bluuebunny/crossref_metadata_2025 huggingface dataset:
Elastic cloaking for a periodic distribution of parallel finite cracks
Authors: Yang Ping , Wang Xu , Schiavone Peter
Published: May 2021

We achieve elastic cloaking for a periodic distribution of an infinite number of parallel finite mode III cracks by means of the complex variable method and the theory of Cauchy singular integral equations. The cloaking bimaterial structure is composed of an undisturbed uniformly stressed left half-plane perfectly bonded via a wavy interface to the right half-plane which contains periodic cracks. The original design of the wavy interface and the positions of the periodic cracks are ultimately reduced to the solution of a Cauchy singular integral equation which can be solved numerically.
Neural bases of Frustration-Aggression Theory: A multi-domain meta-analysis of functional neuroimaging studies
Authors: Dugré Jules R. , Potvin Stéphane
Published: May 2021

Early evidence suggests that unexpected non-reward may increase the risk for aggressive behaviors. Despite the growing interest in understanding brain functions that may be implicated in aggressive behaviors, the neural processes underlying such frustrative events remain largely unknown. Furthermore, meta-analytic results have produced discrepant results, potentially due to substantial differences in the definition of anger/aggression constructs. Therefore, coordinate-based meta-analyses on unexpected non-reward and retaliatory behaviors in healthy subjects were conducted. Conjunction analyses were further examined to discover overlapping brain activations across these meta-analytical maps. Frustrative non-reward deactivated the orbitofrontal cortex, ventral striatum and posterior cingulate cortex, whereas increased activations were observed in midcingulo-insular regions, as well as dorsomedial prefrontal cortex, amygdala, thalamus and periaqueductal gray, when using liberal threshold. Retaliation activated of midcingulo-insular regions, the dorsal caudate and the primary somatosensory cortex. Conjunction analyses revealed that both strongly activated midcingulo-insular regions. Our results underscore the role of anterior midcingulate/pre-supplementary motor area and fronto-insular cortex in both frustration and retaliatory behaviors. A neurobiological framework for understanding frustration-based impulsive aggression is provided.
A comprehensive assessment of statin discontinuation among patients who concurrently initiate statins and CYP3A4-inhibitor drugs; a multistate transition model
Authors: Donneyong Macarius M. , Zhu Yuxi , Chang Teng-Jen , Zhang Pengyue , Li Yiting , Hunold Katherine M. , Chiang ChienWei , Unroe Kathleen , Caterino Jeffrey M. , Li Lang
Published: May 2021

Aims

To describe the 1-year direct and indirect transition probabilities to premature discontinuation of statin therapy after concurrently initiating statins and CYP3A4-inhibitor drugs.

Methods

A retrospective new-user cohort study design was used to identify (N=160828) patients who concurrently initiated CYP3A4-inhibitors (diltiazem, ketoconazole, clarithromycin, others) and CYP3A4-metabolized statins (statin DDI exposed, n = 104774) vs. other statins (unexposed, n = 56054) from the MarketScan Commercial claims database (2012 – 2017). These groups were matched (2:1) through propensity score-matching techniques. We applied a multistate transition model to compare the 1-year transition probabilities involving four distinct states (start, adverse drug events [ADEs], discontinuation of CYP3A4-inhibitor drugs, and discontinuation of statin therapy) between those exposed to statin DDIs, vs. unexposed. Statistically significant differences were assessed by comparing the 95% confidence intervals (CIs) of probabilities.

Results

Patients exposed to statin DDIs, vs. unexposed, were significantly less likely to discontinue statin therapy (71.4 [95% CI: 71.1, 71.6] vs. 73.3 [95% CI: 72.9, 73.6]) but more likely to experience an ADE (3.4 [95% CI: 3.3, 3.5] vs. 3.2 [95% CI: 3.1, 3.3]) and discontinue with CYP3A4-inhibitor therapy (21.0 [95% CI: 20.8, 21.3] vs. 19.5 [95% CI: 19.2, 19.8]) directly after concurrently starting stains and CYP3A. Subsequent to experiencing an ADE, those exposed to statin DDIs were still less likely to discontinue statin therapy but were significantly more likely to discontinue CYP3A4-inhibitor therapy.

Conclusion

While statin DDI exposure was associated with higher likelihood of ADEs, this did not increase the risk of premature statin discontinuation among patients exposed to statin DDIs, versus unexposed.
Identifying Patterns of ALS Progression from Sparse Longitudinal Data
Authors: Ramamoorthy Divya , Severson Kristen , Ghosh Soumya , Sachs Karen ,   Answer ALS, Glass Jonathan D. , Fournier Christina N. ,   Pooled Resource Open-Access ALS Clinical Trials Consortium, Berry James , Ng Kenney , Fraenkel Ernest
Published: May 2021

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that is complex in its onset, pattern of spread, and disease progression. The heterogeneity of ALS makes it extremely challenging to determine if a disease modifying therapy is effectively slowing progression. While accurately modeling ALS progression is critical to developing therapeutics, current computational methods fail to capture the complexity of disease progression. We aimed to robustly characterize disease progression patterns in ALS.

We obtained data from four clinical cohorts that cover more than 3,500 patients and include both observational and clinical trial studies. To determine whether there were common patterns of disease progression, we developed an approach based on a Mixture of Gaussian Processes (MoGP) to model longitudinal clinical data. Our approach automatically identifies clusters of patients who show similar disease progression patterns, modeling their average trajectory and the spread of the distribution in each cluster. Importantly, the method does not require any prior knowledge of the expected number of clusters.

