , Maxwell-Hodkinson Abigail , Roland Damian
Published: April 2021

Background

Bronchiolitis (most frequently caused by Respiratory Syncytial Virus; RSV) is a common winter disease predominantly affecting children under one year of age. It is a common reason for presentations to an Emergency Department (ED) and frequently results in hospital admission, contributing to paediatric units approaching or exceeding capacity each winter. During the SARS-CoV-2 pandemic, the circulation of RSV was dramatically reduced in the United Kingdom and Ireland. Evidence from the Southern Hemisphere and other European countries suggests that as social distancing restrictions for SARS-CoV-2 are relaxed, RSV infection returns, causing delayed or even summer epidemics, with different age distributions.

Study question

The ability to track, anticipate and respond to a surge in RSV cases is critical for planning acute care delivery. There is an urgent need to understand the onset of RSV spread at the earliest opportunity. This will influence service planning, to inform clinicians whether the population at risk is a wider age range than normal, and whether there are changes in disease severity. This information is also needed to inform decision on the timing of passive immunisation of children at higher risk of hospitalisation, intensive care admission or death with RSV infection, which is a public health priority.

Methods and likely impact

This multi-centre prospective observational cohort study will use a well-established research network (Paediatric Emergency Research in the UK and Ireland, PERUKI) to report in real time cases of RSV infection in children aged under two years, through the collection of essential, but non-identifying patient information. Forty centres will gather initial data on age, index of multiple deprivation quintile, clinical features on presentation, and co-morbidities. Each case will be followed up at 7 days to identify treatment, viral diagnosis and outcome. Information be released on a weekly basis and used to support clinical decision making.
Wood ants express uncertainty when engaging with magnetic cues for directional guidance
Authors: Collett Thomas S. , Philippides Andrew O.
Published: April 2021

Wood ants were trained indoors to follow a route in a chosen magnetic direction from the centre of a small, circular arena to find a drop of sucrose at the edge. The arena, surrounded by a white cylindrical wall, was in the centre of a 3D coil system that generated an inclined Earth strength magnetic field in any horizontal direction. Between trials, the chosen magnetic training direction was rotated to a new orientation. Tests were given without food and with fresh or reversed paper on the floor of the arena. In a significant number of tests, ants left the centre facing the goal, or in the opposite direction, but they mostly failed to reach the goal. Tests given early in the day, before any training, show that ants remember the magnetic route direction overnight. On some training trials, the position of the sucrose was also indicated by a black stripe. Not uncommonly, ants first moved in the opposite direction to the stripe before switching to the correct direction. Travel away from the reward seems to express the ant’s uncertainty about the correct path to take. Tests show that this uncertainty may stem from competing directional cues linked to the room, suggesting that ants are reluctant to rely on magnetic information alone. We conclude that ants can remember a route direction defined by an Earth-strength magnetic field and that they express any uncertainty about the correct direction by moving for a stretch in the opposite direction. In a second experiment, an upright and an inverted triangle were fixed 90° from each other to the inside of the cylinder. Sucrose was placed beneath one of the triangles, dependent on the direction of the magnetic field. Ants failed to master this task and to approach the magnetically cued triangle. Instead, they preferred to approach the upright triangle. The ants were again uncertain of the correct direction and expressed this uncertainty through paths that had segments directed towards both the inverted and the upright triangles.
Dimensionality reduction for neural population decoding
Authors: Heller Charles R. , David Stephen V.
Published: April 2021

Rapidly developing technology for large scale neural recordings has allowed researchers to measure the activity of hundreds to thousands of neurons at single cell resolutionin vivo. Neural decoding analyses are a widely used tool used for investigating what information is represented in this complex, high-dimensional neural population activity. Most population decoding methods assume that correlated activity between neurons has been estimated accurately. In practice, this requires large amounts of data, both across observations and across neurons. Unfortunately, most experiments are fundamentally constrained by practical variables that limit the number of times the neural population can be observed under a single stimulus and/or behavior condition. Therefore, new analytical tools are required to study neural population coding while taking into account these limitations. Here, we present a simple and interpretable method for dimensionality reduction that allows neural decoding metrics to be calculated reliably, even when experimental trial numbers are limited. We illustrate the method using simulations and compare its performance to standard approaches for dimensionality reduction and decoding by applying it to single-unit electrophysiological data collected from auditory cortex.
Identification of Key Pathways and Genes in Dementia via Integrated Bioinformatics Analysis
Authors: Vastrad Basavaraj , Vastrad Chanabasayya
Published: April 2021

