bluuebunny/crossref_metadata_2025 huggingface dataset:
A method to reduce ELISA serial dilution assay workload applied to SARS-CoV-2 and seasonal HCoVs
Authors: Pattinson David , Jester Peter , Guan Lizheng , Yamayoshi Seiya , Chiba Shiho , Presler Robert , Rao Hongyu , Iwatsuki-Horimoto Kiyoko , Ikeda Nobuhiro , Hagihara Masao , Uchida Tomoyuki , Mitamura Keiko , Halfmann Peter , Neumann Gabriele , Kawaoka Yoshihiro
Published: September 2021

Objectives

Assays using ELISA measurements on serially diluted serum samples have been heavily used to measure serum reactivity to SARS-CoV-2 antigens and are widely used in virology and elsewhere in biology. We test a method to reduce the workload of these assays, and measure reactivity of SARS-CoV-2 and HCoV antigens to human serum samples collected before and during the COVID-19 pandemic.

Methods

We apply Bayesian hierarchical modelling to ELISA measurements of human serum samples against SARS-CoV-2 and HCoV antigens.

Results

Inflection titers for SARS-CoV-2 full-length spike protein (S1S2), spike protein receptor-binding domain (RBD), and nucleoprotein (N) inferred from three spread-out dilutions correlated with those inferred from eight consecutive dilutions with an R2 value of 0.97 or higher. We confirm existing findings showing a small proportion of pre-pandemic human serum samples contain cross-reactive antibodies to SARS-CoV-2 S1S2 and N, and that SARS-CoV-2 infection increases serum reactivity to the beta-HCoVs OC43 and HKU1 S1S2.

Conclusions

In serial dilution assays, large savings in resources and/or increases in throughput can be achieved by reducing the number of dilutions measured and using Bayesian hierarchical modelling to infer inflection or endpoint titers. We have released software for conducting these types of analysis.
A Deep Learning Method to Detect Opioid Prescription and Opioid Use Disorder from Electronic Health Records
Authors: Kashyap Aditya , Callison-Burch Chris , Boland Mary Regina
Published: September 2021

Objective

As the opioid epidemic continues across the United States, methods are needed to accurately and quickly identify patients at risk for opioid use disorder (OUD). The purpose of this study is to develop two predictive algorithms: one to predict opioid prescription and one to predict OUD.

Materials and Methods

We developed an informatics algorithm that trains two deep learning models over patient EHRs using the MIMIC-III database. We utilize both the structured and unstructured parts of the EHR and show that it is possible to predict both of these challenging outcomes.

Results

Our deep learning models incorporate both structured and unstructured data elements from the EHRs to predict opioid prescription with an F1-score of 0.88 ± 0.003 and an AUC-ROC of 0.93 ± 0.002. We also constructed a model to predict OUD diagnosis achieving an F1-score of 0.82 ± 0.05 and AUC-ROC of 0.94 ± 0.008.

Discussion

Our model for OUD prediction outperformed prior algorithms for specificity, F1 score and AUC-ROC while achieving equivalent sensitivity. This demonstrates the importance of a.) deep learning approaches in predicting OUD and b.) incorporating both structured and unstructured data for this prediction task. No prediction models for opioid prescription as an outcome were found in the literature and therefore this represents an important contribution of our work as opioid prescriptions are more common than OUDs.

Conclusion

Algorithms such as those described in this paper will become increasingly important to understand the drivers underlying this national epidemic.
A system biology approach identifies candidate drugs to reduce mortality in severely ill COVID-19 patients
Authors: Fava Vinicius M. , Bourgey Mathieu , Nawarathna Pubudu M. , Orlova Marianna , Cassart Pauline , Vinh Donald C. , Cheng Matthew Pellan , Bourque Guillaume , Schurr Erwin , Langlais David
Published: September 2021

Despite the availability of highly efficacious vaccines, Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) lacks effective drug treatment which results in a high rate of mortality. To address this therapeutic shortcoming, we applied a system biology approach to the study of patients hospitalized with severe COVID. We show that, at the time of hospital admission, patients who were equivalent on the clinical ordinal scale displayed significant differential monocyte epigenetic and transcriptomic attributes between those who would survive and those who would succumb to COVID-19. We identified mRNA metabolism, RNA splicing, and interferon signaling pathways as key host responses overactivated by patients who would not survive. Those pathways are prime drug targets to reduce mortality of critically ill COVID-19 patients leading us to identify Tacrolimus, Zotatifin, and Nintedanib as three strong candidates for treatment of severely ill patients at the time of hospital admission.

Teaser

Epigenetics distinguishes COVID-19 survivors already at hospital admission: lessons for drug repurposing.
Serum NfL in spinocerebellar ataxia type 1 is increased already at the preataxic stage, correlating with proximity to clinical onset
Authors: Wilke Carlo , Mengel David , Schöls Ludger , Hengel Holger , Rakowicz Maria , Klockgether Thomas , Durr Alexandra , Filla Alessandro , Melegh Bela , Schüle Rebecca , Reetz Kathrin , Jacobi Heike , Synofzik Matthis
Published: September 2021

Background and Objectives

Neurofilament light (NfL) appears a promising fluid biomarker in repeat-expansion spinocerebellar ataxias (SCAs), with piloting studies in mixed SCA cohorts suggesting that NfL might be increased at the ataxic stage of spinocerebellar ataxia type 1 (SCA1). We here hypothesised that NfL is increased not only at the ataxic stage of SCA1, but also at its – likely most treatment-relevant – preataxic stage.