The MoGP approach revealed that ALS progression, as measured using the ALS functional rating scale (ALSFRS-R) or forced vital capacity, is often non-linear with periods of stable disease preceded or followed by rapid decline. Patterns of progression in ALSFRS-R were robust to sparse data. When at least one year of longitudinal data were available, MoGP predictions were significantly more accurate than linear models, which are commonly used in clinical trials. Progression patterns were consistent across different cohorts despite differences in the frequency of data collection and the lengths of follow-up periods. We further showed that clusters identified from one large, publicly available study population could be used to stratify unseen participants in other studies. We also showed that these progression trajectories correspond with survival outcomes.

This work highlights the importance of modeling nonlinear disease progression for developing more advanced clinical trial endpoint analysis models. In ALS, sporadic, rapid decline (“functional cliffs”) and sigmoidal patterns in disease progression in untreated patients may obscure detection of therapeutic efficacy if linear models are used. We provide a pre-trained computational model of observed clinical patterns that can be used by others to analyze new ALS patient cohorts. We expect that the MoGP approach can also be applied to additional ALS outcome measures and to other progressive diseases. Our results provide a critical advance in characterizing the complex disease progression patterns of ALS.
Performance of polygenic risk scores for cancer prediction in a racially diverse academic biobank
Authors: Wang Louise , Desai Heena , Verma Shefali S. , Le Anh , Hausler Ryan , Verma Anurag , Judy Renae , Doucette Abigail , Gabriel Peter E. ,   Regeneron Genetics Center, Nathanson Katherine L. , Damrauer Scott , Mowery Danielle L. , Ritchie Marylyn D. , Kember Rachel L. , Maxwell Kara N.
Published: May 2021

Purpose

Genome-wide association studies (GWAS) have identified hundreds of single nucleotide polymorphisms (SNPs) significantly associated with several cancers, but the predictive ability of polygenic risk scores (PRS) is unclear, especially among non-Whites.

Methods

Genome-wide genotype data was available for 20,079 individuals enrolled in an academic biobank. PRS were derived from significant DNA variants for 15 cancers. We determined the discriminatory accuracy of each cancer-specific PRS in patients of genetically-determined African and European ancestry separately.

Results

Among individuals of European genetic ancestry, PRS for breast, colon, melanoma, and prostate were significantly associated with their respective cancers (OR 1.25-1.47). Among individuals of African genetic ancestry, PRS for breast, colon, and prostate were significantly associated with their respective cancers. The AUC of a model comprised of age, sex, and principal components was 0.617–0.709 and increased by 1-4% with the PRS in individuals of European genetic ancestry. In individuals of African genetic ancestry, AUC was overall higher in the model without PRS (0.740-0.811) but increased < 1% with the PRS in the majority of cancers.

Conclusion

PRS constructed from SNPs moderately increased discriminatory ability for cancer status in individuals of European but not African ancestry. Further large-scale studies are needed to identify ancestry-specific genetic factors in non-White populations to incorporate PRS into cancer risk assessment.
Contact tracing indicators for COVID-19: rapid scoping review and conceptual framework
Authors: Vogt F , Kurup K , Mussleman P , Habrun C , Crowe M , Woodward A , Jaramillo-Gutierrez G , Kaldor J , Vong S , Del Rio Vilas VJ
Published: May 2021

Background

Contact tracing is one of the key interventions in response to the COVID-19 pandemic but its implementation varies widely across countries. There is little guidance on how to monitor contact tracing performance, and no systematic overview of indicators to assess contact tracing systems or conceptual framework for such indicators exists to date.

Methods

We conducted a rapid scoping review using a systematic literature search strategy in the peer-reviewed and grey literature as well as open source online documents. We developed a conceptual framework to map indicators by type (input, process, output, outcome, impact) and thematic area (human resources, financial resources, case investigation, contact identification, contact testing, contact follow up, case isolation, contact quarantine, transmission chain interruption, incidence reduction).

Results

We identified a total of 153 contact tracing indicators from 1,555 peer-reviewed studies, 894 studies from grey literature sources, and 15 sources from internet searches. Two-thirds of indicators were process indicators (102; 67%), while 48 (31%) indicators were output indicators. Only three (2%) indicators were input indicators. Indicators covered seven out of ten conceptualized thematic areas, with more than half being related to either case investigation (37; 24%) or contact identification (44; 29%). There were no indicators for the input area “financial resources”, the outcome area “transmission chain interruption”, and the impact area “incidence reduction”.

Conclusions

Almost all identified indicators were either process or output indicators focusing on case investigation, contact identification, case isolation or contact quarantine. We identified important gaps in input, outcome and impact indicators, which constrains evidence-based assessment of contact tracing systems. A universally agreed set of indicators is needed to allow for cross-system comparisons and to improve the performance of contact tracing systems.
Multicenter cohort study of multisystem inflammatory syndrome in children (MIS-C)
Authors: Merckx Joanna , Cooke Suzette , Tal Tala El , Laxer Ronald M. , Bitnun Ari , Morris Shaun K. , Yeh E. Ann , Yea Carmen , Gill Peter , Papenburg Jesse , Lefebvre Marie-Astrid , Ulloa-Gutierrez Rolando , Brenes-Chacon Helena , Yock-Corrales Adriana , Ivankovich-Escoto Gabriela , Soriano-Fallas Alejandra , Mezerville Marcela Hernandez-de , Dewan Tammie , Restivo Lea , Nateghian Alireza , Aski Behzad Haghighi , Manafi Ali , Dwilow Rachel , Bullard Jared , Lopez Alison , Sadarangani Manish , Roberts Ashley , Barton Michelle , Petel Dara , Saux Nicole Le , Bowes Jennifer , Purewal Rupeena , Lautermilch Janell , Tehseen Sarah , Bayliss Ann , Wong Jacqueline K. , Leifso Kirk , Foo Cheryl , Robinson Joan
Published: May 2021