To provide a better understanding of dementia at the molecular level, this study aimed to identify the genes and key pathways associated with dementia by using integrated bioinformatics analysis. Based on the expression profiling by high throughput sequencing dataset GSE153960 derived from the Gene Expression Omnibus (GEO), the differentially expressed genes (DEGs) between patients with dementia and healthy controls were identified. With DEGs, we performed a series of functional enrichment analyses. Then, a protein–protein interaction (PPI) network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network was constructed, analyzed and visualized, with which the hub genes miRNAs and TFs nodes were screened out. Finally, validation of hub genes was performed by using receiver operating characteristic curve (ROC) analysis. A total of 948 DEGs were screened out, among which 475 genes were up regulated; while 473 were down regulated. Functional enrichment analyses indicated that DEGs were mainly involved in defense response, ion transport, neutrophil degranulation and neuronal system. The hub genes (CDK1, TOP2A, MAD2L1, RSL24D1, CDKN1A, NOTCH3, MYB, PWP2, WNT7B and HSPA12B) were identified from PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network. We identified a series of key genes along with the pathways that were most closely related with dementia initiation and progression. Our results provide a more detailed molecular mechanism for the advancement of dementia, shedding light on the potential biomarkers and therapeutic targets.
Early treatment with nitazoxanide prevents worsening of mild and moderate COVID-19 and subsequent hospitalization
Authors: Rossignol Jean-François , Matthew C. Bardin , Oaks Joshua B. , Bostick B. Gregory , Vora Kishor N. , Fulgencio Jessica , Mogelnicki Dena , Bréchot Christian ,   Vanguard Study Group
Published: April 2021

Background

There is an urgent need for treatments to prevent the progression to severe COVID-19 and hospitalization.

Methods

A randomized double-blind placebo-controlled clinical trial in 36 centers in the U.S. and Puerto Rico investigated the safety and effectiveness of oral nitazoxanide 600 mg twice daily for 5 days in outpatients with symptoms of mild or moderate COVID-19 enrolled within 72 hours of symptom onset. Key objectives were reduction of duration of symptoms (primary) and progression to severe illness (key secondary).

Results

1,092 subjects were enrolled, and 379 with laboratory-confirmed SARS-CoV-2 infection were analyzed. Overall, times to sustained clinical recovery were similar for the two arms. Nitazoxanide treatment was associated with an 85% reduction in the progression to severe COVID-19 (1/184, [0.5%] vs. 7/195, [3.6%], p=0.07) and 82% reduction in the rate of hospitalization, emergency room visit or death (1/184 [0.5%] vs. 6/195 [3.1%], p=0.12). In subjects with mild illness at baseline, treatment was also associated with a 3.1-day reduction in median time to sustained clinical recovery and a 5.2-day reduction in time to return to usual health. Nitazoxanide was safe and well tolerated.

Conclusions

Treatment of mild or moderate COVID-19 with a five-day course of oral nitazoxanide was safe and well tolerated and was associated with an 85% reduction in the progression to severe illness and a 3- to 5-day reduction of the duration of mild illness.
Silver diamine fluoride, atraumatic restorations, and oral health-related quality of life - Results from the CariedAway cluster randomized trial
Authors: Ruff Ryan Richard , Barry Godín Tamarinda J. , Small Topaz Murray , Niederman Richard
Published: April 2021

Objective

Silver diamine fluoride (SDF) is a non-surgical treatment for the arrest and prevention of dental caries that results in irreversible black staining of dental decay. The objective of this study was to evaluate the impact of SDF treatment on oral health-related quality of life (OHRQoL) relative to a standard package of glass ionomer sealants and atraumatic restorative treatment.