Methods

We assessed serum (sNfL) and cerebrospinal fluid (cNfL) levels of NfL in both preataxic and ataxic SCA1, leveraging a multicentric cohort of 40 SCA1 carriers (23 preataxic, 17 ataxic) and >80 controls, and clinical follow-up data including actually observed (rather than only predicted) conversion to the ataxic stage (11 carriers).

Results

sNfL levels were increased with high age-corrected effect sizes at the preataxic (r=0.62) and ataxic stage (r=0.63), paralleling increases of cNfL levels. In preataxic subjects, sNfL levels increased with proximity topredictedataxia onset, with significant sNfL elevations already 5 years before onset, and confirmed in preataxic subjects withactually observedataxia onset. sNfL increases were detected already in preataxic SCA1 subjects without volumetric atrophy of cerebellum or pons, suggesting that sNfL might be more sensitive to early preataxic neurodegeneration than the currently known most change-sensitive regions in volumetric MRI. Using longitudinal sNfL measurements, we estimated sample sizes for clinical trials using the reduction of sNfL as endpoint.

Conclusions

sNfL levels might thus provide easily accessible peripheral biomarkers in both preataxic and ataxic SCA1, allowing stratification of preataxic subjects regarding proximity-to-onset, early detection of neurodegeneration even before volumetric MRI alterations, and potentially capture of treatment response in clinical trials.
Accurately Estimating Unreported Infections using Information Theory
Authors: Cui Jiaming , Adhikari Bijaya , Haddadan Arash , Haque A S M Ahsan-Ul , Vreeken Jilles , Vullikanti Anil , Prakash B. Aditya
Published: September 2021

One of the most significant challenges in combating against the spread of infectious diseases was the difficulty in estimating the true magnitude of infections. Unreported infections could drive up disease spread, making it very hard to accurately estimate the infectivity of the pathogen, therewith hampering our ability to react effectively. Despite the use of surveillance-based methods such as serological studies, identifying the true magnitude is still challenging. This paper proposes an information theoretic approach for accurately estimating the number of total infections. Our approach is built on top of Ordinary Differential Equations (ODE) based models, which are commonly used in epidemiology and for estimating such infections. We show how we can help such models to better compute the number of total infections and identify the parametrization by which we need the fewest bits to describe the observed dynamics of reported infections. Our experiments on COVID-19 spread show that our approach leads to not only substantially better estimates of the number of total infections but also better forecasts of infections than standard model calibration based methods. We additionally show how our learned parametrization helps in modeling more accurate what-if scenarios with non-pharmaceutical interventions. Our approach provides a general method for improving epidemic modeling which is applicable broadly.
Monitoring the COVID-19 immunisation programme through a National Immunisation Management System – England’s experience
Authors: Tessier Elise , Stowe Julia , Tsang Camille , Rai Yuma , Clarke Eleanor , Lakhani Anissa , Makwana Ashley , Heard Heather , Rickeard Tim , Kirsebom Freja , Quinot Catherine , Lakhani Shreya , Power Linda , Edelstein Michael , Evans Andy , Ramsay Mary , Lopez-Bernal Jamie , White Joanne , Gower Charlotte , Andrews Nick , Campbell Colin
Published: September 2021

In England, the National Immunisation Management System (NIMS) has been used to deliver COVID-19 vaccinations across England, monitor vaccine coverage, and assess vaccine effectiveness and safety.

The NIMS was developed by a joint collaboration between a range of health and digital government agencies. Vaccinations delivered at large vaccination sites, pharmacies, hospitals and in primary care are entered on a point of care application which is verified using the unique NHS number in a centralised system containing information for everyone resident and registered with a GP in England. Vaccination details and additional data from hospital and GP records (such as priority groups) are sent to NHS Digital for data linkage. The NIMS constantly receives updated details from NHS Digital for all individuals and these data are provided to Public Health England (PHE) in a secure environment.

PHE primarily use the NIMS for vaccine coverage, vaccine effectiveness and safety. Daily access to individual-level vaccine data has allowed PHE to rapidly and accurately estimate vaccine coverage and provide some of the world’s first vaccine effectiveness estimates.

Other countries evaluating the roll-out and effect of COVID-19 vaccine programmes should consider a vaccine register or immunisation information system similar to the NIMS.
COVID-19 Vaccine Hesitancy in India: An Exploratory Analysis
Authors: Agarwal Sandip K. , Naha Maharnab
Published: September 2021

Vaccine hesitancy is context specific and varies over time and space. Therefore, strategies to tackle vaccine hesitancy based on evidence from high income countries are unlikely to serve the purpose adequately in LMICs. We use district level evidence on COVID-19 vaccine uptake rates from an LMIC - India to provide evidence of COVID-19 vaccine hesitancy. We argue that vaccination rates during the different phases of COVID-19 vaccination across the districts is likely to be related to vaccine hesitancy. Districts with larger rural population and lower literacy rates had lower vaccination rates. High past child immunization rates were positively correlated with COVID-19 vaccination uptake. Across the four phases of vaccination drive, vaccine hesitancy was the highest during the third phase of the vaccination drive, and therefore the above correlations were strongest during the third and the fourth phase. Measures of family planning indicators too seem to be correlated with vaccine uptakes during the third phase which indicate the regions most susceptible to vaccine hesitancy.
Startle responses in Duchenne muscular dystrophy: a novel biomarker of brain dystrophin deficiency
Authors: Maresh Kate , Papageorgiou Andriani , Ridout Deborah , Harrison Neil A. , Mandy William , Skuse David , Muntoni Francesco
Published: September 2021

