bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection and discrimination of single nucleotide polymorphisms by quantification of CRISPR-Cas catalytic efficiency
Authors: Blanluet Charles , Huyke Diego A. , Ramachandran Ashwin , Avaro Alexandre S. , Santiago Juan G.
Published: May 2022

The specificity of CRISPR-Cas12 assays is attractive for the detection of single nucleotide polymorphisms (SNPs) implicated in, e.g., SARS-CoV-2 variants. Such assays often employ endpoint measurements of SNP or wild type (WT) activated Cas12 trans-cleavage activity; however, the fundamental kinetic effects of SNP versus WT activation remain unknown. We here show that endpoint-based assays are limited by arbitrary experimental choices (like used reporter concentration and assay duration) and work best for known target concentrations. More importantly, we show that SNP (versus WT) activation results in measurable shifts in the Cas12 trans-cleavage substrate affinity (KM) and apparent catalytic efficiency . To address endpoint-based assay limitations, we then develop an assay based on the quantification of Michalis-Menten parameters and apply this assay to a 20-base pair WT target of the SARS-CoV-2 E gene. We find that the measured for WT is 130-fold greater than the lowest among all 60 measured SNPs (compared to a 4.8-fold for endpoint fluorescence of the same SNP). KM also offers strong ability to distinguish SNPs, varies 27-fold over all the cases, and is insensitive to target concentration. Lastly, we point out trends among kinetic rates and SNP base and location within the CRISPR-Cas12 targeted region.
Utilization of Landscape of Kinases and Phosphosites To Predict Kinase-Substrate Association
Authors: Ayati Marzieh , Yılmaz Serhan , Blasco Tavares Pereira Lopes Filipa , Chance Mark R. , Koyutürk Mehmet
Published: May 2022

Motivation

Protein phosphorylation is a key post-translational modification that plays a central role in many cellular processes. With recent advances in biotechnology, thousands of phosphorylated sites can be identified and quantified in a given sample, enabling proteome-wide screening of cellular signaling. However, the kinase(s) that phosphorylate most (> 90%) of the identified phosphorylation sites are unknown. Knowledge of kinase-substrate associations is also mostly limited to a small number of well-studied kinases, with 20% of known kinases accounting for the phosphorylation of 87% of currently annotated sites. The scarcity of available annotations calls for the development of computational algorithms for more comprehensive and reliable prediction of kinase-substrate associations.

Results

To broadly utilize available structural, functional, evolutionary, and contextual information in predicting kinase-substrate associations, we develop a network-based machine learning framework. Our framework integrates a multitude of data sources to characterize the landscape of functional relationships and associations among phosphosites and kinases. To construct a phosphosite-phosphosite association network, we use sequence similarity, shared biological pathways, co-evolution, co-occurrence, and co-phosphorylation of phosphosites across different biological states. To construct a kinase-kinase association network, we integrate protein-protein interactions, shared biological pathways, and membership in common kinase families. We use node embeddings computed from these heterogeneous networks to train machine learning models for predicting kinase-substrate associations. Our systematic computational experiments using the PhosphositePLUS database shows that the resulting algorithm, NetKSA, outperforms state-of-the-art algorithms and resources, including KinomeXplorer and LinkPhinder, in reliably predicting KSAs. By stratifying the ranking of kinases, NetKSA also enables annotation of phosphosites that are targeted by relatively less-studied kinases. Finally, we observe that the performance of NetKSA is robust to the choice of network embedding algorithms, while each type of network contributes valuable information that is complementary to the information provided by other networks.

Conclusion

Representation of available functional information on kinases and phosphorylation sites, along with integrative machine learning algorithms, has the potential to significantly enhance our knowledge on kinase-substrate associations.