Methods

CariedAway is a pragmatic, longitudinal, cluster-randomized non-inferiority trial of non-surgical interventions for caries. Secondary study outcomes included OHRQoL and academic performance. Oral health-related quality of life was measured at each study visit using the Child Oral Health Impact Profile. Change in OHRQoL was assessed using linear regression and non-inferiority was determined using t-tests.

Results

Untreated decay at baseline was associated with signifcantly worse ORHQoL and treatment in both groups resulted in incremental improvement. Quality of life in children receiving silver diamine fluoride was non-inferior to those receiving sealants and ART at least six months post-treatment. Additionally, change in OHRQoL did not depend on the severity of baseline decay.

Conclusions

ORHQoL is related to untreated dental caries, however no appreciable change was observed following SDF treatment relative to standard preventive therapies.
Identification of Key Influencers for Secondary Distribution of HIV Self-Testing among Chinese MSM: A Machine Learning Approach
Authors: Jing Fengshi , Ye Yang , Zhou Yi , Ni Yuxin , Yan Xumeng , Lu Ying , Ong Jason J , Tucker Joseph D , Wu Dan , Xiong Yuan , Xu Chen , He Xi , Huang Shanzi , Li Xiaofeng , Jiang Hongbo , Wang Cheng , Dai Wencan , Huang Liqun , Mei Wenhua , Cheng Weibin , Zhang Qingpeng , Tang Weiming
Published: April 2021

Background

HIV self-testing (HIVST) has been rapidly scaled up and additional strategies further expand testing uptake. Secondary distribution has people (indexes) apply for multiple kits and pass these kits to people (alters) in their social networks. However, identifying key influencers is difficult. This study aimed to develop an innovative ensemble machine learning approach to identify key influencers among Chinese men who have sex with men (MSM) for HIVST secondary distribution.

Method

We defined three types of key influencers: 1) key distributors who can distribute more kits; 2) key promoters who can contribute to finding first-time testing alters; 3) key detectors who can help to find positive alters. Four machine learning models (logistic regression, support vector machine, decision tree, random forest) were trained to identify key influencers. An ensemble learning algorithm was adopted to combine these four models. Simulation experiments were run to validate our approach.

Results

309 indexes distributed kits to 269 alters. Our approach outperformed human identification (self-reported scales cut-off), exceeding by an average accuracy of 11·0%, could distribute 18·2% (95%CI: 9·9%-26·5%) more kits, find 13·6% (95%CI: 1·9%-25·3%) more first-time testing alters and 12·0% (95%CI: -14·7%-38·7%) more positive-testing alters. Our approach could also increase simulated intervention efficiency by 17·7% (95%CI: -3·5%-38·8%) than human identification.

Conclusion

We built machine learning models to identify key influencers among Chinese MSM who were more likely to engage in HIVST secondary distribution.

Key Findings (can also be found in Figure.2-Infographic)

Our proposed ensemble machine learning approach outperformed human identification (self-reported scales cut-off) in accuracy & F1 by classification metrics and in intervention efficiency by simulation experiments. Our model could also distribute more kits, find more first-time/positive-testing alters than human identification.
CFHloss in human RPE cells leads to inflammation and complement system dysregulationviathe NF-κB pathway
Authors: Armento Angela , Schmidt Tiziana L , Sonntag Inga , Merle David , Jarboui Mohamed Ali , Kilger Ellen , Clark Simon J. , Ueffing Marius
Published: April 2021

Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease and chronic inflammatory processes may be involved. Besides ageing and lifestyle factors as drivers of AMD, a strong genetic association to AMD is found in genes of the complement system, with a single polymorphism in the complement factor H gene (CFH), accounting for the majority of AMD risk. However, the exact mechanism by whichCFHdysregulation confers such a great risk for AMD and its role in RPE cells homeostasis is unclear. To explore the role of endogenousCFHlocally in RPE cells, we silencedCFHin human hTERT-RPE1 cells. We demonstrate that endogenously expressedCFHin RPE cells modulates inflammatory cytokine production and complement regulation, independent of external complement sources or stressors. We show that loss of the factor H protein (FH) results in increased levels of inflammatory mediators (e.g. IL-6, IL-8, GM-CSF) and altered levels of complement proteins (e.g. C3, CFBupregulation andC5downregulation) that are known to play a role in AMD. Moreover, we identified the NF-κB pathway as the major pathway involved in the regulation of these inflammatory and complement factors. Our findings suggest that in RPE cells, FH and the NF-κB pathway work in synergy to maintain inflammatory and complement balance and in case either one of them is dysregulated, the RPE microenvironment changes towards a pro-inflammatory AMD-like phenotype.
Perfecting and extending the near-infrared biological window
Authors: Feng Zhe , Tang Tao , Wu Tianxiang , Yu Xiaoming , Zhang Yuhuang , Wang Meng , Zheng Junyan , Ying Yanyun , Chen Siyi , Zhou Jing , Fan Xiaoxiao , Li Shengliang , Zhang Mingxi , Qian Jun
Published: April 2021

In vivofluorescence imaging in the second near-infrared window (NIR-II) has been considered as a promising technique for visualizing the mammals. However, the definition of the NIR-II region and the mechanism accounting for the excellent performance still need to be perfected. Herein, we simulated bioimaging in the NIR spectral range (to 2340 nm), confirmed the positive contribution of moderate light absorption by water in intravital imaging and perfected the NIR-II window as 900-1880 nm, where the 1400-1500 nm was defined as NIR-IIx region and the 1700-1880 nm was defined as NIR-IIc region, respectively. Moreover, the 2080-2340 nm was newly proposed as the third near-infrared (NIR-III) window, which was believed to provide the best imaging quality. The wide-field fluorescence microscopy in brain, in addition, was performed around NIR-IIx region with excellent optical sectioning strength and the largest imaging depth of in vivo NIR-II fluorescence microscopy to date. We also proposed 1400 nm long-pass detection in off-peak NIR-II imaging whose profits exceeded those of NIR-IIb imaging, using bright fluorophores with short peak emission wavelength.
An Evaluation of Curriculum change in Physiology: A Mixed method research design
Authors: Teli Shivayogappa. S. , M. Senthil velou , K. Soundariya , Velusami Deepika , K Senthamil selvi , S Mangani Mangalavalli
Published: April 2021

Introduction

The quality of both teaching and learning techniques in health sciences determines the competency of the doctors produced and the patient care. Realizing the necessity of active learning at the undergraduate level, curricular reforms were crucial to ensure that students play an active role in the learning process and imbibe all the prerequisite qualities of a competent health professional. The objective of this study was to implement and evaluate case-based learning in the physiology curriculum.

Methods

The study included 150 first-year MBBS students. We followed a mixed research design in this study. A short lecture on anemia was followed by two sessions of CBL with a gap of one week. A structured questionnaire on a 5-point Likert scale was used to collect students’ perceptions. The internal consistency of the questionnaire was Cronbach α-statistic = 0.8. Faculties’ feedback was collected through Focus Group Discussion (FGD).

Results

Out of 145 participants, 117 responded to feedback. Students perceived that the CBL method was effective in understanding anemia topic (71%); promoted meaningful learning (83%); encouraged teamwork (69%); improved communication skills (65%); helps in future application of knowledge (81%); motivated self-directed learning (66%); helped to understand physiology concepts better (72%); leads to the development of problem-solving abilities (70%); and better student-teacher relationship (72%). Faculties suggested developing an assessment plan for future CBL sessions.