Duchenne muscular dystrophy (DMD) is characterised by loss of dystrophin in muscle. Patients affected by DMD also have variable degree of intellectual disability and neurobehavioural co-morbidities. In contrast to muscle, in which a single full-length isoform (Dp427) is produced, multiple dystrophin isoforms are produced in the brain, and their deficiency accounts for the variability of CNS manifestations, with increased risk of comorbidities in patients carrying mutations affecting the 3’ end of gene, disrupting the shorter Dp140 and Dp71 isoforms. The mdx mouse model of DMD lacks Dp427 in muscle and CNS and exhibits exaggerated startle responses to threat, linked to the deficiency of dystrophin in limbic structures such as the amygdala, which normalise with postnatal brain dystrophin-restoration therapies. A pathological startle response is not a recognised feature of DMD, and its characterisation has implications for improved clinical management and translational research.

To investigate startle responses in DMD, we used a novel fear-conditioning task in an observational study of 56 males aged 7-12 years (31 DMD, mean age 9.7±1.8 years; 25 Controls, mean age 9.6±1.4 years). Trials of two neutral visual stimuli were presented to participants: one ‘safe’ cue presented alone; one ‘threat’ cue paired with an aversive noise to enable conditioning of physiological startle responses (skin conductance response, SCR; heart rate, HR). Retention of conditioned physiological responses was subsequently tested with presentation of both cues without the aversive noise in an ‘extinction’ phase. Primary outcomes were the magnitude of the initial unconditioned SCR and HR change responses to the aversive ‘threat’ and acquisition and retention of conditioned responses after conditioning. Secondary outcomes were neuropsychological measures and genotype associations.

The initial (unconditioned) mean SCR to threat was greater in DMD than Controls (Mean difference 3.0 µS (95% CI 1.0, 5.1), P=.004), associated with a significant threat-induced bradycardia only in the DMD group (mean difference -5.6 bpm (95% CI 0.51, 16.9); P=.04). DMD participants found the task more aversive than Controls, consequently early termination during the extinction phase occurred in 26% of the DMD group (vs. 0% Controls; P=.007).

This study provides the first evidence that boys with DMD show increased unconditioned startle responses to threat, similar to the mdx mouse phenotype that also responds to brain dystrophin restoration. Our study provides new insights into the neurobiology underlying the complex neuropsychiatric co-morbidities in DMD and defines an objective measure of this CNS phenotype, which will be valuable for future CNS-targeted dystrophin-restoration studies.
The removal of airborne SARS-CoV-2 and other microbial bioaerosols by air filtration on COVID-19 surge units
Authors: Conway-Morris Andrew , Sharrocks Katherine , Bousfield Rachel , Kermack Leanne , Maes Mailis , Higginson Ellen , Forrest Sally , Pereira-Dias Joana , Cormie Claire , Old Tim , Brooks Sophie , Hamed Islam , Koenig Alicia , Turner Andrew , White Paul , Floto R. Andres , Dougan Gordon , Gkrania-Klotsas Effrossyni , Gouliouris Theodore , Baker Stephen , Navapurkar Vilas
Published: September 2021

Background

The COVID-19 pandemic has overwhelmed the respiratory isolation capacity in hospitals; many wards lacking high-frequency air changes have been repurposed for managing patients infected with SARS-CoV-2 requiring either standard or intensive care. Hospital-acquired COVID-19 is a recognised problem amongst both patients and staff, with growing evidence for the relevance of airborne transmission. This study examined the effect of air filtration and ultra-violet (UV) light sterilisation on detectable airborne SARS-CoV-2 and other microbial bioaerosols.

Methods

We conducted a crossover study of portable air filtration and sterilisation devices in a repurposed ‘surge’ COVID ward and ‘surge’ ICU. National Institute for Occupational Safety and Health (NIOSH) cyclonic aerosol samplers and PCR assays were used to detect the presence of airborne SARS-CoV-2 and other microbial bioaerosol with and without air/UV filtration.

Results

Airborne SARS-CoV-2 was detected in the ward on all five days before activation of air/UV filtration, but on none of the five days when the air/UV filter was operational; SARS-CoV-2 was again detected on four out of five days when the filter was off. Airborne SARS-CoV-2 was infrequently detected in the ICU. Filtration significantly reduced the burden of other microbial bioaerosols in both the ward (48 pathogens detected before filtration, two after, p=0.05) and the ICU (45 pathogens detected before filtration, five after p=0.05).

Conclusions

These data demonstrate the feasibility of removing SARS-CoV-2 from the air of repurposed ‘surge’ wards and suggest that air filtration devices may help reduce the risk of hospital-acquired SARS-CoV-2.

Funding

Wellcome Trust, MRC, NIHR
Mortality in Rural Coastal Kenya measured using the Kilifi Health and Demographic Surveillance System: A 16-year descriptive analysis
Authors: Otiende Mark , Bauni Evasius , Nyaguara Amek , Amadi David , Nyundo Christopher , Tsory Emmanuel , Walumbe David , Kinuthia Michael , Kihuha Norbert , Kahindi Michael , Nyutu Gideon , Moisi Jennifer , Deribew Amare , Agweyu Ambrose , Marsh Kevin , Tsofa Benjamin , Bejon Philip , Bottomley Christian , Williams Thomas N. , Scott J. Anthony G.
Published: September 2021

Background

The Kilifi Health and Demographic Surveillance System (KHDSS) was established in 2000 to define the incidence and prevalence of local diseases and evaluate the impact of community-based interventions. KHDSS morbidity data have been reported comprehensively but mortality has not been described. This analysis describes mortality in the KHDSS over 16 years.

