bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Background

Recurrent 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.

Method

We 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.

Results

Carriage 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.

Conclusion

This 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

Background

Studies 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.

Methods

Participants (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.

Results

457/1,154 (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.

Conclusion

Participants 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

The 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.
Inter-group Heterogeneity of Regional Homogeneity (REHO)
Authors: Jiang Yan , Alaoui Mhamdi Mohammed Ayoub , Butler Russell
Published: September 2022

Regional Homogeneity (REHO) measures the similarity between the time series of a given voxel and those of its neighbors. First discovered in a task-activation paradigm, REHO was considered as a complementary method to model-driven analysis of fMRI time series. With the increased popularity of resting-state paradigms, REHO has become a widely used method for inferring neural activity in the resting state. However, the neural/physiological processes that give rise to REHO are poorly understood. Differences in REHO across groups may not be indicative of differences in neuronal activity. Here, we investigate physiological contributions to REHO across 412 subjects in 9 separate datasets downloaded from OpenNeuro where both physiological signals (respiratory rate, heart rate, and motion) and resting state data are available. Overall, we find an inverse correlation between heart rate and REHO across subjects, an inverse correlation between respiratory rate and REHO across time, and differences in REHO across groups is driven primarily by FWHM of data and motion. We conclude that, due to REHO’s highly significant correlation with motion, heart rate, and respiratory rate, REHO should be used with caution to infer differences in neuronal activity across groups.
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

The 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

The 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.
Molecular Insights into the Role of Water in Early-stage Human Amylin Aggregation
Authors: Guo Ashley Z. , de Pablo Juan J.
Published: September 2022

Human islet amyloid polypeptide (hIAPP or human amylin) is known to aggregate into amyloid fibrils and is implicated in the development of type II diabetes. Prefibrillar species in particular have been linked to cell loss, prompting detailed investigation of early-stage hIAPP aggregation. Insights into the mechanisms underlying early-stage aggregation and the key intermediate structures formed during aggregation are valuable in understanding disease onset at the molecular level and guiding design of effective therapeutic strategies. Here, we use atomistic molecular dynamics simulations with the finite temperature string method to identify and compare multiple pathways for hIAPP trimer formation in water. We focus on the comparison between trimerization from three disordered hIAPP chains (which we call “3-chain assembly”) and trimerization from an hIAPP dimer approached by a single disordered chain (called “2+1 assembly”). We show that trimerization is a process uphill in free energy, regardless of the trimerization mechanism, and that a high free energy barrier of 40 kBT must be crossed in 2+1 assembly compared to a moderate barrier of 12 kBT for 3-chain assembly. We find this discrepancy to originate from differences in molecular-level water interactions involved in the two trimerization scenarios. Furthermore, we find that the more thermodynamically favorable 3-chain assembly begins from a previously identified dimer intermediate exhibiting transient β-sheet character, which is then incorporated into a similar trimer intermediate, suggesting stepwise aggregation dynamics.
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

Background

Smoking 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.

Methods

We 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.

Results

Respondents 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.

Conclusions

Vaping 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 ADDS

What 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 policy

Vaping 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

The 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

The 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

There 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

Our 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

Recent 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.
TMEM16A activation for the fast block to polyspermy in the African clawed frog does not require conventional activation of egg PLCs
Authors: Komondor Kayla M. , Bainbridge Rachel E. , Sharp Katherine G. , Rosenbaum Joel C. , Carlson Anne E.
Published: September 2022