BACKGROUND

SARS-CoV-2 infection can lead to multisystem inflammatory syndrome in children (MIS-C). We investigated risk factors for severe disease and explored changes in severity over time.

METHODS

Children up to 17 years of age admitted March 1, 2020 through March 7th, 2021 to 15 hospitals in Canada, Iran and Costa Rica with confirmed or probable MIS-C were included. Descriptive analysis and comparison by diagnostic criteria, country, and admission date was performed. Adjusted absolute average risks (AR) and risk differences (RD) were estimated for characteristics associated with ICU admission or cardiac involvement.

RESULTS

Of 232 cases (106 confirmed) with median age 5.8 years, 56% were male, and 22% had comorbidities. ICU admission occurred in 73 (31%) but none died. Median length of stay was 6 days (inter-quartile range 4-9). Children 6 to 12 years old had the highest AR for ICU admission (44%; 95% confidence interval [CI] 34-53). Initial ferritin greater than 500 mcg/L was associated with ICU admission. When comparing cases admitted up to October 31, 2020 to those admitted later, the AR for ICU admission increased from 25% (CI 17-33) to 37% (CI 29-46) and for cardiac involvement from 44% (CI 35-53) to 75% (CI 66-84). Risk estimates for ICU admission in the Canadian cohort demonstrated a higher risk in December 2020-March 2021 compared to March-May 2020 (RD 25%; 95%CI 7-44).

INTERPRETATION

MIS-C occurred primarily in previously well children. Illness severity appeared to increase over time. Despite a high ICU admission incidence, most children were discharged within one week.
Will there be a third COVID-19 wave? A SVEIRD model based study of India’s situation
Authors: Kannan Dwarakesh , Gurusriram R , Banerjee Rudra , Bhattacharjee Srijit , Varadwaj Pritish Kumar
Published: May 2021

Since first patient detected in India in late February, 2020, SARS-CoV-II virus is playing havoc on India. After the first wave, India is now riding the 2nd wave. As was in the case of European countries like Italy and UK, the 2nd wave is more contagious and at the time of writing this paper, the per day infection is as high as 400,000. The alarming thing is it is not uncommon that people is getting infected multiple time. On the other hand, mass vaccination has started step by step. There is also growing danger of potential 3rd wave is unavoidable, which can even infect kids and minors.

In this situation, an estimation of the dynamics of SARS-CoV-2 is absolutely necessary to combat the pandemic. We have used a modified SEIRD model, that includes vaccination and repeat infection as well. We have studied India and 8 Indian states with varying SARS-CoV-2 infection. We have shown that, Covid-19 wave will be repeated time to time, but the intensity will slow down with time. In most possible situation, our calculation shows COVID-19 will remain as endemic for foreseeable future, unless we are able to increase our vaccination rate manifold.
Comparison of dried blood spots and venous blood for the detection of SARS-CoV-2 antibodies in a population of nursing home residents
Authors: Meyers Eline , Heytens Stefan , Formukong Asangwing , Vercruysse Hanne , De Sutter An , Geens Tom , Hofkens Kenneth , Janssens Heidi , Nys Eveline , Padalko Elizaveta , Deschepper Ellen , Cools Piet
Published: May 2021

Introduction

In the current SARS-CoV-2 pandemic, testing for SARS-CoV-2 specific antibodies is paramount to monitor immune responses in post-authorization vaccination and sero-epidemiology studies. However, large scale and iterative serological testing by venipuncture in older persons can be challenging. Capillary blood sampled using a finger prick and collected on protein saver cards, i.e., dried blood spots (DBS), has already proven to be a promising alternative. However, elderly persons have a reduced cutaneous microvasculature, which may affect DBS-based antibody testing. Therefore, we aimed to evaluate the performance of DBS for the detection of SARS-CoV-2 antibodies in nursing homes residents.

Materials and methods

We collected venous blood and paired Whatman and EUROIMMUN DBS from nursing home residents, and from staff as a reference population. Venous blood samples were analyzed for the presence of SARS-CoV-2 IgG antibodies using the Abbot chemiluminescent microparticle immunoassay (CMIA). DBS were analyzed by the EUROIMMUN enzyme-linked immuno sorbent assay (ELISA) for SARS-CoV-2 IgG antibodies. We performed a statistical assessment to optimize the ELISA cut-off value for the DBS using the Youden’s J index.

Results

A total of 273 paired DBS-serum samples were analyzed, of which 129 were positive as assessed by the reference test. The sensitivities and specificities of DBS ranged from 95.0% to 97.1% and from 97.1% to 98.8%, respectively, depending on population (residents or staff) or DBS card type.