Availability

The code and data are available atcompbio.case.edu/NetKSA.
Genetic elements orchestrating Lactobacillus crispatus glycogen metabolism in the vagina
Authors: Hertzberger Rosanne , May Ali , Kramer Gertjan , van Vondelen Isabelle , Molenaar Douwe , Kort Remco
Published: May 2022

Glycogen in the female lower reproductive tract is a major carbon source for vaginal colonization and acidification by common vaginal Lactobacillus species, such as Lactobacillus crispatus. Previously we identified the pullulanase gene pulA in Lactobacillus crispatus, correlating with its ability to autonomously utilize glycogen for growth. Here we further characterize genetic variation and differential regulation of pulA affecting the presence of its gene product on the outer surface layer. We show that alpha-glucan degrading activity dissipates when Lactobacilllus crispatus is grown on glucose, maltose and maltotriose, in agreement with carbon catabolite repression elements flanking the pulA gene. Proteome analysis of the S-layer confirmed that the pullulanase protein is highly abundant in an S-layer enriched fraction, but not in a strain with a defective pullulanase variant or in a pullulanase-sufficient strain grown on glucose. In addition, we provide evidence that Lactobacillus crispatus pulA mutants are relevant in vivo, as they are commonly observed in metagenome datasets of human vaginal microbial communities. Analysis of the largest publicly available human vaginal metagenome dataset indicates that 15 out of 272 samples, containing a Lactobacillus crispatus pulA gene, contain a defective variant of this gene. Another 23 out of 272 samples show large deletions or transposon insertions. Taken together, these results demonstrate that both environmental as well as genetic factors explain variation of Lactobacillus crispatus alpha-glucosidases in the vaginal environment.
Depicting pseudotime-lagged causality across single-cell trajectories for accurate gene-regulatory inference
Authors: Reagor Caleb C. , Velez-Angel Nicolas , Hudspeth A. J.
Published: May 2022

Identifying the causal interactions in gene-regulatory networks requires an accurate understanding of the time-lagged relationships between transcription factors and their target genes. Here we describe DELAY, a convolutional neural network for the inference of gene-regulatory relationships across pseudotime-ordered single-cell trajectories. We show that combining supervised deep learning with joint-probability matrices of pseudotime-lagged trajectories allows the network to overcome important limitations of ordinary Granger causality-based methods, such as the inability to infer cyclic relationships such as feedback loops. Our network outperforms several common methods for inferring gene regulation and predicts novel regulatory networks from scRNA-seq and scATAC-seq datasets given partial ground-truth labels. To validate this approach, we used DELAY to identify important genes and modules in the regulatory network of auditory hair cells, as well as likely DNA-binding partners for two hair cell cofactors (Hist1h1c and Ccnd1) and a novel binding sequence for the hair cell-specific transcription factor Fiz1. We provide an open-source implementation of DELAY at https://github.com/calebclayreagor/DELAY.
Deconstructing body axis morphogenesis in zebrafish embryos using robot-assisted tissue micromanipulation
Authors: Özelçi Ece , Mailand Erik , Rüegg Matthias , Oates Andrew C. , Sakar Mahmut Selman
Published: May 2022

Microsurgical techniques, such as those used in the early 1900s by Mangold and Spemann, were not only foundational for experimental embryology, but are still in use today. Here, we build on these classic techniques by introducing a user-friendly robotic microsurgery platform that allows precise mechanical manipulation of soft tissues in zebrafish embryos. As a proof of principle, we investigated the contribution of different embryonic tissues to vertebrate anteroposterior (AP) axis elongation and segmentation. Using our platform, we reproducibly targeted precise regions of tail explants, and quantified the response in real-time by following notochord and presomitic mesoderm (PSM) morphogenesis and segmentation clock dynamics. We find an extension force generated through the posterior notochord, independent of notochord cell vacuolation, that is strong enough to buckle the structure. Our data suggest that this force generates a unidirectional notochord extension towards the tailbud because PSM tissue around the posterior notochord does not let it slide anteriorly. These results complement existing biomechanical models of axis elongation, revealing a critical coupling between the posterior notochord, the tailbud, and the PSM, and show that somite patterning is robust against structural perturbations.
The shifting importance of abiotic and biotic factors across the life cycles of wild pollinators
Authors: Ogilvie Jane E. , CaraDonna Paul J.
Published: May 2022

Organisms living in seasonal environments are exposed to different environmental conditions as they transition from one life stage to the next across their life cycle. How different life stages respond to these varying conditions is a fundamental aspect of biology and is critical for understanding how organisms will respond to environmental change.