Methods

We calculated mortality rates from 2003-2018 in four intervals of equal duration and assessed differences in mortality across these intervals by age and sex. We calculated the period survival function and median survival using the Kaplan-Meier method and mean life expectancies using abridged life tables. We estimated trend and seasonality by decomposing a time series of monthly mortality rates. We used choropleth maps and random effects Poisson regression to investigate geographical heterogeneity.

Results

Mortality declined by 36% overall between 2003-2018 and by 59% in children aged <5 years. Most of the decline occurred between 2003 and 2006. Among adults, the greatest decline (49%) was observed in those aged 15-54 years. Life expectancy at birth increased by 12 years. Females outlived males by 6 years. Seasonality was only evident in the 1-4 year age group in the first four years. Geographical variation in mortality was +/-10% of the median value and did not change over time.

Conclusions

Between 2003-2018 mortality among children and young adults has improved substantially. The steep decline in 2003-2006 followed by a much slower reduction thereafter suggests improvements in health and wellbeing have plateaued in the last 12 years. However, there is substantial inequality in mortality experience by geographical location.
Real-world serologic responses to Extended-interval and Heterologous COVID-19 mRNA vaccination in Frail Elderly - Interim report from a prospective observational cohort study
Authors: Vinh Donald C. , Gouin Jean-Philippe , Cruz-Santiago Diana , Canac-Marquis Michelle , Bernier Stéphane , Bobeuf Florian , Sengupta Avik , Brassard Jean-Philippe , Guerra Alyssa , Dziarmaga Robert , Perez Anna , Sun Yichun , Li Yongbiao , Roussel Lucie , Langelier Mélanie J. , Ke Danbing , Arnold Corey , Pelchat Martin , Langlois Marc-André , Evans Timothy G. , Zhang Xun , Mazer Bruce D.
Published: September 2021

Background

The Coronavirus disease 2019 (Covid-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has prompted accelerated vaccines development. Their use was prioritized to protect the most vulnerable, notably, the elderly. Because of fluctuations in vaccine availability, strategies such as delayed second dose and heterologous prime-boost have been employed. The effectiveness of these strategies in the frail elderly are unknown.

Methods

In this real-world vaccination study, under a government-decreed rationing strategy, elderly adults residing in long-term care facilities, with or without previously-documented SARS-CoV-2 infection, were administered homologous or heterologous mRNA vaccines, with an extended 16-week interval between doses. Clinical data and blood were serially collected during and after this interval period. Sera were tested for SARS-CoV-2-specific IgG antibodies (to trimeric S; RBD; nucleocapsid) by automated chemiluminescent ELISA.

Findings

After a significant increase 4 weeks post-prime dose, there was a significant decline in anti-RBD and anti-S IgG levels until the boost dose, followed by an increase 4 weeks later. Previously uninfected individuals exhibited lower antibody responses up to 16 weeks post-prime dose, but achieved comparable levels to previously infected counterparts by 4 weeks post-second dose. Individuals primed with BNT162b2 exhibited larger decrease in anti-RBD and anti-S IgG levels with 16-week interval between doses, compared to those who received mRNA-1273. No differences in antibody levels 4 weeks after the second dose were noted between the two vaccines, in either homologous or heterologous combinations.

Interpretations

These interim results of this ongoing longitudinal study show that, among frail elderly, neither age, sex, nor comorbidity affect antigenicity of mRNA-based COVID vaccines, but previous SARS-CoV-2 infection and type of mRNA vaccine influenced antibody responses when used with a 16-week interval between doses. Homologous/heterologous use of mRNA vaccines was not associated with significant differences in antibody responses 4 weeks following second dose, supporting their interchangeability.

Funding

This project was supported by funding from the Public Health Agency of Canada, through the Vaccine Surveillance Reference group and the COVID-19 Immunity Task Force (CITF).
Central oxidative stress and early vocational outcomes in first episode psychosis: A 7-Tesla Magnetic Resonance Spectroscopy study of glutathione
Authors: MacKinley Michael , Ford Sabrina D. , Jeon Peter , Théberge Jean , Palaniyappan Lena
Published: September 2021

Following the first episode of psychosis, some patients develop poor social and occupational outcomes, while others display a pattern of preserved functioning. Several lines of evidence from preclinical, genetic and biochemical studies suggest a role for high oxidative stress in poor functional outcomes. The measurement of intracortical glutathione (GSH) using magnetic resonance spectroscopy (MRS) provides an opportunity to investigate the relationship between central antioxidant tone and functional outcomes at the time of first episode psychosis (FEP). A body of epidemiological studies indicates better functional outcomes in patients at early stages of schizophrenia compared to patients at a chronic, established phase of illness. We scanned 57 patients with FEP and 30 matched healthy controls and estimated GSH resonance using 7-Tesla MRS. We minimised the confounding effects of illness chronicity, long-term treatment exposure and metabolic complications by recruiting patients with <2 weeks of lifetime antipsychotic exposure on average and followed up this cohort for the next 1 year to determine functional outcomes. Patients with FEP who achieved employment/education or training status (EET) in the first year, had higher GSH at the baseline than healthy controls. Social and occupational functioning assessment scale (SOFAS) scores were also significantly higher in patients with higher GSH levels at the outset, after adjusting for various confounds including baseline SOFAS. Patients who were not in employment, education or training (NEET) did not differ from healthy subjects in their GSH levels. Our observations support a key role for the central antioxidant tone in the functional outcomes of early psychosis.
Effectiveness of vaccination in preventing severe SARS CoV-2 infection in South India-a hospital-based cross-sectional study
Authors: Charles Pon Ruban A , Aazmi M , Shantaraman K.
Published: September 2021

Background & objectives

Establishing concrete evidence on the effect of vaccination on the severity of SARS CoV-2 infections in real-world situations is the need of the hour. This study aims to estimate the effectiveness of Covid 19 vaccines in preventing the new and severe SARS CoV-2 infections.