Conclusion

DBS sampling is a valid alternative to venipuncture for the detection of SARS-CoV-2 antibodies in the elderly.
Local prevalence of transmissible SARS-CoV-2 infection: an integrative causal model for debiasing fine-scale targeted testing data
Authors: Nicholson George , Lehmann Brieuc , Padellini Tullia , Pouwels Koen B , Jersakova Radka , Lomax James , King Ruairidh E , Mallon Ann-Marie , Diggle Peter J , Richardson Sylvia , Blangiardo Marta , Holmes Chris
Published: May 2021

Targeted surveillance testing schemes for SARS-CoV-2 focus on certain subsets of the population, such as individuals experiencing one or more of a prescribed list of symptoms. These schemes have routinely been used to monitor the spread of SARS-CoV-2 in countries across the world. The number of positive tests in a given region can provide local insights into important epidemiological parameters, such as prevalence and effective reproduction number. Moreover, targeted testing data has been used inform the deployment of localised non-pharmaceutical interventions. However, surveillance schemes typically suffer from ascertainment bias; the individuals who are tested are not necessarily representative of the wider population of interest. Here, we show that data from randomised testing schemes, such as the REACT study in the UK, can be used to debias fine-scale targeted testing data in order to provide accurate localised estimates of the number of infectious individuals. We develop a novel, integrative causal framework that explicitly models the process underlying the selection of individuals for targeted testing. The output from our model can readily be incorporated into longitudinal analyses to provide local estimates of the reproduction number. We apply our model to characterise the size of the infectious population in England between June 2020 and January 2021. Our local estimates of the effective reproduction number are predictive of future changes in positive case numbers. We also capture local increases in both prevalence and effective reproductive number in the South East from November 2020 to December 2020, reflecting the spread of the Kent variant. Our results illustrate the complementary roles of randomised and targeted testing schemes. Preparations for future epidemics should ensure the rapid deployment of both types of schemes to accurately monitor the spread of emerging and ongoing infectious diseases.
Screening of renal function among a group of physicians working in a hospital who are often self neglected
Authors: Kashem MA , Ullah Ahsan , Biswas Rajat Sanker Roy
Published: May 2021

Background

Prevalence of chronic kidney disease (CKD) has been increasing rapidly worldwide and early screening to detect kidney disease, particularly at its early stages is pivotal to stop its further deterioration. Population based study on detection at early stage of kidney disease and it’s prevalence are scanty in our country, especially among the medical professional personnel. Hence taking advantage of the observance of World Kidney Day 2020, we conducted a screening program for kidney disease organized at the Chattogram Maa O Shishu Hospital (CMOSH) premises among a group of physicians of the hospital.

Methods

This was a cross sectional observational study among 67 physicians of different ranks (medical officer to professor), working at our hospital in different discipline. Age, body weight, height, Body Mass Index (BMI), blood pressure were documented, and urinary protein and serum creatinine were measured at a single sitting. Kidney function was estimated by calculating the glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) formula. Kidney function was classified according to estimated GFR (eGFR) and Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines.

Results

A total of 67 working physicians of the hospital were studied. Among them majority subjects (30) were in the age group of 20 to 29 years. Among all 11.9% participants had proteinuria (trace to 1 plus). The distribution of eGFR was symmetrical, with the majority (70.10%) of subjects in the 60 to 89 ml/min category; 11.90% had 30 to 59 ml/min category and only 17.90% of the study population had eGFR > 90 ml/min. An inverse relation between eGFR and age, and a direct relation between eGFR and BMI were observed.

Conclusion

Proteinuria, low eGFR levels might be related with future decline in renal function among the studied subjects and so regular health check-up is important to abate the potential epidemic of kidney disease among the health professionals.
Trait mindfulness is associated with less amyloid, tau, and cognitive decline in individuals at risk for Alzheimer’s disease
Authors: Strikwerda-Brown Cherie , Ozlen Hazal , Binette Alexa Pichet , Chapleau Marianne , Marchant Natalie L. , Breitner John C. S. , Villeneuve Sylvia ,   for the PREVENT-AD Research Group
Published: May 2021

BACKGROUND AND OBJECTIVES

Mindfulness, defined as non-judgmental awareness of the present moment, has been associated with an array of mental and physical health benefits, including improved cognitive functioning and changes to brain structure and function. Mindfulness may also represent a protective factor for Alzheimer’s disease (AD). Here, we tested the potential protective effect of trait mindfulness on cognitive decline and AD pathology in older adults at risk for AD dementia.

METHODS

Two hundred sixty-one nondemented older adults with a family history of AD dementia were included from the PREVENT-AD observational cohort study, including 124 with Aβ- and tau-positron emission tomography (PET) scans. All participants completed measures of trait mindfulness and longitudinal cognitive assessments. Multivariate partial least squares analyses were used to examine relationships between combinations of different facets of trait mindfulness and (1) cognitive decline, (2) Aβ, and (3) tau.

RESULTS

Higher levels of mindful nonjudgment, describing, and nonreactivity were associated with less cognitive decline in attention, global cognition, and immediate and delayed memory. Higher levels of mindful nonjudgment and nonreactivity were related to less Aβ-PET signal in bilateral medial and lateral temporoparietal and frontal regions. Higher levels of mindful acting with awareness, describing, nonjudgment, and nonreactivity were associated with less tau-PET signal in bilateral temporal regions, namely entorhinal cortex, amygdala, and parahippocampal, fusiform, and inferior temporal gyri. These relationships remained significant when additional demographic (age, sex, education and APOE status) and psychological (personality traits and neuropsychiatric symptoms) were included in analyses. When mindfulness, personality traits, and neuropsychiatric symptoms were entered into the same model, mindful nonjudgment showed the strongest association with cognitive decline and Aβ.