Despite the importance of animal pollinators, we lack a basic understanding of the influence of different environmental factors across their life cycles. We investigated the relative importance of climate conditions, food availability, and previous life stage abundance in a community of wild bumble bee species, asking: how do these three factors influence bee abundance at each life stage?

We used a 7-year dataset to examine the importance of environmental conditions on the abundance of life stages in seven wild bumble bee species. We monitored climate conditions, the abundance of floral resources, and abundances of bees in each life stage across the active colony life cycle in a highly seasonal subalpine ecosystem in the Colorado Rocky Mountains, USA.

Bee abundance at different life stages responded to environmental conditions in a consistent manner across the seven species. The survival and recruitment stage of the life cycle (assessed as abundance of overwintered queens) responded negatively to longer winters; the growth stage (assessed as abundance of workers) responded positively to floral resource availability; and the reproductive stage (assessed as abundance of males) was positively related to the abundance of the previous life stage (workers).

Our long-term examination of annual bumble bees reveals a consistent set of responses in the abundance of each life stage to climate conditions, floral resource availability, and previous life stage abundance. Across species, these three factors each influenced a distinct life stage, illustrating how their relative importance can shift throughout the life cycle. The life-cycle approach we have taken with wild bumble bees highlights that important details about pollinator demography are overlooked without considering life stage-specific responses. Ultimately, it is these life-stage specific responses that shape population outcomes, not only for animal pollinators, but for many organisms living in seasonal environments.
ILC3s select for RORγt+ Tregs and establish tolerance to intestinal microbiota
Authors: Lyu Mengze , Suzuki Hiroaki , Kang Lan , Gaspal Fabrina , Zhou Wenqing , Goc Jeremy , Zhou Lei , Zhou Jordan , Zhang Wen , Live Cell Bank JRI , Shen Zeli , Fox James G. , Sockolow Robbyn E. , Laufer Terri M. , Fan Yong , Eberl Gerard , Withers David R. , Sonnenberg Gregory F.
Published: May 2022

Microbial colonization of the mammalian intestine elicits inflammatory or tolerogenic T cell responses, but the mechanisms controlling these distinct outcomes remain poorly understood and accumulating evidence indicates that aberrant immunity to intestinal microbiota is causally associated with infectious, inflammatory, and malignant diseases1–8. Here, we define a critical pathway controlling the fate of inflammatory versus tolerogenic T cells that are specific for the microbiota and express the transcription factor RORγt. We profiled all RORγt+ immune cells at single cell resolution from the intestine-draining lymph nodes of mice and reveal a dominant presence of Tregs and lymphoid tissue-induced (LTi)-like group 3 innate lymphoid cells (ILC3s), which co-localize at interfollicular regions. These ILC3s have interconverting potential with RORγt+ extrathymic Aire-expressing cells, abundantly express major histocompatibility complex class II, and are necessary and sufficient to promote microbiota-specific RORγt+ Tregs and prevent their expansion as inflammatory T helper (Th)17 cells. This occurs through ILC3-mediated antigen-presentation, interleukin-2 gradients, and αv integrin. Finally, single-cell analyses demonstrate that ILC3 and RORγt+ Treg interactions are impaired in inflammatory bowel disease. Our results define a novel paradigm whereby ILC3s positively select for antigen specific RORγt+ Tregs, and against Th17 cells, to establish immune tolerance to the microbiota and intestinal health.
Initial refinement of data from video-based single-cell tracking
Authors: Suárez Korsnes Mónica , Korsnes Reinert
Published: May 2022

Background

Video recording of cells offers a straightforward way to gain valuable information from their response to treatments. An indispensable step in obtaining such information involves tracking individual cells from the recorded data. A subsequent step is reducing such data to represent essential biological information. This can help to compare various single-cell tracking data providing a novel source of information. The vast array of potential data sources highlights the significance of methodologies prioritizing simplicity, robustness, transparency, affordability, sensor independence, and freedom from reliance on specific software or online services.