Fertilization of an egg by more than one sperm, a condition known as polyspermy, leads to gross chromosomal abnormalities and is embryonic lethal for most animals. Consequently, eggs have evolved multiple processes to stop supernumerary sperm from entering the nascent zygote. For external fertilizers, such as frogs and sea urchins, fertilization signals a depolarization of the egg membrane, which serves as the fast block to polyspermy. Sperm can bind to, but will not enter, depolarized eggs. In eggs from the African clawed frog, Xenopus laevis, the fast block depolarization is mediated by the Ca2+ activated Cl− channel TMEM16A. To do so, fertilization activates a phospholipase C, which generates IP3 to signal a Ca2+ release from the ER. Currently, the signaling pathway by which fertilization activates PLC remains unknown. Here, we sought to uncover this pathway by targeting the canonical activation of the PLC isoforms present in the X. laevis egg: PLCγ and PLCβ. We observed no changes to the fast block in X. laevis eggs inseminated in inhibitors of tyrosine phosphorylation, used to stop activation of PLCγ, or inhibitors of Gαq/11 pathways, used to stop activation of PLCβ. These data suggest that the PLC that signals the fast block depolarization in X. laevis is activated by a novel mechanism.
Multi-tissue landscape of somatic mtDNA mutations indicates tissue specific accumulation and removal in aging
Authors: Sanchez-Contreras Monica , Sweetwyne Mariya T. , Tsantilas Kristine A. , Whitson Jeremy A. , Campbell Matthew D. , Kohrn Brendan F. , Kim Hyeon Jeong , Hipp Micheal J. , Fredrickson Jeanne , Nguyen Megan M. , Hurley James B. , Marcinek David J. , Rabinovitch Peter S. , Kennedy Scott R.
Published: September 2022

Accumulation of somatic mutations in the mitochondrial genome (mtDNA) during aging has long been proposed as a possible mechanism of mitochondrial and tissue dysfunction. A thorough characterization of age-associated mtDNA somatic mutations has been hampered by the limited ability to detect low frequency mutations. Here, we used Duplex Sequencing on eight tissues of an aged mouse cohort to detect >89,000 independent somatic mtDNA mutations and show significant tissue-specific increases during aging across all tissues examined which did not correlate with mitochondrial content and tissue function. G→A/C→T substitutions, indicative of replication errors and/or cytidine deamination, were the predominant mutation type across all tissues and increased with age, whereas G→T/C→A substitutions, indicative of oxidative damage, were the second most common mutation type, but did not increase with age regardless of tissue. We also show that clonal expansions of mtDNA mutations with age is tissue and mutation type dependent. Unexpectedly, mutations associated with oxidative damage rarely formed clones in any tissue and were significantly reduced in the hearts and kidneys of aged mice treated at late age with Elamipretide or nicotinamide mononucleotide. Thus, the lack of accumulation of oxidative damage-linked mutations with age indicates a life-long dynamic clearance of either the oxidative lesions or mtDNA genomes harboring oxidative damage.
New algorithms for accurate and efficient de-novo genome assembly from long DNA sequencing reads
Authors: Gonzalez-Garcia Laura , Guevara-Barrientos David , Lozano-Arce Daniela , Gil Juanita , Díaz-Riaño Jorge , Duarte Erick , Andrade Germán , Bojacá Juan Camilo , Hoyos Maria Camila , Chavarro Christian , Guayazan Natalia , Chica Luis Alberto , Buitrago Acosta Maria Camila , Bautista Edwin , Trujillo Miller , Duitama Jorge
Published: September 2022

Producing de-novo genome assemblies for complex genomes is possible thanks to long-read DNA sequencing technologies. However, maximizing the quality of assemblies based on long reads is a challenging task that requires the development of specialized data analysis techniques. In this paper, we present new algorithms for assembling long-DNA sequencing reads from haploid and diploid organisms. The assembly algorithm builds an undirected graph with two vertices for each read based on minimizers selected by a hash function derived from the k-mers distribution. Statistics collected during the graph construction are used as features to build layout paths by selecting edges, ranked by a likelihood function that is calculated from the inferred distributions of features on a subset of safe edges. For diploid samples, we integrated a reimplementation of the ReFHap algorithm to perform molecular phasing. The phasing procedure is used to remove edges connecting reads assigned to different haplotypes and to obtain a phased assembly by running the layout algorithm on the filtered graph. We ran the implemented algorithms on PacBio HiFi and Nanopore sequencing data taken from bacteria, yeast, Drosophila, rice, maize, and human samples. Our algorithms showed competitive efficiency and contiguity of assemblies, as well as superior accuracy in some cases, as compared to other currently used software. We expect that this new development will be useful for researchers building genome assemblies for different species.
In vitro selection of Engineered Transcriptional Repressors for targeted epigenetic silencing and initial evaluation of their specificity profile
Authors: Migliara Alessandro , Cappelluti Martino Alfredo , Valsoni Sara , Merelli Ivan , Cittaro Davide , Lombardo Angelo
Published: September 2022