Conclusion

In our experience, CBL is an effective, active teaching-learning tool that improves students’ understanding of basic concepts, clinical knowledge, problem-solving abilities, teamwork, communication skills, student-teacher relationship, and self-directed learning.
Positive modulation of cerebellar α6GABAAreceptors for treating essential tremor: a proof-of-concept study in harmaline-treated mice
Authors: Huang Ya-Hsien , Lee Ming Tatt , Sieghart Werner , Knutson Daniel E. , Wimmer Laurin R. , Sharmin Dishary , Cook James , Mihovilovic Marko D. , Chiou Lih-Chu
Published: April 2021

Background

The etiology of essential tremor (ET) remains unclear but may involve abnormal firing of Purkinje cells, which receive excitatory inputs from granule cells in the cerebellum. Since α6 subunit-containing GABAAreceptors (α6GABAARs) are abundantly expressed in granule cells, we validated a hypothesis that α6GABAAR-selective positive allosteric modulators (PAMs) are promising pharmacological interventions for ET therapy.

Methods

Employing the harmaline-induced ET model in male ICR mice, we evaluated the possible anti-tremor effects of four α6GABAAR-selective PAMs, the pyrazoloquinolinones Compound 6 and LAU-463 and their respective deuterated derivatives. Propranolol, a clinical anti-tremor agent, was employed as positive control. To investigate the involvement of cerebellar α6GABAARs in the antitremor effect of intraperitoneal (i.p.) Compound 6, furosemide, an α6GABAAR antagonist, was intracerebellarly (i.cb.) co-administered with Compound 6. The burrowing activity, an indicator of wellbeing in rodents, was measured concurrently.

Results

Harmaline (10-30 mg/kg,s.c.) induced action tremor in ICR mice dose-dependently and markedly reduced their burrowing activity. Compound 6 (3 and 10 mg/kg,i.p.) significantly attenuated harmaline (20 mg/kg)-induced action tremor and burrowing activity impairment. Propranolol (20 mg/kg,i.p.) diminished tremor but failed to restore the burrowing activity in harmaline-treated mice. Importantly, both anti-tremor and burrowing activity restorative effects of Compound 6 (10 mg/kg,i.p.) was significantly reversed by co-administration ofi.cb.furosemide at a dose (10 nmol/0.5 μl) having no effectper se. All four α6GABAAR PAMs exhibited a similar therapeutic efficacy.

Conclusion

α6GABAAR-selective PAMs significantly attenuated action tremor and restored physical well-being in a mouse model mimicking ET by acting in the cerebellum. Thus, α6GABAAR-selective PAMs may be potential therapeutic agents for ET.
Controlled Fluorescent Labelling of Metal Oxide Nanoparticles for Artefact-free Live Cell Microscopy
Authors: Kokot Boštjan , Kokot Hana , Umek Polona , van Midden Katarina Petra , Pajk Stane , Garvas Maja , Eggeling Christian , Koklič Tilen , Urbančič Iztok , Štrancar Janez
Published: April 2021

Nanotechnologies hold great promise for various applications. To predict and guarantee the safety of novel nanomaterials, it is essential to understand their mechanism of action in an organism, causally connecting adverse outcomes with early molecular events. They are best investigated using non-invasive advanced optical methods, such as high-resolution live-cell fluorescence microscopy, which require stable labelling of nanoparticles with fluorescent dyes. When performed inadequately, unbound fluorophores and inadvertently altered chemical and physical properties of the nanoparticles can, however, result in experimental artefacts and erroneous conclusions.

To prevent such unintentional errors, we here describe a minimal combination of experimental methods to enable artefact-free fluorescent labelling of metal-oxide nanoparticles – the largest subpopulation of nanoparticles by industrial production and applications – and demonstrate its application in the case of TiO2nanotubes. We 1) characterize potential changes of the nanoparticles’ surface charge and morphology that might occur during labelling, and 2) assess stable binding of the fluorescent dye to nanomaterial, which ensures correct nanoparticle localization. Together, these steps warrant the reliability and reproducibility of advanced optical tracking, which is necessary to explore nanomaterials’ mechanism of action and will foster widespread and safe use of new nanomaterials.

