bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lived experiences of caregivers of persons with epilepsy attending an epilepsy clinic at a tertiary hospital, eastern Uganda: A phenomenological approach
Authors: Okiah Lindah , Olowo Samuel , Iramiot Stanely J. , Nekaka Rebecca , Ssenyonga Lydia VN. 
Published: September 2022

AbstractIntroductionEpilepsy has been found to affect caregivers’ quality of life, life style, psychological health, social well-being and their working time. Caregivers in Uganda as in the rest of the world are important in assisting a person with epilepsy in complying with medical directions and can be actively involved in communicating with health care professionals. Little is known about the lived experiences of caregivers of persons afflicted with epilepsy in Uganda. The purpose of the study was to determine the lived experiences of caregivers of persons with epilepsy attending the epilepsy clinic at Mbale regional referral hospital, eastern Uganda.Methods and materialsForty participants were selected for the study through purposive sampling. Face to face in-depth interviews with unstructured interview guide were conducted to gather participants’ information. The investigator conceptualized the interview guide, reviewed by co-investigators, and revised and approved as the final data collection instrument after an extensive and comprehensive literature review. The interview guide comprised of two sections, the first section comprised of the questions that elicited the participants’ social demographic information. The second section comprised questions that explored caregivers experiences of persons afflicted with epilepsy. Notations were taken and a digital recorder was used purposely for audio-recordings. All interviews lasted for an hour and were audio-recorded with the participants’ consent. An inductive thematic analysis was employed and adopted to identify the patterns emerging from the texts.ResultsThe caregivers majorly perceived epilepsy as a burden. Four main themes were revealed from the analysis and these are; psychological, social, economic, and physical burdens.ConclusionThe caregivers majorly perceived epilepsy as a serious burden. This burden can be psychological, social, economic, and physical. Therefore, services and plans targeting patients with epilepsy need to consider the burden that caregivers encounter to comprehensively manage epilepsy and its resultant burden.
Deep Phenotypic Analysis of Psychiatric Features in Genetically Defined Cohorts: Application to XYY Syndrome
Authors: Raznahan Armin , Rau Srishti , Schaffer Luke , Liu Siyuan , Fish Ari M. , Mankiw Catherine , Xenophontos Anastasia , Clasen Liv S. , Joseph Lisa , Thurm Audrey , Blumenthal Jonathan D. , Bassett Dani S. , Torres Erin N. 
Published: September 2022

ABSTRACTBackgroundRecurrent gene dosage disorders impart substantial risk for psychopathology. Yet, understanding that risk is hampered by complex presentations that challenge classical diagnostic systems. Here, we present a suite of generalizable analytic approaches for parsing this clinical complexity, which we illustrate through application to XYY syndrome.MethodWe gathered high-dimensional measures of psychopathology in 64 XYY individuals and 60 XY controls, plus additional interviewer-based diagnostic data in the XYY group. We provide the first comprehensive diagnostic description of psychiatric morbidity in XYY syndrome and show how diagnostic morbidity relates to functioning, subthreshold symptoms, and ascertainment bias. We then map behavioral vulnerabilities and resilience across 67 behavioral dimensions before borrowing techniques from network science to resolve the mesoscale architecture of these dimensions and links to observable functional outcomes.ResultsCarriage of an extra Y-chromosome increases risk for diverse psychiatric diagnoses, with clinically impactful subthreshold symptomatology. Highest rates are seen for neurodevelopmental and affective disorders, and a lower-bound of <25% of carriers are free of any diagnosis. Dimensional analysis of 67 scales details the profile of psychopathology in XYY, which survives control for ascertainment bias, specifies attentional and social domains as the most impacted, and refutes stigmatizing historical associations between XYY and violence. Network modeling compresses all measured symptom scales into 8 modules with dissociable links to cognitive ability, adaptive function, and caregiver strain. Hub modules offer efficient proxies for the full symptom network.ConclusionThis study parses the complex behavioral phenotype of XYY syndrome by applying new and generalizable analytic approaches for analysis of deep-phenotypic psychiatric data in neurogenetic disorders.
A case-crossover study of the effect of vaccination on SARS-CoV-2 transmission relevant behaviours during a period of national lockdown in England and Wales
Authors: Serisier Aimee , Beale Sarah , Boukari Yamina , Hoskins Susan , Nguyen Vincent , Byrne Thomas , Fong Wing Lam Erica , Fragaszy Ellen , Geismar Cyril , Kovar Jana , Yavlinsky Alexei , Hayward Andrew , Aldridge Robert W 
Published: September 2022