Gene inactivation is instrumental to study gene function and represents a promising strategy for the treatment of a broad range of diseases. Among traditional technologies, RNA interference suffers from partial target abrogation and requirement for life-long treatments. On the other hand, artificial nucleases can impose stable gene inactivation through induction of DNA Double Strand Breaks, but recent studies are questioning the safety of this approach. Targeted epigenetic editing via Engineered Transcriptional Repressors (ETRs) may represent a solution, as a single administration of specific ETRs combinations can lead to durable silencing without DNA breaks induction. ETRs are proteins containing a programmable DNA Binding Domain (DBD) and effectors from naturally occurring transcriptional repressors. Specifically, a combination of three ETRs equipped with the KRAB domain of human ZNF10, the catalytic domain of human DNMT3A and human DNMT3Lwas shown to induce heritable repressive epigenetic states on the ETR-target gene. The hit-and-run nature of this platform, the lack of impact on the DNA sequence of the target, and the possibility to revert on-demand the repressive state by DNA demethylation, make epigenetic silencing a game-changing tool. A critical step is the identification of the proper position on the target gene where to tether the ETRs in order to maximize on target and minimizing off-target silencing. Performing this step in the final ex vivo or in vivo preclinical setting can be cumbersome. Taking CRISPR-Cas9 system as a paradigmatic DBD for ETRs, here we describe a protocol consisting in the in vitro screen of gRNAs coupled to the triple ETRs combination for efficient on-target silencing, followed by evaluation of the genome-wide specificity profile of top hits. This allows to reduce the initial repertoire of candidate gRNAs to a short list of promising ones, whose complexity is suitable for their final evaluation in the therapeutically relevant setting of interest.
Travel distance to the general practitioner. Do patients move closer to the services when starting to use them?1
Authors: Johed Rosanna N. I. , Telle Kjetil
Published: September 2022

Objectives

The main objectives were 1) to calculate and describe travel time by car from the home of Norwegian residents to the office of their named general practitioner (GP); 2) to estimate changes in travel time for residents who started to visit the GP and, if so, to 3) to explore if the residents changed GP or moved to reduce their travel time.

Methods

We used nation-wide individual-level annual registry data 2009-2017 on the exact location of the home of every resident and the GP-office to calculate travel time in minutes by car from home to their assigned GP. First, using data for 2017 only, we calculated travel time at the median and 90th percentile, and by sex, age, immigrant background, county of residence and use of GP in 2017. Second, with annual data 2009-2017, and restricting the sample to residents who had not used their GP over the last two years (t-2 and t-1), we used a difference-indifferences model to estimate changes in travel time in the next two years (t+1 and t+1) for patients with a visit in year t compared with those with no visit in t. Separate models were run for those who changed GP and those who moved from t-2 to t., and for the 20% who lived farthest away in t-1.

Results

We could calculate the travel time for 3,976,910 residents in 2017, with a median travel time from home to the GP of 4.9 minutes and a travel time at the 90th percentile of 18.3 minutes. In the most sparsely populated northern county of Norway, travel time was about 5 minutes at the median and below 45 minutes at the 90th percentile. Elderly residents and residents who used their GP in 2017 had a somewhat shorter travel time than other groups of the population. Using annual data for 2009-2017 in the difference-in-differences analysis (16,388,151 resident-year observations), travel time dropped by 2.5 minutes (95% confidence interval 2.4 to 2.6) in t+1 and t+2 for patients with a visit in t compared with similar patients with no visit in t. The drop was similar for patients who did and did not change GP, but larger for patients who moved (10.0 minutes; 95%CI 9.7 to 10.4) compared with those who did not move (0.6 minutes; 95%CI 0.5 to 0.7), and particularly large for the 20% living farthest away in t-1 (24.2 minutes; 95%CI 23.3 to 25.2).