DISCUSSION

Trait mindfulness is associated with less cognitive decline and less Aβ and tau in the brain in older adults at risk for AD dementia. In addition to its other health benefits, trait mindfulness may also represent a psychological protective factor for AD dementia. Longitudinal studies examining the temporal relationship between trait mindfulness and AD markers, along with mindfulness intervention studies with cognition and pathology as outcome variables, will be important for further clarifying the potential protective benefits of mindfulness on AD risk.
Frailty is a predictor of medication-related harm requiring healthcare utilisation: a multicentre prospective cohort study
Authors: Stevenson Jennifer M. , Parekh Nikesh , Chua Kia-Chong , Davies J. Graham , Schiff Rebekah , Rajkumar Chakravarthi , Ali Khalid
Published: May 2021

Objectives

To determine the association between frailty and medication-related harm requiring healthcare utilisation.

Design

Prospective observational cohort study.

Setting

6 primary and 5 secondary care sites across South East England, September 2013 – November 2015.

Participants

1280 participants, 65 years old or over, who were due for discharge from general medicine and older persons’ wards following an acute episode of care. Exclusion criteria were limited life expectancy, transfer to another hospital and consent not gained.

Main outcome measures

Medication-related harm requiring healthcare utilisation, including adverse drug reactions, non-adherence and medication error determined via triangulation of: patient/carer reports gathered through a structured telephone interview; primary care medical record review; and prospective consultant-led review of re-admission to recruiting hospital. Frailty was measured using a Frailty Index, developed using a standardised approach. Marginal estimates were obtained from logistic regression models to examine how probabilities of healthcare service use due to medication-related harm were associated with increasing polypharmacy and frailty.

Results

Healthcare utilisation due to medication-related harm was significantly associated with frailty (OR = 10.06, 95% CI 2.06 to 49.26, p = 0.004), independent of age, gender, and polypharmacy. With increasing polypharmacy, the need for healthcare use as a result of MRH increases from a probability of around 0.2 to 0.4. This is also the case for frailty.

Conclusions

Frailty is as important as polypharmacy in its association with MRH. Reducing the burden of frailty through an integrated health and social care approach, alongside strategies to reduce inappropriate polypharmacy, may reduce MRH related healthcare utilisation.

Trial registration

Approved by the National Research Ethics Service, East of England (REC Reference 13/EE/0075)
Systematic characterization of short intronic splicing-regulatory elements
Authors: Gao Yuan , Lin Kuan-Ting , Yang Yang , Bai Jialin , Wang Li , Sun Junjie , Sheng Lei , Krainer Adrian R. , Hua Yimin
Published: May 2021

Intronic splicing enhancers and silencers (ISEs and ISSs) are two groups of splicing-regulatory elements (SREs) that play critical roles in determining splice-site selection, particularly for alternatively spliced introns or exons. SREs are often short motifs; their mutation or dysregulation of their cognate proteins frequently causes aberrant splicing and results in disease. To date, however, knowledge about SRE sequences and how they regulate splicing remains limited. Here, using an SMN2 minigene, we generated a complete pentamer-sequence library that comprises all possible combinations of 5 nucleotides in intron 7, at a fixed site downstream of the 5′ splice site. We systematically analyzed the effects of all 1023 mutant pentamers on exon 7 splicing, in comparison to the wild-type minigene, in HEK293 cells. Our data show that the majority of pentamers significantly affect exon 7 splicing: 584 of them are stimulatory and 230 are inhibitory. To identify actual SREs, we utilized a motif set enrichment analysis (MSEA), from which we identified groups of stimulatory and inhibitory SRE motifs. We experimentally validated several strong SREs in SMN1/2 and MAPT minigene settings. Our results provide a valuable resource for understanding how short RNA sequences regulate splicing. Many novel SREs can be explored further to elucidate their mechanism of action.
Protein cost minimization promotes the emergence of coenzyme redundancy
Authors: Goldford Joshua E. , George Ashish B. , Flamholz Avi I. , Segrè Daniel
Published: May 2021

Coenzymes distribute a variety of chemical moieties throughout cellular metabolism, participating in group (e.g., phosphate, acyl) and electron transfer. For a variety of reactions requiring acceptors or donors of specific resources, there often exist degenerate sets of molecules (e.g., NAD(H) and NADP(H)) that carry out similar functions. Although the physiological roles of various coenzyme systems are well established, it is unclear what selective pressures may have driven the emergence of coenzyme redundancy. Here we use genome-wide metabolic modeling approaches to decompose the selective pressures driving enzymatic specificity for either NAD(H) or NADP(H) in the metabolic network ofEscherichia coli. We found that few enzymes are thermodynamically constrained to using a single coenzyme, and in principle, a metabolic network relying on only NAD(H) is feasible. However, structural and sequence analyses revealed widespread conservation of residues that retain selectivity for either NAD(H) or NADP(H), suggesting that additional forces may shape specificity. Using a model accounting for the cost of oxidoreductase enzyme expression, we found that coenzyme redundancy universally reduces the minimal amount of protein required to catalyze coenzyme-coupled reactions, inducing individual reactions to strongly prefer one coenzyme over another when reactions are near thermodynamic equilibrium. We propose that protein minimization generically promotes coenzyme redundancy, and that coenzymes typically thought to exist in a single pool (e.g., CoA) may exist in more than one form (e.g., dephospho-CoA).