ABSTRACTBackgroundStudies of COVID-19 vaccine effectiveness show increases in COVID-19 cases within 14 days of a first dose, potentially reflecting post-vaccination behaviour changes associated with SARS-CoV-2 transmission before vaccine protection. However, direct evidence for a relationship between vaccination and behaviour is lacking. We aimed to examine the association between vaccination status and self-reported non-household contacts and non-essential activities during a national lockdown in England and Wales.MethodsParticipants (n=1,154) who had received the first dose of a COVID-19 vaccine reported non-household contacts and non-essential activities from February to March 2021 in monthly surveys during a national lockdown in England and Wales. We used a case-crossover study design and conditional logistic regression to examine the association between vaccination status (pre-vaccination vs. 14 days post-vaccination) and self-reported contacts and activities within individuals. Stratified subgroup analyses examined potential effect heterogeneity by sociodemographic characteristics such as sex, household income or age group.Results457/1,154 (39.60%) participants reported non-household contacts post-vaccination compared with 371/1,154 (32.15%) participants pre-vaccination. 100/1,154 (8.67%) participants reported use of non-essential shops or services post-vaccination compared with 74/1,154 (6.41%) participants pre-vaccination. Post-vaccination status was associated with increased odds of reporting non-household contacts (OR 1.65, 95% CI 1.31-2.06, p<0.001) and use of non-essential shops or services (OR 1.50, 95% CI 1.03-2.17, p=0.032). This effect varied between men and women and different age groups.ConclusionParticipants had higher odds of reporting non-household contacts and use of non-essential shops or services within 14 days of their first COVID-19 vaccine compared to pre-vaccination. Public health emphasis on maintaining protective behaviours during this post-vaccination time period when individuals have yet to develop full protection from vaccination could reduce risk of SARS-CoV-2 infection.
Boolean modeling of mechanosensitive Epithelial to Mesenchymal Transition and its reversal
Authors: Sullivan Emmalee , Harris Marlayna , Bhatnagar Arnav , Guberman Eric , Zonfa Ian , Ravasz Regan Erzsébet 
Published: September 2022

SUMMARYThe significance of biophysical modulators of the Epithelial to Mesenchymal Transition (EMT) is demonstrated by experiments that document full EMT on stiff, nano-patterned substrates in the absence of biochemical induction. Yet, current models focus on biochemical triggers of EMT without addressing its mechanosensitive nature. Here we built a Boolean model of EMT triggered by mechanosensing – mitogen crosstalk. Our model reproduces epithelial, hybrid E/M and mesenchymal phenotypes, the role of autocrineTGFβsignaling in maintaining mesenchymal cells in the absence of external drivers, inhibition of proliferation byTGFβ, and its apoptotic effects on soft ECM. We offer testable predictions on the density-dependence of partial EMT, its molecular drivers, and the conflict between mitosis and hybrid E/M stability. Our model opens the door to modeling the effects of the biomechanical environment on cancer cell stemness linked to the hybrid E/M state, as well as the mutually inhibitory crosstalk between EMT and senescence.
Molecular fate-mapping of serum antibodies reveals the effects of antigenic imprinting on repeated immunization
Authors: Schiepers Ariën , van ’t Wout Marije F. L. , Greaney Allison J. , Zang Trinity , Muramatsu Hiromi , Lin Paulo J. C. , Tam Ying K. , Mesin Luka , Starr Tyler N. , Bieniasz Paul D. , Pardi Norbert , Bloom Jesse D. , Victora Gabriel D. 
Published: September 2022