Design

Cross-sectional study

Setting& Participants

We did this cross-sectional study among the 4565 patients consecutive adult inpatients admitted in the Covid 19 wards of a tertiary care hospital from May 7, 2021, to October 7, 2021, during the second wave of the Covid 19 pandemic. Information on basic demographic variables, RT PCR status, vaccination status, outcome and clinical severity of illness were obtained from the electronic hospital patient records.

Results

Only 4% of the study participants had prior vaccination. The type of vaccine and number of doses didn’t have any protective effect against the new SARS CoV-2 infection and breakthrough infection. Fully vaccinated RTPCR positive patients had an 82% reduction in the need for ICU admission (OR 0.09; AOR 0.18, CI (0.04 to 0.8), P <0.05) and a non-significant 79% in mortality (OR 0.19; AOR 0.21, CI (0.04 to 1.1) P>0.05).

Conclusion

Vaccination doesn’t protect against new SARS Cov-2 infection and breakthrough infection however significant protection was documented against severe SARS Cov-2 infection. The protective effect shown by the vaccines in preventing the severe form of SARS Cov-2 infection among fully vaccinated patients was 82%. Vaccination coverage should be increased urgently to halt the impending wave of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Topological relationships between perivascular spaces and progression of white matter hyperintensities: a pilot study in a sample of the Lothian Birth Cohort 1936
Authors: Barnes Abbie , Ballerini Lucia , Valdés Hernández Maria del C. , Chappell Francesca M. , Muñoz Maniega Susana , Meijboom Rozanna , Backhouse Ellen V. , Stringer Michael S. , Coello Roberto Duarte , Brown Rosalind , Bastin Mark E. , Cox Simon R. , Deary Ian J. , Wardlaw Joanna M.
Published: September 2021

Enlarged perivascular spaces (PVS) and white matter hyperintensities (WMH) are features of cerebral small vessel disease which can be seen in brain magnetic resonance imaging (MRI). Given the associations and proposed mechanistic link between PVS and WMH, they are hypothesised to also have topological proximity. However, this, and the influence of their spatial proximity on WMH progression are unknown. We analysed longitudinal MRI data from 29/32 participants (mean age at baseline = 71.9 years) in a longitudinal study of cognitive ageing, from three waves of data collection at 3-year intervals, alongside semi-automatic segmentation masks for PVS and WMH, to assess relationships. The majority of deep WMH clusters were found adjacent to or enclosing PVS (Wave – 1: 77%; 2: 76%; 3: 69%), especially in frontal, parietal and temporal regions. Of the WMH clusters in the deep white matter that increased between waves, most increased around PVS (Waves – 1-2: 73%; 2-3: 72%). Formal statistical comparisons of severity of each if these two SVD markers yielded no associations between deep WMH progression and PVS proximity. These findings may suggest deep WMH clusters preferentially form and grow around PVS, possibly reflecting the consequences of impaired interstitial fluid drainage via PVS. The utility of these relationships as predictors of WMH progression remains unclear.
Long-term low-dose acetylsalicylic use shows protective potential for the development of both vascular dementia and Alzheimer’s disease in patients with coronary heart disease but not in other individuals from the general population: results from two large cohort studies
Authors: Mai Nguyen Thi Ngoc , Chen Li-Ju , Trares Kira , Stocker Hannah , Holleczek Bernd , Beyreuther Konrad , Brenner Hermann , Schöttker Ben
Published: September 2021

Objectives

To investigate the association between long term low-dose acetylsalicylic acid (LDASA) use and the development of all-cause dementia, Alzheimer’s disease (AD) and vascular dementia (VD).

Design

Meta-analysis of individual participant data from two prospective cohort studies.

Setting

Community-dwelling older adults from Germany (ESTHER) and United Kingdom (UK Biobank).

Participants

5,258 ESTHER and 305,394 UK Biobank participants who were 55 years or older and completed drug assessment were included for analysis.

Main outcome measures

Cox regression models with inverse probability of treatment weighting to model the underlying cardiovascular risk were used to assess the associations of LDASA use with all-cause dementia, AD and VD incidence.

Results

476 cases of all-cause dementia, 157 cases of AD and 183 cases of VD were diagnosed over a median of 14.3 years of follow-up in ESTHER. In the UK Biobank, 5,584 participants were diagnosed with all-cause dementia, 2,029 with AD and 1,437 with VD over a median of 11.6 years. The meta-analysis of both cohorts revealed a weak reduction in hazards for all-cause dementia (HR [95% CI]: 0.96 [0.93 to 0.99]). The strongest protective effect of LDASA was observed in participants with coronary heart disease (CHD) in both cohorts, and a significant interaction was detected. In particular, in meta-analysis, a 31% reduction in hazard for AD, 69% for VD and 34% for all-cause dementia were observed (HR [95% CI]: 0.69 [0.59 to 0.80], 0.31 [0.27 to 0.35], 0.46 [0.42 to 0.50], respectively). Furthermore, compared to non-users, users of LDASA for 10 years or longer (who likely use it because they have CHD or a related diagnosis putting them at an increased risk for cardiovascular events) demonstrated a strong protective effect on all dementia outcomes, especially for VD (HR [95% CI]: 0.48 [0.42 to 0.56]) whereas no protective associations were observed with shorter LDASA use.