Significance statement

Metabolism relies on a small class of molecules (coenzymes) that serve as universal donors and acceptors of key chemical groups and electrons. Although metabolic networks crucially depend on structurally redundant coenzymes (e.g., NAD(H) and NADP(H)) associated with different enzymes, the criteria that led to the emergence of this redundancy remain poorly understood. Our combination of modeling, and structural and sequence analysis indicates that coenzyme redundancy is not essential for metabolism, but rather an evolved strategy promoting efficient usage of enzymes when biochemical reactions are near equilibrium. Our work suggests that early metabolism may have operated with fewer coenzymes, and that adaptation for metabolic efficiency may have driven the rise of coenzyme diversity in living systems.
The mirror neuron system compensates for amygdala dysfunction-associated social deficits in individuals with higher autistic traits
Authors: Xu Lei , Zheng Xiaoxiao , Yao Shuxia , Li Jialin , Fu Meina , Li Keshuang , Zhao Weihua , Li Hong , Becker Benjamin , Kendrick Keith M.
Published: May 2021

The amygdala is a core node in the social brain which exhibits structural and functional abnormalities in Autism spectrum disorder and there is evidence that the mirror neuron system (MNS) can functionally compensate for impaired emotion processing following amygdala lesions. In the current study, we employed an fMRI paradigm in 241 subjects investigating MNS and amygdala responses to observation, imagination and imitation of dynamic facial expressions and whether these differed in individuals with higher as opposed to lower autistic traits. Results indicated that individuals with higher compared to lower autistic traits showed reduced left amygdala responses to imitation and enhanced responses in the left superior temporal sulcus (STS) of the MNS to observation, imagination and imitation. Additionally, functional connectivity between the left amygdala and the left STS as well as some other MNS regions was increased in individuals with higher autistic traits, especially during imitation of fearful expressions. The amygdala-MNS connectivity significantly moderated autistic group differences on recognition memory for fearful faces and real-life social network indices, indicating that increased amygdala-MNS connectivity could diminish the social behavioral differences between higher and lower autistic trait groups. Overall, findings demonstrate decreased imitation-related amygdala activity in individuals with higher autistic traits in the context of increased cortical MNS activity and amygdala-MNS connectivity which may functionally compensate for amygdala dysfunction and social deficits. Training targeting the MNS may capitalize on this compensatory mechanism for therapeutic benefits in Autism spectrum disorder.
Assessment of the infectious threshold of SARS-CoV-2 in primary airway epithelial cells
Authors: Essaidi-Laziosi Manel , Perez Rodriguez Francisco Javier , Sattonnet-Roche Pascale , Hulo Nicolas , Jacquerioz Frederique , Kaiser Laurent , Eckerle Isabella
Published: May 2021

Comparison of virus isolation success from clinical samples across a range of viral loads inoculated in parallel on Vero E6 and human airway epithelia (HAE) showed lower success of virus isolation in HAE, suggesting an overestimation of actual infectiousness in humans using Vero E6 cell lines, commonly considered as reference.
Interval timing and midfrontal delta oscillations are impaired in Parkinson’s disease patients with freezing of gait
Authors: Bosch Taylor J. , Barsainya Richa , Ridder Andrew , Santosh KC , Singh Arun
Published: May 2021

Gait abnormalities and cognitive dysfunction are common in patients with Parkinson’s disease (PD) and get worst with disease progression. Recent evidence has suggested a strong relationship between gait abnormalities and cognitive dysfunction in PD patients and impaired cognitive control could be one of the causes for abnormal gait patterns. However, the pathophysiological mechanisms of cognitive dysfunction in PD patients with gait problems are unclear. Here, we collected scalp electroencephalography (EEG) signals during a 7-second interval timing task to investigate the cortical mechanisms of cognitive dysfunction in PD patients with (PDFOG+, n=34) and without (PDFOG–, n=37) freezing of gait, as well as control subjects (n=37). Results showed that the PDFOG+ group exhibited the lowest maximum response density at around 7 seconds compared to PDFOG– and control groups, and this response density peak correlated with gait abnormalities as measured by FOG scores. EEG data demonstrated that PDFOG+ had decreased midfrontal delta-band power at the onset of the target cue, which was also correlated with maximum response density and FOG scores. In addition, our classifier performed better at discriminating PDFOG+ from PDFOG– and controls with an area under the curve of 0.93 when midfrontal delta power was chosen as a feature. These findings suggest that abnormal midfrontal activity in PDFOG+ is related to cognitive dysfunction and describe the mechanistic relationship between cognitive and gait functions in PDFOG+. Overall, these results could advance the development of novel biosignatures and brain stimulation approaches for PDFOG+.
Chromatin interaction maps identify Wnt responsivecis-regulatory elements coordinatingPaupar-Pax6expression in neuronal cells
Authors: Pavlaki Ioanna , Shapiro Michael , Pisignano Giuseppina , Telenius Jelena , Descalzo Silvia Muñoz , Williams Robert J. , Hughes Jim R. , Vance Keith W.
Published: May 2021