AbstractThe ability of serum antibody to protect against pathogens arises from the interplay of antigen-specific B cell clones of different affinities and fine specificities. These cellular dynamics are ultimately responsible for serum-level phenomena such as antibody imprinting or “Original Antigenic Sin” (OAS), a proposed propensity of the immune system to rely repeatedly on the first cohort of B cells that responded to a stimulus upon exposure to related antigens. Imprinting/OAS is thought to pose a barrier to vaccination against rapidly evolving viruses such as influenza and SARS-CoV-2. Precise measurement of the extent to which imprinting/OAS inhibits the recruitment of new B cell clones by boosting is challenging because cellular and temporal origins cannot readily be assigned to antibodies in circulation. Thus, the extent to which imprinting/OAS impacts the induction of new responses in various settings remains unclear. To address this, we developed a “molecular fate-mapping” approach in which serum antibodies derived from specific cohorts of B cells can be differentially detected. We show that, upon sequential homologous boosting, the serum antibody response strongly favors reuse of the first cohort of B cell clones over the recruitment of new, naÏve-derived B cells. This “primary addiction” decreases as a function of antigenic distance, allowing secondary immunization with divergent influenza virus or SARS-CoV-2 glycoproteins to overcome imprinting/OAS by targeting novel epitopes absent from the priming variant. Our findings have implications for the understanding of imprinting/OAS, and for the design and testing of vaccines aimed at eliciting antibodies to evolving antigens.
Evolution of an extreme hemoglobin phenotype contributed to the sub-Arctic specialization of extinct Steller’s sea cows
Authors: Signore Anthony V. , Morrison Phillip R. , Brauner Colin J. , Fago Angela , Weber Roy E. , Campbell Kevin L. 
Published: September 2022

AbstractThe extinct Steller’s sea cow (Hydrodamalis gigas; †1768) was a whale-sized marine mammal that manifested profound morphological specializations to exploit the harsh coastal climate of the North Pacific. Yet despite first-hand accounts of their biology, little is known regarding the physiological adjustments underlying their evolution to this environment. Here, the adult-expressed hemoglobin (Hb; α2β/δ2) of this sirenian is shown to harbor a fixed amino acid replacement at an otherwise invariant position (β/δ82Lys→Asn) that alters multiple aspects of Hb function. First, our functional characterization of recombinant sirenian Hb proteins demonstrate that the Hb–O2affinity of this sub-Arctic species was less affected by temperature than those of living (sub)tropical sea cows. This phenotype presumably safeguarded O2delivery to cool peripheral tissues and largely arises from a reduced intrinsic temperature sensitivity of theH. gigasprotein. Additional experiments onH. gigasβ/δ82Asn→Lys mutant Hb further reveal this exchange renders Steller’s sea cow Hb unresponsive to the potent intraerythrocytic allosteric effector 2,3-diphosphoglycerate, a radical modification that is the first documented example of this phenotype among mammals. Notably, β/δ82Lys→Asn moreover underlies the secondary evolution of a reduced blood–O2affinity phenotype that would have promoted heightened tissue and maternal/fetal O2delivery. This conclusion is bolstered by analyses of two Steller’s sea cow prenatal Hb proteins (Hb Gower I; ζ2ε2and HbF; α2γ2) that suggest an exclusive embryonic stage expression pattern, and reveal uncommon replacements inH. gigasHbF (γ38Thr→Ile and γ101Glu→Asp) that increased Hb–O2affinity relative to dugong HbF. Finally, the β/δ82Lys→Asn replacement of the adult/fetal protein is shown to increase protein solubility, which may have elevated red blood cell Hb content within both the adult and fetal circulations and contributed to meeting the elevated metabolic (thermoregulatory) requirements and fetal growth rates associated with this species cold adaptation.
Vaping and Socioeconomic Inequalities in Smoking Cessation and Relapse: A Longitudinal Analysis of the UK Household Longitudinal Study
Authors: Hardie Iain , Green Michael J. 
Published: September 2022