Conclusions

Travel time from home to ones GP is short for the vast majority of the population in the sparsely populated country of Norway. However, residents move closer to the GP when they start using the services, especially patients who used to live far away. This relocation may reflect strong preferences for proximity to the services, and we conclude that more knowledge is needed to enable transparent balancing of costs and benefits of centralizing GP-services, at least in rural areas.

JEL classification

I10, E32, J6
Impact of COVID-19 and Effects of Vaccination with BNT162b2 on Patient-Reported Health-Related Quality of Life, Symptoms, and Work Productivity Among US Adult Outpatients with SARS-CoV-2
Authors: Fusco Manuela Di , Sun Xiaowu , Moran Mary M. , Coetzer Henriette , Zamparo Joann M. , Puzniak Laura , Alvarez Mary B. , Tabak Ying P. , Cappelleri Joseph C.
Published: September 2022

Background

Although there is extensive literature on the clinical benefits of COVID-19 vaccination, data on humanistic effects are limited. This study evaluated the impact of SARS-CoV-2 infection on symptoms, Health Related Quality of Life (HRQoL) and Work Productivity and Impairment (WPAI) prior to and one month following infection, and compared results between individuals vaccinated with BNT162b2 and those unvaccinated.

Methods

Subjects with ≥1 self-reported symptom and positive RT-PCR for SARS-CoV-2 at CVS Health US test sites were recruited between 01/31/2022-04/30/2022. Socio-demographics, clinical characteristics and vaccination status were evaluated. Self-reported symptoms, HRQoL, and WPAI outcomes were assessed using questionnaires and validated instruments (EQ-5D-5L, WPAI-GH) across acute COVID time points from pre-COVID to Week 4, and between vaccination groups. Mixed models for repeated measures were conducted for multivariable analyses, adjusting for several covariates. Effect size (ES) of Cohen’s d was calculated to quantify the magnitude of outcome changes within and between vaccination groups.

Results

The study population included 430 subjects: 197 unvaccinated and 233 vaccinated with BNT162b2. Mean (SD) age was 42.4 years (14.3), 76.0% were female, 38.8% reported prior infection and 24.2% at least one comorbidity. Statistically significant differences in outcomes were observed compared with baseline and between groups. The EQ-Visual analogue scale scores and Utility Index dropped in both cohorts at Day 3 and increased by Week 4, but did not return to pre-COVID levels. The mean changes were statistically lower in the BNT162b2 cohort at Day 3 and Week 4. The BNT162b2 cohort reported lower prevalence and fewer symptoms at index date and Week 4. At Week 1, COVID-19 had a large impact on all WPAI-GH domains: the work productivity time loss among unvaccinated and vaccinated was 65.0% and 53.8%, and the mean activity impairment was 50.2% and 43.9%, respectively. With the exception of absenteeism at Week 4, the BNT162b2 cohort was associated with statistically significant less worsening in all WPAI-GH scores at both Week 1 and 4.

Conclusions

COVID-19 negatively impacted HRQoL and work productivity among mildly symptomatic outpatients. Compared with unvaccinated, those vaccinated with BNT162b2 were less impacted by COVID-19 infection and recovered faster.
The causal relationship between gastro-esophageal reflux disease and idiopathic pulmonary fibrosis: A bidirectional two-sample Mendelian randomization study
Authors: Reynolds Carl J , Del Greco M Fabiola , Allen Richard J , Flores Carlos , Jenkins R Gisli , Maher Toby M , Molyneaux Philip L , Noth Imre , Oldham Justin M , Wain Louise V , An Jiyuan , Ong Jue-Sheng , MacGregor Stuart , Yates Tom A. , Cullinan Paul , Minelli Cosetta
Published: September 2022

Background

Gastro-esophageal reflux disease (GERD) is associated with idiopathic pulmonary fibrosis (IPF) in observational studies. It is not known if this association arises because GERD causes IPF, or IPF causes GERD, or because of confounding by factors, such as smoking, associated with both GERD and IPF. We used bidirectional Mendelian randomisation (MR), where genetic variants are used as instrumental variables to address issues of confounding and reverse causation, to examine how, if at all, GERD and IPF are causally related.