Conclusions

The protective potential of LDASA for all-cause dementia, AD and VD seems to strongly depend on pre-existing CHD and the willingness of patients to take it for a minimum of ten years.
GPER-dependent estrogen signaling increases cardiac GCN5L1 expression and MCAD activity
Authors: Manning Janet R. , Thapa Dharendra , Zhang Manling , Stoner Michael W. , Sembrat John C. , Rojas Mauricio , Scott Iain
Published: September 2021

Reversible lysine acetylation regulates the activity of cardiac metabolic enzymes, including those controlling fuel substrate metabolism. Mitochondrial-targeted GCN5L1 and SIRT3 have been shown to regulate the acetylation status of mitochondrial enzymes, which results in alterations to the relative oxidation rates of fatty acids, glucose, and other fuels for contractile activity. However, the role that lysine acetylation plays in driving metabolic differences between male and female hearts is not currently known. In this study, we report that estrogens induce the expression of GCN5L1 via GPER agonism in cardiac cells, which increases the enzymatic activity and acetylation status of the fatty acid oxidation enzyme medium chain acyl-CoA dehydrogenase (MCAD).
Cryo-electron tomography reveals structural insights into the membrane binding and remodeling activity of dynamin-like EHDs
Authors: Melo Arthur A. , Sprink Thiemo , Noel Jeffrey K. , Vázquez Sarandeses Elena , van Hoorn Chris , Loerke Justus , Spahn Christian M. T. , Daumke Oliver
Published: September 2021

Dynamin-related Eps15-homology domain containing proteins (EHDs) oligomerize on membrane surfaces into filaments leading to membrane remodeling. EHD crystal structures in an open and a closed conformation were previously reported, but structural information on the membrane-bound EHD oligomeric structure has remained enigmatic. Consequently, mechanistic insight into EHD-mediated membrane remodeling is lacking. Here, by using cryo-electron tomography and subtomogram averaging, we determined the structure of an EHD4 filament on a tubular membrane template at an average resolution of 7.6 Å. Assembly of EHD4 is mediated via interfaces in the G-domain and the helical domain. The oligomerized EHD4 structure resembles the closed conformation, where the tips of the helical domains protrude into the membrane. The variation in filament geometry and tube radius suggests the AMPPNP-bound filament has a spontaneous curvature of approximately 1/70 nm-1. Combining the available structural and functional data, we propose a model of EHD-mediated membrane remodeling.
Exposure to the gut microbiota from cigarette smoke-exposed mice exacerbates cigarette smoke extract-induced inflammation in zebrafish larvae
Authors: Morris Simone , Wright Kathryn , Malyla Vamshikrishna , Britton Warwick J , Hansbro Philip M , Cholan Pradeep Manuneedhi , Oehlers Stefan H
Published: September 2021

Cigarette smoke (CS)-induced inflammation leads to a range of diseases including chronic obstructive pulmonary disease and cancer. The gut microbiota is a major modifying environmental factor that determine the severity of cigarette smoke-induced pathology. Microbiomes and metabolites from CS-exposed mice exacerbate lung inflammation via the gut-lung axis of shared mucosal immunity in mice but these systems are expensive to establish and analyse. Zebrafish embryos and larvae have been used to model the effects of cigarette smoking on a range of physiological processes and offer an amenable platform for screening modifiers of cigarette smoke-induced pathologies with key features of low cost and rapid visual readouts. Here we exposed zebrafish larvae to cigarette smoke extract (CSE) and characterised a CSE-induced leukocytic inflammatory phenotype with increased neutrophilic and macrophage inflammation in the gut. The CSE-induced phenotype was exacerbated by co-exposure to microbiota from the faeces of CS-exposed mice, but not control mice. Microbiota could be recovered from the gut of zebrafish and studied in isolation in a screening setting. This demonstrates the utility of the zebrafish-CSE exposure platform for identifying environmental modifiers of cigarette smoking-associated pathology and demonstrates that the CS-exposed mouse gut microbiota potentiates the inflammatory effects of CSE across host species.
DNA motif analysis of shear stress responsive endothelial enhancers reveals differential association of KLF and ETV/ETS binding sites with gained and lost enhancers
Authors: Tsaryk Roman , Yucel Nora , Leonard Elvin V. , Diaz Noelia , Bondareva Olga , Odenthal-Schnittler Maria , Arany Zoltan , Vaquerizas Juan M. , Schnittler Hans , Siekmann Arndt F.
Published: September 2021