ABSTRACTBackgroundSmoking is a key cause of socioeconomic health inequalities. Vaping is considered less harmful than smoking and has become a popular smoking cessation aid. However, there is currently limited evidence on the impact of vaping on inequalities in smoking.MethodsWe used longitudinal data from 25,102 participants in waves 8-10 (2016-2020) of the UK Household Longitudinal Study to examine how vaping affects socioeconomic inequalities in smoking cessation and relapse. Marginal structural models were used to investigate whether vaping mediates or moderates associations between educational attainment and smoking cessation and relapse over time. Multiple Imputation and weights were used to adjust for missing data.ResultsRespondents without degrees were less likely to stop smoking than those with a degree (OR: 0.65; 95% CI: 0.54-0.77), and more likely to relapse (OR: 1.67; 95% CI: 1.26-2.23) but regular vaping eliminated the inequality in smoking cessation (OR: 0.99; 95% CI: 0.54-1.82). Sensitivity analyses suggested that this finding did not hold when comparing those with or without any qualifications. Inequalities in smoking relapse did not differ by vaping status.ConclusionsVaping may help reduce inequalities in smoking cessation between those with and without degree-level education and policy should favour vaping as a smoking cessation aid. Nevertheless, other supports or aids may be needed to reach the most disadvantaged (i.e. those with no qualifications) and to help people avoid relapse after cessation.WHAT THIS PAPER ADDSWhat is already known on this topic?Socioeconomic inequalities in smoking cessation have narrowed in recent years since e-cigarettes have become more widely available as a cessation aid.It is not clear whether this was as a result of increased vaping or other due to other confounding factors.Existing research on vaping and socioeconomic inequalities in smoking cessation have been limited to using cross-sectional data.What this study adds?Using longitudinal data, over 2 years of follow-up, our study suggests that increased vaping among those of lower SEP (i.e. without degrees) is likely to have reduced socioeconomic inequalities in smoking cessation.However, the positive impact of vaping on inequalities is focused around the upper to middle end of the educational distribution, and does not appear to help the most disadvantaged, or help with inequalities in smoking relapse.How this study might affect research, practice or policyVaping can most likely have a net positive impact on inequalities in smoking. Policy should favour vaping, although other aids may be needed for the most disadvantaged and to help people avoid smoking relapse.
Heterogeneity in vaccinal immunity to SARS-CoV-2 can be addressed by a personalized booster strategy
Authors: Stoddard Madison , Yuan Lin , Sarkar Sharanya , Mangalaganesh Shruthi , Nolan Ryan P. , Bottino Dean , Hather Greg , Hochberg Natasha S. , White Laura F. , Chakravarty Arijit 
Published: September 2022

AbstractThe ongoing COVID-19 pandemic has placed an unprecedented burden on global health. Crucial for managing this burden, the existing SARS-CoV-2 vaccines have substantially reduced the risk of severe disease and death up to this point. The induction of neutralizing antibodies (nAbs) by these vaccines leads to protection against both infection and severe disease. However, pharmacokinetic (PK) waning and rapid viral evolution degrade neutralizing antibody binding titers, leading to a rapid loss of vaccinal protection against infection occurring on the order of months after vaccination. Additionally, inter-individual heterogeneity in the strength and durability of the vaccine-induced neutralizing response to SARS-CoV-2 can create a further public-health risk by placing a subset of the population at risk. Here we incorporate the heterogeneity in inter-individual response into a pharmacokinetic/ pharmacodynamic (PK/PD) model to project the degree of heterogeneity in immune protection. We extend our model-based approach to examine the impact of evolutionary immune evasion on vaccinal protection. Our findings suggest that viral evolution can be expected to impact the effectiveness of vaccinal protection against severe disease, particularly for individuals with a shorter duration of immune response. One possible solution to immune heterogeneity may be more frequent boosting for individuals with a weaker immune response. We demonstrate a model-based approach to targeted boosting that involves the use of the ECLIA RBD assay to identify individuals whose immune response is insufficient for protection against severe disease. Our work suggests that vaccinal protection against severe disease is not assured and provides a path forward to reducing the risk to immunologically vulnerable individuals.
Racism and Racial Injustice During COVID-19: Impact on University Student Mental Health
Authors: Boitet Laurence M. , Estep Claire , Schwiebert Lisa , Upshaw Kalani , Wolfner Caro , Chatham Amy Hutson , Garner Sherilyn , Stowe Angela , Lanzi Robin Gaines 
Published: September 2022

AbstractThe purpose of the study is to understand how undergraduate, graduate, and professional students were affected by the events of racial injustice and the COVID-19 pandemic. Data gathered from an online campus-wide survey administered during July and August 2020 indicated high levels of stress and rates of depression across all stages of training. A majority of these students also indicated that, while events around racism negatively impacted their mental health, such events did not affect students’ academic success as COVID-19 did. Although previous studies have demonstrated that student mental health has been negatively affected during COVID-19, this study shows that student mental health is also impacted by events driven by racism and racial injustice concurrent to the pandemic. In light of these findings, it is recommended that institutions adopt an intersectional approach toward addressing such contemporaneous stressors with initiatives that can adapt to multiple events simultaneously.
Mera: A scalable high throughput automated micro-physiological system
Authors: Cliffe Finola E. , Madden Conor , Costello Patrick , Devitt Shane , Mukkunda Sumir Ramesh , Keshava Bhairavi Bengaluru , Fearnhead Howard O. , Vitkauskaite Aiste , Dehkordi Mashid H. , Chingwaru Walter , Przyjalgowski Milosz , Rebrova Natalia , Lyons Mark 
Published: September 2022