Methods and results

A bidirectional two-sample MR was performed to estimate the causal effect of GERD on IPF risk, and of IPF on GERD risk, using genetic data from the largest GERD (78,707 cases and 288,734 controls) and IPF (4,125 cases and 20,464 controls) genome-wide association meta-analyses currently available. GERD increased the risk of IPF, with an odds ratio (OR) of 1.6 (95% Confidence Interval, CI: 1.04-2.49; p=0.032). There was no evidence of a causal effect of IPF on the risk of GERD, with an OR of 0.99 (95%CI: 0.97-1.02; p=0.615).

Conclusion

We found that GERD increases the risk of IPF, but found no evidence that IPF increases the risk of GERD. GERD should be considered in future studies of IPF risk, and interest in it as a potential therapeutic target should be renewed. The mechanisms underlying the effect of GERD on IPF should also be investigated.
Low levels of monkeypox virus neutralizing antibodies after MVA-BN vaccination in healthy individuals
Authors: Zaeck Luca M. , Lamers Mart M. , Verstrepen Babs E. , Bestebroer Theo M. , van Royen Martin E. , Götz Hannelore , Shamier Marc C. , van Leeuwen Leanne P.M. , Schmitz Katharina S. , Alblas Kimberley , van Efferen Suzanne , Bogers Susanne , Scherbeijn Sandra , Rimmelzwaan Guus F. , van Gorp Eric C.M. , Koopmans Marion P.G. , Haagmans Bart L. , GeurtsvanKessel Corine H. , de Vries Rory D.
Published: September 2022

In July 2022, the ongoing monkeypox (MPX) outbreak was declared a public health emergency of international concern by the World Health Organization. Modified vaccinia virus Ankara (MVA-BN, also known as Imvamune, Jynneos, or Imvanex) is a 3rd generation smallpox vaccine that was generated by serial passaging of the more pathogenic parental vaccinia virus (VACV), and is authorized as a vaccine against MPX in humans in a two-shot regimen. Up to now, there is a lack of data that demonstrate MPX virus (MPXV)-neutralizing antibodies in vaccinated individuals and vaccine efficacy data against MPXV infection. Here, we measure MVA-, VACV-, and MPXV-reactive binding and neutralizing antibodies with validated in-house assays in cohorts of historically smallpox-vaccinated, MPXV PCR-positive, and recently MVA-BN-vaccinated individuals. We show that MPXV neutralizing antibodies were detected across all cohorts in individuals with MPXV exposure as well as those who received historic (VACV) vaccination. However, a primary MVA-BN immunization series in non-primed individuals yields relatively low levels of MPXV neutralizing antibodies. As the role of MPXV neutralizing antibodies for protection against disease and transmissibility is currently unclear and no correlate of protection against MPXV infection has been identified yet, this raises the question how well vaccinated individuals are protected. Dose-sparing leads to lower antibody levels, whereas a third MVA vaccination further boosts the antibody response. Cohort studies following vaccinated individuals are necessary to further assess vaccine efficacy in risk populations and determine correlates of protection for this emerging pathogen.
Atherosclerotic Cardiovascular Disease and Health-Related Quality of Life Among Adults in the United States: National Health Interview Survey 2013-2017
Authors: Hagan Kobina K. , Javed Zulqarnain , Acquah Isaac , Yahya Tamer , Valero-Elizondo Javier , Hyder Adnan A. , Mossiolas Elias , Lahan Shubham , Cainzos-Achirica Miguel , Nasir Khurram
Published: September 2022

Background

A brief health-related quality of life (HRQoL) tool with construct validity for atherosclerotic cardiovascular disease (ASCVD) may facilitate integration into healthcare delivery. We examined ASCVD-related changes in the Health and Activity Limitation Index (HALex), a generic HRQoL measure comprising perceived health and activity limitation.

Methods

Using data of 155,130 respondents of the National Health Interview Survey 2013-2017, we evaluated HALex scores by ASCVD (angina, heart attack, and stroke). Lower HALex scores reflected worse HRQoL and a 0.03 change was regarded as the threshold for clinical significance. Multivariable two-part models were used to assess HALex changes (β, 95%CI) associated with ASCVD overall and in sex, age, and race/ethnicity groups.