Endothelial cells (EC) lining blood vessels are exposed to mechanical forces, such as shear stress exerted by the flowing blood. These forces control many aspects of EC biology, including vascular tone, cell migration and proliferation in addition to cell size and shape. Despite a good understanding of the genes and signaling pathways responding to shear stress, our insights into the transcriptional regulation of these responses is much more limited. In particular, we do not know the different sets of regulatory elements (enhancers) that might control increases or decreases in gene expression. Here, we set out to study changes in the chromatin landscape of human umbilical vein endothelial cells (HUVEC) exposed to laminar shear stress. To do so, we performed ChIP-Seq for H3K27 acetylation, indicative of active enhancer elements and ATAC-Seq to mark regions of open chromatin in addition to RNA-Seq on HUVEC exposed to 6 hours of laminar shear stress. Our results show a correlation of gained and lost enhancers with up- and downregulated genes, respectively. DNA motif analysis revealed an over-representation of KLF transcription factor (TF) binding sites in gained enhancers, while lost enhancers contained more ETV/ETS motifs. We validated a subset of flow responsive enhancers using luciferase-based reporter constructs and CRISPR-Cas9 mediated genome editing. Lastly, we characterized shear stress responsive genes in ECs of zebrafish embryos using RNA-Seq. Together, our results reveal the presence of shear stress responsive DNA regulatory elements and lay the groundwork for the future exploration of these elements and the TFs binding to them in controlling EC biology.
A mechanism for migrating bacterial populations to non-genetically adapt to new environments
Authors: Mattingly Henry , Emonet Thierry
Published: September 2021

Populations of chemotactic bacteria can rapidly expand into new territory by consuming and chasing an attractant cue in the environment, increasing the population’s overall growth in nutrient-rich environments. Although the migrating fronts driving this expansion contain cells of multiple swimming phenotypes, the consequences of non-genetic diversity for population expansion are unknown. Here, through theory and simulations, we predict that expanding populations non-genetically adapt their phenotype composition to migrate effectively through multiple physical environments. Swimming phenotypes in the migrating front are spatially sorted by chemotactic performance, but the mapping from phenotype to performance depends on the environment. Therefore, phenotypes that perform poorly localize to the back of the group, causing them to selectively fall behind. Over cell divisions, the group composition dynamically enriches for high-performers, enhancing migration speed and overall growth. Furthermore, non-genetic inheritance controls a trade-off between large composition shifts and slow responsiveness to new environments, enabling a diverse population to out-perform a non-diverse one in varying environments. These results demonstrate that phenotypic diversity and collective behavior can synergize to produce emergent functionalities. Non-genetic inheritance may generically enable bacterial populations to transiently adapt to new situations without mutations, emphasizing that genotype-to-phenotype mappings are dynamic and context-dependent.
A plastidial retrograde-signal potentiates biosynthesis of systemic stress response activators
Authors: Zeng Liping , Wang Jin-Zheng , He Xiang , Ke Haiyan , Lemos Mark , Gray William M. , Dehesh Katayoon
Published: September 2021

Plants employ an array of intricate and hierarchical signaling cascades to perceive and transduce informational cues to synchronize and tailor adaptive responses. Systemic stress response (SSR) is a recognized complex signaling and response network quintessential to plant’s local and distal responses to environmental triggers, however, the identity of the initiating signals has remained fragmented.

Here, we show that both biotic (aphids and viral pathogens) and abiotic (high-light and wounding) stresses induce accumulation of the plastidial-retrograde-signaling metabolite, methylerythritol cyclodiphosphate (MEcPP), leading to reduction of the phytohormone, auxin, and the subsequent decreased expression of the phosphatase, PP2C.D1.

This enables phosphorylation of mitogen-activated protein kinases (MAPK3/6), and the consequential induction of the downstream events ultimately resulting in biosynthesis of the two SSR priming metabolites, pipecolic- and N-hydroxy-pipecolic acid.

This work identifies plastids as the initiation site, and the plastidial retrograde-signal, MEcPP as the initiator of a multi-component signaling cascade potentiating the biosynthesis of SSR activators, in response to biotic and abiotic triggers.
Membrane-mediated dimerization potentiates PIP5K lipid kinase activity
Authors: Hansen Scott D. , Lee Albert A. , Groves Jay T.
Published: September 2021

The phosphatidylinositol 4-phosphate 5-kinase (PIP5K) family of lipid modifying enzymes generate the majority of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) lipids found at the plasma membrane in eukaryotic cells. PI(4,5)P2 lipids serve a critical role in regulating receptor activation, ion channel gating, endocytosis, and actin nucleation. Here we describe how PIP5K activity is regulated by cooperative binding to PI(4,5)P2 lipids and membrane-mediated dimerization of the kinase domain. In contrast to constitutively dimeric phosphatidylinositol 5-phosphate 4-kinase (PIP4K, type II PIPK), solution PIP5K exists in a weak monomer-dimer equilibrium. PIP5K monomers can associate with PI(4,5)P2 containing membranes and dimerize in a protein density dependent manner. Although dispensable for PI(4,5)P2 binding and lipid kinase activity, dimerization enhances the catalytic efficiency of PIP5K through a mechanism consistent with allosteric regulation. Additionally, dimerization amplifies stochastic variation in the kinase reaction velocity and strengthens effects such as the recently described stochastic geometry sensing. Overall, the mechanism of PIP5K membrane binding creates a broad dynamic range of lipid kinase activities that are coupled to the density of PI(4,5)P2 and membrane bound kinase.
Using all gene families vastly expands data available for phylogenomic inference
Authors: Smith Megan L. , Vanderpool Dan , Hahn Matthew W.
Published: September 2021