Central nervous system-expressed long non-coding RNAs (lncRNAs) are often located in the genome close to protein coding genes involved in transcriptional control. Such lncRNA-protein coding gene pairs are frequently temporally and spatially co-expressed in the nervous system and are predicted to act together to regulate neuronal development and function. Although some of these lncRNAs also bind and modulate the activity of the encoded transcription factors, the regulatory mechanisms controlling co-expression of neighbouring lncRNA-protein coding genes remain unclear. Here, we used high resolution NG Capture-C to map thecis-regulatory interaction landscape of the key neuro-developmentalPaupar-Pax6lncRNA-mRNA locus. The results defined chromatin architecture changes associated with highPaupar-Pax6expression in neurons and identified both promoter selective as well as sharedcis-regulatory interactions with thePauparandPax6promoters involved in regulatingPaupar-Pax6co-expression in neuronal cells. The TCF7L2 transcription factor, a major regulator of chromatin architecture and effector of the Wnt signalling pathway, binds to a subset of these candidatecis-regulatory elements to coordinatePauparandPax6co-expression. We identify a functional TCF7L2 boundcis-regulatory element within thePaupargene, suggesting that thePauparDNA locus itself regulatesPax6expression in addition to its previously described transcriptdependent modes of action. Our work provides important insights into the chromatin interactions, signalling pathways and transcription factors controlling co-expression of adjacent lncRNAs and protein coding genes in the brain.
Standard PBMC cryopreservation selectively decreases detection of nine clinically-relevant T-cell markers
Authors: Capelle Christophe M. , Cire Séverine , Ammerlaan Wim , Konstantinou Maria , Balling Rudi , Betsou Fay , Cosma Antonio , Ollert Markus , Hefeng Feng Q.
Published: May 2021

Biobanking is an operational component of various epidemiological studies and clinical trials. Although peripheral blood is routinely acquired and stored in biobanks, the effects of specimen processing on cell composition and clinically-relevant functional markers of T cells still require a systematic evaluation. Here we assessed 25 relevant T-cell markers and showed that the detection of nine membrane markers, e.g., PD-1, CTLA4, KLRG1, CD25, CD122, CD127 and others reflecting exhaustion, senescence and other functions was reduced among at least one T-cell subset following standard processing, although the frequency of CD4, CD8 and regulatory T cells was unaffected. Nevertheless, a six-month-long cryopreservation did not impair the expression levels of many other membrane and all the eight tested intracellular lineage or functional T-cell markers. Our findings uncover that several clinically-relevant markers are particularly affected by processing and the interpretation of those results in clinical trials and translational research should be done with caution.
Permutation-based significance analysis reduces the type 1 error rate in bisulfite sequencing data analysis of human umbilical cord blood samples
Authors: Laajala Essi , Halla-aho Viivi , Grönroos Toni , Ullah Ubaid , Vähä-Mäkilä Mari , Nurmio Mirja , Kallionpää Henna , Lietzén Niina , Mykkänen Juha , Rasool Omid , Toppari Jorma , Orešič Matej , Knip Mikael , Lund Riikka , Lahesmaa Riitta , Lähdesmäki Harri
Published: May 2021

Background

DNA methylation patterns are largely established in-utero and might mediate the impacts of in-utero conditions on later health outcomes. Associations between perinatal DNA methylation marks and pregnancy-related variables, such as maternal age and gestational weight gain, have been earlier studied with methylation microarrays, which typically cover less than 2 % of human CpG sites. To detect such associations outside these regions, we chose the bisulfite sequencing approach.

Methods

We collected and curated all available clinical data on 200 newborn infants; whose umbilical cord blood samples were analyzed with the reduced representation bisulfite sequencing (RRBS) method. A generalized linear mixed effects model was fit for each high coverage CpG site, followed by spatial and multiple testing adjustment of P values to identify differentially methylated cytosines (DMCs) and regions (DMRs) associated with clinical variables such as maternal age, mode of delivery, and birth weight. Type 1 error rate was then evaluated with a permutation analysis.

Results

We discovered a strong inflation of spatially adjusted P values through the permutation analysis, which we then applied for empirical type 1 error control. Based on empirically estimated significance thresholds, very little differential methylation was associated with any of the studied clinical variables, other than sex. With this analysis workflow, the sex-associated differentially methylated regions were highly reproducible across studies, technologies, and statistical models.

Conclusions

The inflation of P values was caused by a common method for spatial adjustment and DMR detection, implemented in tools comb-p and RADMeth. With standard significance thresholds, type 1 error rates were high with both these implementations, across alternative parameter settings and analysis strategies. We conclude that comb-p and RADMeth are convenient methods for the detection of differentially methylated regions, but the statistical significance should either be determined empirically or before the spatial adjustment. Our RRBS data analysis workflow is available inhttps://github.com/EssiLaajala/RRBS_workflow.
Renal Angiotensinogen is Predominantly Liver-Derived in Nonhuman Primates
Authors: Kukida Masayoshi , Cai Lei , Ye Dien , Sawada Hisashi , Katsumata Yuriko , Franklin Michael K. , Hecker Peter I. , Campbell Kenneth S. , Danser A.H. Jan , Mullick Adam E. , Daugherty Alan , Temel Ryan E. , Lu Hong S.
Published: May 2021

AGT (Angiotensinogen) is the unique substrate of the renin-angiotensin system. Liver is the primary source of circulating AGT. The present study determined whether hepatocyte-derived AGT regulates renal AGT accumulation by injecting ASO (antisense oligonucleotides) targeting hepatocyte-derived AGT (GalNAc AGT ASO) into female cynomolgus monkeys. Hepatocyte-specific inhibition of AGT led to profound reductions of plasma AGT concentrations. AGT protein in S1 and S2 of renal proximal tubules was greatly diminished by GalNAc AGT ASO. Given the similarity between nonhuman primates and human, our findings support the notion that renal AGT is predominantly derived from liver, and liver regulates renal angiotensin II production in humans.