Results

Overall, participants with ASCVD – 6.8%, representing 15.7 million adults – had lower HALex scores (0.67) than those without ASCVD (0.87). Females, age ≥ 65 years, and non-Hispanic Blacks had the lowest HALex scores. Overall, ASCVD was associated with a substantial decrement in HALex (−0.10, [−0.10, −0.09]). Interactions between ASCVD and sex, and race/ethnicity were both significant (p < 0.001). ASCVD-associated decrement in HALex was clinically greater in: females (−0.11, [−0.12, −0.10]) than in males (−0.08, [−0.09, −0.07]); and non-Hispanic Black (−0.13, [−0.15, −0.1]) than in non-Hispanic White (−0.09, [−0.10, −0.08]). Though ASCVD impact on HALex was greater in age 18-64 years (−0.09, [−0.10, −0.08]), it was not statistically different from the elderly (−0.06, [−0.07, −0.06]).

Conclusions

ASCVD was consistently associated with lower HRQoL, as measured by HALex, across major demographics. HALex presents a feasible HRQoL tool to implement in healthcare.
Mapping the adaptor protein complex interaction network in Arabidopsis identifies P34 as a common stability regulator
Authors: Wang Peng , Siao Wei , Zhao Xiuyang , Arora Deepanksha , Wang Ren , Eeckhout Dominique , Leene Jelle Van , Kumar Rahul , Houbaert Anaxi , Winne Nancy De , Mylle Evelien , Vandorpe Michael , Korver Ruud A. , Testerink Christa , Gevaert Kris , Vanneste Steffen , Jaeger Geert De , Damme Daniël Van , Russinova Eugenia
Published: September 2022

Adaptor protein (AP) complexes are evolutionarily conserved vesicle transport regulators that recruit coat proteins, membrane cargos and coated vesicle accessory proteins. Since in plants endocytic and post-Golgi trafficking intersect at the trans-Golgi network, unique mechanisms for sorting cargos of overlapping vesicular routes are anticipated. The plant AP complexes are part of the sorting machinery, but despite some functional information, their cargoes, accessory proteins, and regulation remain largely unknown. Here, by means of various proteomics approaches, we generated the overall interactome of the five AP and the TPLATE complexes in Arabidopsis thaliana. The interactome converged on a number of hub proteins, including the thus far unknown adaptin binding-like protein, designated P34. P34 interacted with the clathrin-associated AP complexes, controlled their stability and, subsequently, influenced clathrin-mediated endocytosis and various post-Golgi trafficking routes. Altogether, the AP interactome network offers substantial resources for further discoveries of unknown endomembrane trafficking regulators in plant cells.
mTOR pathway inhibition stimulates pharmacologically induced nonsense suppression
Authors: Wittenstein Amnon , Caspi Michal , Rippin Ido , Elroy-Stein Orna , Eldar-Finkelmn Hagit , Thoms Sven , Rosin-Arbesfeld Rina
Published: September 2022

A large number of human genetic diseases result from premature termination codons (PTCs) caused by splicing defects, insertions, deletions or point mutations also termed nonsense mutations. Nonsense mutations are the source of various genetic diseases, ranging from rare neuro-metabolic disorders to relatively common inheritable cancer syndromes and muscular dystrophies. Over the years, a wide spectrum of studies has shown that certain antibiotics and other synthetic molecules can act as nonsense mutation suppressors, by inducing readthrough of the stop-codon leading to the expression of a full-length protein. Unfortunately, most readthrough-inducing agents have limited effects and are toxic. Thus, efforts are made to improve the clinical outcome of nonsense mutation suppressors.

Here we show that the mTOR pathway is involved in antibiotic-mediated readthrough of nonsense mutations at the level of protein translation initiation. We demonstrate that inhibition of the mTOR translation-initiation-controlling eIF4E branch induces antibiotic-mediated nonsense mutation readthrough, paving the way to the development of a novel therapeutic strategy for enhancing the restoration of these disease-causing mutated transcripts.