Abstract Figure
Cytosolic fumarase acts as a metabolic fail-safe for both high and low temperature acclimation ofArabidopsis thaliana
Authors: Herrmann Helena A. , Calzadilla Pablo I. , Schwartz Jean-Marc , Johnson Giles N.
Published: April 2021

Plants acclimate their photosynthetic capacity in response to changing environmental conditions. InArabidopsis thaliana,photosynthetic acclimation to cold requires the accumulation of the organic acid fumarate, catalysed by a cytosolic fumarase FUM2. However, the role of this accumulation is currently unknown. In this study, we use an integrated experimental and modelling approach to examine the role of FUM2 and fumarate across the physiological temperature range. Using physiological and biochemical analyses, we demonstrate that FUM2 is necessary for high as well as low temperature acclimation. We have adapted a reliability engineering technique, Failure Mode and Effect Analysis (FMEA), to formalize a rigorous approach for ranking metabolites according to the potential risk that they pose to the metabolic system. FMEA identifies fumarate as a low-risk metabolite, while its precursor, malate, is shown to be high-risk and liable to cause system instability. We conclude that the role of cytosolic fumarase, FUM2, is to provide a fail-safe, controlling malate concentration, maintaining system stability in a changing environment. We argue that FMEA is a technique that is not only useful in understanding plant metabolism but can also be used to study reliability in other systems and synthetic pathways.
Origin and diversification of fibroblasts from the sclerotome in zebrafish
Authors: Ma Roger C. , Kocha Katrinka M. , Méndez-Olivos Emilio E. , Ruel Tyler D. , Huang Peng
Published: April 2021

Fibroblasts play an important role in maintaining tissue integrity by secreting components of the extracellular matrix and initiating response to injury. Although the function of fibroblasts has been extensively studied in adults, the embryonic origin and diversification of different fibroblast subtypes during development remain largely unexplored. Using zebrafish as a model, we show that the sclerotome, a sub-compartment of the somite, is the embryonic source of multiple fibroblast subtypes including tenocytes (tendon fibroblasts), blood vessel associated fibroblasts, fin mesenchymal cells, and interstitial fibroblasts. High-resolution imaging shows that different fibroblast subtypes occupy unique anatomical locations with distinct morphologies. Long-term Cre-mediated lineage tracing reveals that the sclerotome also contributes to cells closely associated with the axial skeleton. Ablation of sclerotome progenitors results in extensive skeletal defects. Using photoconversion-based cell lineage analysis, we find that sclerotome progenitors at different dorsal-ventral and anterior-posterior positions display distinct differentiation potentials. Single-cell clonal analysis combined with in vivo imaging suggests that the sclerotome mostly contains unipotent and bipotent progenitors prior to cell migration, and the fate of their daughter cells is biased by their migration paths and relative positions. Together, our work demonstrates that the sclerotome is the embryonic source of trunk fibroblasts as well as the axial skeleton, and local signals likely contribute to the diversification of distinct fibroblast subtypes.
The mouse papillomavirus epigenetic signature is characterised by DNA hypermethylation after lesion regression
Authors: Tschirley Allison M. , Stockwell Peter A. , Rodger Euan J. , Eltherington Oliver , Morison Ian M. , Christensen Neil , Chatterjee Aniruddha , Hibma Merilyn
Published: April 2021

The β genus of human papillomaviruses (HPVs) infect cutaneous epidermis. They contribute to the development of cutaneous squamous cell carcinoma (cSCC) in individuals with epidermodysplasia verruciformis, and increase susceptibility to UV-induced cSCC. This has been demonstrated in UV-exposed mice previously infected with mouse papillomavirus (MmuPV1). However, the mechanism by which β-HPVs contribute to cSCC is unclear. We propose that viral infection leaves a DNA methylation signature following resolution of the active lesion that may contribute to increased susceptibility to UV-induced cSCC.

To test this, we carried out Reduced Representation Bisulphite Sequencing on DNA from tail skin of mice with actively infected lesions, MmuPV1-infected then healed lesions (regressed infection), and mock-infected control mice. Genome-scale DNA methylation libraries were generated and analysed for differentially methylated regions throughout the genome, and for HPV sequences.