Abstract Figure
The METTL5-TRMT112N6-methyladenosine methyltransferase complex regulates metabolism and development via translation
Authors: Sepich-Poore Caraline , Zheng Zhong , Schmitt Emily , Wen Kailong , Zhang Zijie Scott , Cui Xiao-Long , Dai Qing , Zhu Allen C. , Zhang Linda , Castillo Arantxa Sanchez , Zhuang Xiaoxi , He Chuan , Nachtergaele Sigrid
Published: May 2021

Ribosomal RNAs (rRNAs) have long been known to carry modifications, including numerous sites of 2’O-methylation and pseudouridylation, as well asN6-methyladenosine (m6A), andN6,6-dimethyladenosine. While the functions of many of these modifications are unclear, some are highly conserved and occur in regions of the ribosome critical for mRNA decoding. Both 28S rRNA and 18S rRNA carry m6A, and while ZCCHC4 has been identified as the methyltransferase responsible for the 28S rRNA m6A site, the methyltransferase responsible for the 18S rRNA m6A site has remained uncharacterized until recently. Here, we show that the METTL5-TRMT112 complex is the methyltransferase responsible for installing m6A at position 1832 of human 18S rRNA. TRMT112 is required for the metabolic stability of METTL5, and human METTL5 mutations associated with microcephaly and intellectual disability disrupt this interaction. Loss of METTL5 in human cancer lines alters the translation of transcripts associated with mitochondrial biogenesis and function.Mettl5knockout mice display reduced body size and evidence of metabolic defects. This m6A site is located on the 3’ end of 18S rRNA, which may become surface-exposed under some circumstances and thus may play a regulatory role in translation of specific transcripts. While recent work has focused heavily on m6A modifications in mRNA and its roles in mRNA processing and translation, deorphanizing putative methyltransferase enzymes is revealing previously unappreciated regulatory roles for m6A in noncoding RNAs.
Genetics and material culture support repeated expansions into Paleolithic Eurasia from a population hub out of Africa
Authors: Vallini Leonardo , Marciani Giulia , Aneli Serena , Bortolini Eugenio , Benazzi Stefano , Pievani Telmo , Pagani Luca
Published: May 2021

The population dynamics that followed the out of Africa expansion (OoA) and the whereabouts of the early migrants before the differentiation that ultimately led to the formation of Oceanian, West and East Eurasian macro populations have long been debated. Shedding light on these events may, in turn, provide clues to better understand cultural evolution in Eurasia between 50kya and 35kya.

Here we analyze Eurasian Paleolithic DNA evidence to provide a comprehensive population model and validate it in light of available material culture. Leveraging on our integrated approach we propose the existence of a Eurasian population Hub, where Homo sapiens lived between the OoA and the broader colonization of Eurasia, which was characterized by multiple events of expansion and local extinction. A major population wave out of Hub, of which Ust’Ishim, Bacho Kiro and Tianyuan are unadmixed representatives, is broadly associated with Initial Upper Paleolithic lithics and populated West and East Eurasia before or around 45 kya, before getting largely extinct in Europe. In this light, we suggest a parsimonious placement of Oase1 as an individual related to Bacho Kiro who experienced additional Neanderthal introgression. Another expansion, started before 38 kya, is broadly associated with Upper Paleolithic industries and repopulated Europe with sporadic admixtures with the previous wave (GoyetQ116-1) and more systematic ones while moving through Siberia (Yana, Mal’ta).
Single-dose immunisation with a multimerised SARS-CoV-2 receptor binding domain (RBD) induces an enhanced and protective response in mice
Authors: Salzer Ralf , Clark Jordan J. , Vaysburd Marina , Chang Veronica T. , Albecka Anna , Kiss Leo , Sharma Parul , Llamazares Andres Gonzalez , Kipar Anja , Hiscox Julian A. , Owen Andrew , Aricescu A. Radu , Stewart James P. , James Leo C. , Löwe Jan
Published: May 2021

The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, has triggered a worldwide health emergency. So far, several different types of vaccines have shown strong efficacy. However, both the emergence of new SARS-CoV-2 variants and the need to vaccinate a large fraction of the world’s population necessitate the development of alternative vaccines, especially those that are simple and easy to store, transport and administer. Here, we showed that ferritin-like Dps protein from hyperthermophilic Sulfolobus islandicus can be covalently coupled with different SARS-CoV-2 antigens via the SpyCatcher system, to form extremely stable and defined multivalent dodecameric vaccine nanoparticles that remain intact even after lyophilisation. Immunisation experiments in mice demonstrated that the SARS-CoV-2 receptor binding domain (RBD) coupled to Dps (RBD-S-Dps) shows particular promise as it elicited a higher antibody titre and an enhanced neutralising antibody response compared to the monomeric RBD. Furthermore, we showed that a single immunisation with the multivalent RBD-S-Dps completely protected hACE2-expressing mice from serious illness and led to efficient viral clearance from the lungs upon SARS-CoV-2 infection. Our data highlight that multimerised SARS-CoV-2 subunit vaccines are a highly efficacious modality, particularly when combined with an ultra-stable scaffold.