AbstractThere is an urgent need for scalable Microphysiological Systems (MPS’s)1that can better predict drug efficacy and toxicity at the preclinical screening stage. Here we present Mera, an automated, modular and scalable system for culturing and assaying microtissues with interconnected fluidics, inbuilt environmental control and automated image capture. The system presented has multiple possible fluidics modes. Of these the primary mode is designed so that cells may be matured into a desired microtissue type and in the secondary mode the fluid flow can be re-orientated to create a recirculating circuit composed of inter-connected channels to allow drugging or staining. We present data demonstrating the prototype system Mera using an Acetaminophen/HepG2 liver microtissue toxicity assay with Calcein AM and Ethidium Homodimer (EtHD1) viability assays. We demonstrate the functionality of the automated image capture system. The prototype microtissue culture plate wells are laid out in a 3 × 3 or 4 × 10 grid format with viability and toxicity assays demonstrated in both formats. In this paper we set the groundwork for the Mera system as a viable option for scalable microtissue culture and assay development.
The translating bacterial ribosome at 1.55 Å resolution by open access cryo-EM
Authors: Fromm Simon A. , O’Connor Kate M. , Purdy Michael , Bhatt Pramod R. , Loughran Gary , Atkins John F. , Jomaa Ahmad , Mattei Simone 
Published: September 2022

AbstractOur understanding of protein synthesis has been conceptualised around the structure and function of the bacterial ribosome1–4. This complex macromolecular machine is the target of important antimicrobial drugs5, an integral line of defence against infectious diseases. Here, we describe how open access to state-of-the-art cryogenic electron microscopy facilities combined with bespoke user support offered by the newly established EMBL Imaging Centre enabled structural determination of the translating ribosome from Escherichia coli at 1.55 Å resolution. The obtained structures allow for direct determination of the rRNA sequence to identify ribosome polymorphism sites in the E. coli strain used in this study and enables interpretation of the ribosomal active and peripheral sites at unprecedented resolution. This includes scarcely populated chimeric hybrid states of the ribosome engaged in several tRNA translocation steps resolved at ~2 Å resolution. The current map not only improves our understanding of protein synthesis but also allows for more precise structure-based drug design of antibiotics to tackle rising bacterial resistance.
Entropic overcompensation of the N501Y mutation on SARS-CoV-2 S binding to ACE2
Authors: Vergara Natasha Gupta , Gatchel Meghan , Abrams Cameron F. 
Published: September 2022

AbstractRecent experimental work has shown that the N501Y mutation in the SARS-CoV-2 S glycoprotein’s receptor binding domain (RBD) increases binding affinity to the angiotensin-converting enzyme 2 (ACE2), primarily by overcompensating for a less favorable enthalpy of binding by a greatly reducing the entropic penalty for complex formation, but the basis for this entropic overcompensation is not clear [Prévost et al., J. Biol. Chem. (2021) 297;101151]. We use all-atom molecular dynamics simulations and free-energy calculations to qualitatively assess the impact of the N501Y mutation on enthalpy and entropy of binding of RBD to ACE2. Our calculations correctly predict that N501Y causes a less favorable enthalpy of binding to ACE2 relative to the original strain. Further, we show that this is overcompensated for by a more entropically favorable increase in large-scale quaternary flexibility and intra-protein root-mean squared fluctuations of residue positions upon binding in both RBD and ACE2. The enhanced quaternary flexibility stems from N501Y’s ability to remodel the interresidue interactions between the two proteins away from interactions central to the epitope and toward more peripheral interactions. These findings suggest that an important factor in determining protein-protein binding affinity is the degree to which fluctuations are distributed throughout the complex, and that residue mutations that may seem to result in weaker interactions than their wild-type counterparts may yet result increased binding affinity thanks to their ability to suppress unfavorable entropy changes upon binding.