We found that DNA of active lesions was not differentially methylated compared to matched control mice. In contrast, 834 differentially methylated fragments were identified in regressed lesions compared to mock-infected control skin. An analysis of MmuPV1 viral DNA demonstrated retention of viral DNA in some of the lesions that had regressed. Overall, the viral sequences identified showed over-representation of sequences from the E4 region. The DNA hypermethylation that we found in regressed MmuPV1 lesions may be a factor in the increased susceptibility of mice to UV-induced cSCC.

AUTHOR SUMMARY

Papillomavirus infections can be asymptomatic, can cause warts, and in some cases can lead to cancer. There is direct evidence for mouse papillomavirus infection resulting in increased susceptibility to UV-induced cutaneous squamous cell carcinoma in a mouse model. We propose that DNA methylation following viral infection may contribute to the increased susceptibility. We describe the DNA methylation landscape during an active infection with mouse papillomavirus and following regression of the lesion. We found that there were very few differentially methylated DNA fragments during active infection. In contrast, over 800 differentially methylated DNA fragments were identified following regression of the lesion. This is the first description of the genome-wide DNA methylation landscape for mouse papillomavirus, to our knowledge. The dramatic DNA hypermethylation that we observe following resolution of infection may contribute to a ‘hit and run’ mechanism for the increased susceptibility to UV-induced cancer by papillomaviruses.
occAssess: An R package for assessing potential biases in species occurrence data
Authors: Boyd R. J. , Powney G. , Carvell C. , Pescott O. L.
Published: April 2021

Species occurrence records from a variety of sources are increasingly aggregated into heterogeneous databases and made available to ecologists for immediate analytical use. However, these data are typically biased, i.e. they are not a probability sample of the target population of interest, meaning that the information they provide may not be an accurate reflection of reality. It is therefore crucial that species occurrence data are properly scrutinised before they are used for research. In this article, we introduce occAssess, an R package that enables straightforward screening of species occurrence data for potential biases. The package contains a number of discrete functions, each of which returns a measure of the potential for bias in one or more of the taxonomic, temporal, spatial and environmental dimensions. Users can opt to provide a set of time periods into which the data will be split; in this case separate outputs will be provided for each period, making the package particularly useful for assessing the suitability of a dataset for estimating temporal trends in species’ distributions. The outputs are provided visually (as ggplot2 objects) and do not include a formal recommendation as to whether data are of sufficient quality for any given inferential use. Instead, they should be used as ancillary information and viewed in the context of the question that is being asked, and the methods that are being used to answer it. We demonstrate the utility of occAssess by applying it to data on two key pollinator taxa in South America: leaf-nosed bats (Phyllostomidae) and hoverflies (Syrphidae). In this worked example, we briefly assess the degree to which various aspects of data coverage appear to have changed over time. We then discuss additional applications of the package, highlight its limitations, and point to future development opportunities.
What canonical online and offline measures of statistical learning can and cannot tell us
Authors: Kiai Ava , Melloni Lucia
Published: April 2021

Statistical learning (SL) allows individuals to rapidly detect regularities in the sensory environment. We replicated previous findings showing that adult participants become sensitive to the implicit structure in a continuous speech stream of repeating tri-syllabic pseudowords within minutes, as measured by standard tests in the SL literature: a target detection task and a 2AFC word recognition task. Consistent with previous findings, we found only a weak correlation between these two measures of learning, leading us to question whether there is overlap between the information captured by these two tasks. Representational similarity analysis on reaction times measured during the target detection task revealed that reaction time data reflect sensitivity to transitional probability, triplet position, word grouping, and duplet pairings of syllables. However, individual performance on the word recognition task was not predicted by similarity measures derived for any of these four features. We conclude that online detection tasks provide richer and multi-faceted information about the SL process, as compared with 2AFC recognition tasks, and may be preferable for gaining insight into the dynamic aspects of SL.
Programmable and Contractile Materials Through Cell Encapsulation in Fibrous Hydrogel Assemblies
Authors: Davidson Matthew D. , Prendergast Margaret E. , Ban Ehsan , Xu Karen L. , Mickel Gabriel , Mensah Patricia , Dhand Abhishek , Janmey Paul A. , Shenoy Vivek B. , Burdick Jason A.
Published: April 2021