Traditionally, single-copy orthologs have been the gold standard in phylogenomics. Most phylogenomic studies identify putative single-copy orthologs using clustering approaches and retain families with a single sequence per species. This limits the amount of data available by excluding larger families. Recent advances have suggested several ways to include data from larger families. For instance, tree-based decomposition methods facilitate the extraction of orthologs from large families. Additionally, several methods for species tree inference are robust to the inclusion of paralogs, and could use all of the data from larger families. Here, we explore the effects of using all families for phylogenetic inference by examining relationships among 26 primate species in detail, and by analyzing five additional datasets. We compare single-copy families, orthologs extracted using tree-based decomposition approaches, and all families with all data. We explore several species tree inference methods, finding that identical trees are returned across nearly all subsets of the data and methods for primates. The relationships among Platyrrhini remain contentious; however, the species tree inference method matters more than the subset of data used. Using data from larger gene families drastically increases the number of genes available and leads to consistent estimates of branch lengths, nodal certainty and concordance, and inferences of introgression in primates. For the other datasets, topological inferences are consistent whether single-copy families or orthologs extracted using decomposition approaches are analyzed. Using larger gene families is a promising approach to include more data in phylogenomics without sacrificing accuracy, at least when high-quality genomes are available.
Dynamic regulation and requirement for ribosomal RNA transcription during mammalian development
Authors: Falcon Karla T. , Watt Kristin E.N. , Dash Soma , Zhao Ruonan , Sakai Daisuke , Moore Emma L. , Fitriasari Sharien , Childers Melissa , Sardiu Mihaela E. , Swanson Selene , Tsuchiya Dai , Unruh Jay , Bugarinovic George , Li Lin , Shiang Rita , Achilleos Annita , Dixon Jill , Dixon Michael J. , Trainor Paul A.
Published: September 2021

Ribosomal RNA (rRNA) transcription by RNA Polymerase I (Pol I) is a critical rate-limiting step in ribosome biogenesis, which is essential for cell survival. Despite its global function, disruptions in ribosome biogenesis cause tissue-specific birth defects called ribosomopathies, which frequently affect craniofacial development. Here, we describe a cellular and molecular mechanism underlying the susceptibility of craniofacial development to disruptions in Pol I transcription. We show that Pol I subunits are highly expressed in the neuroepithelium and neural crest cells (NCC), which generate most of the craniofacial skeleton. High expression of Pol I subunits sustains elevated rRNA transcription in NCC progenitors, which supports their high tissue-specific levels of protein translation, but also makes NCC particularly sensitive to rRNA synthesis defects. Consistent with this model, NCC-specific deletion of Pol I subunits Polr1a, Polr1c, and associated factor Tcof1 in mice cell-autonomously diminishes rRNA synthesis, which causes an imbalance between rRNA and ribosomal proteins. This leads to increased binding of ribosomal proteins Rpl5 and Rpl11 to Mdm2 and concomitantly diminished binding between Mdm2 and p53. Consequently, p53 protein accumulates, resulting in NCC apoptosis and craniofacial anomalies. Furthermore, compound mutations in Pol I subunits and associated factors specifically exacerbates the craniofacial anomalies characteristic of the ribosomopathies Treacher Collins Syndrome and Acrofacial Dysostosis-Cincinnati Type. Altogether, our novel results demonstrate a dynamic spatiotemporal requirement for rRNA transcription during mammalian cranial NCC development and corresponding tissue-specific threshold sensitivities to disruptions in rRNA transcription in the pathogenesis of congenital craniofacial disorders.

Significance statement

RNA Polymerase I (Pol I) mediated rRNA transcription is required for protein synthesis in all tissues for normal growth and survival as well as for proper embryonic development. Interestingly, disruptions in Pol I mediated transcription perturb ribosome biogenesis and lead to tissue-specific birth defects, which commonly affect the head and face. Our novel results show that during mouse development, Pol I mediated rRNA transcription and protein translation is tissue-specifically elevated in neural crest cells, which give rise to bone, cartilage, and ganglia of the head and face. Using new mouse models, we further show that neural crest cells are highly sensitive to disruptions in Pol I and that when rRNA synthesis is genetically downregulated, it specifically results in craniofacial anomalies.
Pink-beam serial femtosecond crystallography for accurate structure-factor determination at an X-ray free-electron laser
Authors: Nass Karol , Bacellar Camila , Cirelli Claudio , Dworkowski Florian , Gevorkov Yaroslav , James Daniel , Johnson Philip J. M. , Kekilli Demet , Knopp Gregor , Martiel Isabelle , Ozerov Dmitry , Tolstikova Alexandra , Vera Laura , Weinert Tobias , Yefanov Oleksandr , Standfuss Jörg , Reiche Sven , Milne Christopher J.
Published: September 2021

Serial femtosecond crystallography (SFX) at X-ray free-electron lasers (XFELs) enables essentially radiation-damage-free macromolecular structure determination using microcrystals that are too small for synchrotron studies. However, SFX experiments often require large amounts of sample in order to collect highly redundant data where some of the many stochastic errors can be averaged out to determine accurate structure-factor amplitudes. In this work, the capability of the Swiss X-ray free-electron laser (SwissFEL) was used to generate large-bandwidth X-ray pulses [Δλ/λ = 2.2% full width at half-maximum (FWHM)], which were applied in SFX with the aim of improving the partiality of Bragg spots and thus decreasing sample consumption while maintaining the data quality. Sensitive data-quality indicators such as anomalous signal from native thaumatin micro-crystals and de novo phasing results were used to quantify the benefits of using pink X-ray pulses to obtain accurate structure-factor amplitudes. Compared with data measured using the same setup but using X-ray pulses with typical quasi-monochromatic XFEL bandwidth (Δλ/λ = 0.17% FWHM), up to fourfold reduction in the number of indexed diffraction patterns required to obtain similar data quality was achieved. This novel approach, pink-beam SFX, facilitates the yet underutilized de novo structure determination of challenging proteins at XFELs, thereby opening the door to more scientific breakthroughs.