The natural extracellular matrix (ECM) within tissues is physically contracted and remodeled by cells, allowing the collective shaping of functional tissue architectures. Synthetic materials that facilitate self-assembly similar to natural ECM are needed for cell culture, tissue engineering, andin vitromodels of development and disease. To address this need, we develop fibrous hydrogel assemblies that are stabilized with photocrosslinking and display fiber density dependent strain responsive properties (strain-stiffening, alignment). Encapsulated mesenchymal stromal cells locally contract low fiber density assemblies, resulting in macroscopic volumetric changes with increased cell densities and moduli. Due to properties such as shear-thinning and self-healing, assemblies can be processed into microtissues with aligned ECM deposition or through extrusion bioprinting and photopatterning to fabricate constructs with programmed shape changes due to cell contraction. These materials provide a synthetic approach to mimic features of natural ECM, which can now be processed for applications in biofabrication and tissue engineering.
Fine tuning the mechanism of Antigen 43 self-association to modulate aggregation levels ofEscherichia colipathogens
Authors: Vo Julieanne L , Martínez Ortiz Gabriela C , Totsika Makrina , Lo Alvin , Whitten Andrew E. , Hor Lilian , Peters Kate M , Ageorges Valentin , Caccia Nelly , Desvaux Mickaël , Schembri Mark A , Paxman Jason J , Heras Begoña
Published: April 2021

Bacterial aggregates and biofilms allow bacteria to colonise a diverse array of surfaces that can ultimately lead to infections, where the protection they afford permits bacteria to resist anti-microbials and host immune factors. Despite these advantages there is a trade-off, whereby bacterial spread is reduced. As such, biofilm development needs to be regulated appropriately to suit the required niche. Here we investigate members from one of largest groups of bacterial adhesins, the autotransporters, for their critical role in the formation of bacterial aggregates and biofilms. We describe the structural and functional characterisation of autotransporter Ag43 homologues from diverse pathogenicEscherichiastrains. We reveal a common mode of trans-association that leads to cell clumping and show that subtle variations in these interactions governs their aggregation kinetics. Our in depth investigation reveals an underlying molecular basis for the ‘tuning’ of bacterial aggregation.
Molecular architecture of black widow spider neurotoxins
Authors: Chen Minghao , Blum Daniel , Engelhard Lena , Raunser Stefan , Wagner Richard , Gatsogiannis Christos
Published: April 2021

Latrotoxins (LaTXs) are presynaptic pore-forming neurotoxins found in the venom ofLatrodectusspiders. The venom contains a toxic cocktail of seven LaTXs, with one of them targeting vertebrates (α-latrotoxin (α-LTX)), five specialized on insects (α, β, γ, δ, ɛ-latroinsectotoxins (LITs), and one on crustaceans (α-latrocrustatoxin (α-LCT)). LaTXs bind to specific receptors on the surface of neuronal cells, inducing the release of neurotransmitters either by directly stimulating exocytosis or by forming Ca2+-conductive tetrameric pores in the membrane. Despite extensive studies in the past decades, a high-resolution structure of a LaTX is not yet available and the precise mechanism of LaTX action remains unclear.

Here, we report cryoEM structures of the α-LCT monomer and the δ-LIT dimer. The structures reveal that LaTXs are organized in four domains. A C-terminal domain of ankyrin-like repeats shields a central membrane insertion domain of six parallel α-helices. Both domains are flexibly linked via an N-terminal α-helical domain and a small β-sheet domain. A comparison between the structures suggests that oligomerization involves major conformational changes in LaTXs with longer C-terminal domains. Based on our data we propose a cyclic mechanism of oligomerization, taking place prior membrane insertion. Both recombinant α-LCT and δ-LIT form channels in artificial membrane bilayers, that are stabilized by Ca2+ions and allow calcium flux at negative membrane potentials. Our comparative analysis between α-LCT and δ-LIT provides first crucial insights towards understanding the molecular mechanism of the LaTX family.