Methods

The provided data presents single-cell tracking of clonal (A549) cells as they grow in two-dimensional (2D) monolayers over 94 hours, spanning several cell cycles. The cells are exposed to three different concentrations of yessotoxin (YTX). The data treatments showcase the parametrization of population growth curves, as well as other statistical descriptions. These include the temporal development of cell speed in family trees with and without cell death, correlations between sister cells, single-cell average displacements, and the study of clustering tendencies.

Results

Various statistics obtained from single-cell tracking reveal patterns suitable for data compression and parametrization. These statistics encompass essential aspects such as cell division, movements, and mutual information between sister cells.

Conclusion

This work presents practical examples that highlight the abundant potential information within large sets of single-cell tracking data. Data reduction is crucial in the process of acquiring such information which can be relevant for phenotypic drug discovery and therapeutics, extending beyond standardized procedures. Conducting meaningful big data analysis typically necessitates a substantial amount of data, which can stem from standalone case studies as an initial foundation.
Cortical response variability is driven by local excitability changes with somatotopic organization
Authors: Stephani T. , Nierula B. , Villringer A. , Eippert F. , Nikulin V.V.
Published: May 2022

Identical sensory stimuli can lead to different neural responses depending on the instantaneous brain state. Specifically, neural excitability in sensory areas may shape the brain’s response already from earliest cortical processing onwards. However, whether these dynamics affect a given sensory domain globally or occur on a spatially local level is largely unknown. We studied this in the somatosensory domain of 38 human participants with EEG, presenting stimuli to the median and tibial nerves alternatingly, and testing the co-variation of initial cortical responses in hand and foot areas, as well as their relation to pre-stimulus oscillatory states. We found that amplitude fluctuations of initial cortical responses to hand and foot stimulation – the N20 and P40 components of the somatosensory evoked potential (SEP), respectively – were not related, indicating local excitability changes in primary sensory regions. In addition, effects of pre-stimulus alpha (8-13 Hz) and beta (18-23 Hz) band amplitude on hand-related responses showed a robust somatotopic organization, thus further strengthening the notion of local excitability fluctuations. However, for foot-related responses, the spatial specificity of pre-stimulus effects was less consistent across frequency bands, with beta appearing to be more foot-specific than alpha. Connectivity analyses in source space suggested this to be due to a somatosensory alpha rhythm that is primarily driven by activity in hand regions while beta frequencies may operate in a more hand-region-independent manner. Altogether, our findings suggest spatially distinct excitability dynamics within the primary somatosensory cortex, yet with the caveat that frequency-specific processes in one sub-region may not readily generalize to other sub-regions.
Coupling of NOD2 to GIV is Required for Bacterial Sensing
Authors: Katkar Gajanan D. , Anandachar Mahitha Shree , Sinha Saptarshi , Ibeawuchi Stella-Rita , Espinoza Celia R. , Coates Jane , Malhotra Yashaswat S. , Mullick Madhubanti , Castillo Vanessa , Vo Daniella T. , Sahoo Debashis , Ghosh Pradipta
Published: May 2022

ABSTRACT/SUMMARY

Sensing of pathogens by Nucleotide oligomerization domain (NOD)-like 2 receptor (NOD2) induces a protective inflammatory response that coordinates bacterial clearance. Polymorphisms in NOD2 impair bacterial clearance, leading to chronic gut inflammation in Crohn’s disease (CD) via mechanisms that remain incompletely understood. We identify GIV/Girdin (CCDC88A) as a NOD2-interactor that shapes bacterial sensing-and-signaling in macrophages. Myeloid-specific GIV depletion exacerbated and protracted infectious colitis and abolished the protective effect of muramyl dipeptide (MDP) in both chemical colitis and severe sepsis. In the presence of GIV, macrophages enhance anti-bacterial pathways downstream of NOD2, clear microbes rapidly and concomitantly suppress inflammation. GIV’s actions are mediated via its C-terminus, which directly binds the terminal leucine-rich repeat (LRR#10) of NOD2; binding is augmented by MDP and ATP, precedes receptor oligomerization, and is abolished by the1007fsCD-risk variant which lacks LRR#10. Findings illuminate mechanisms that underlie protective NOD2 signaling and loss of function in the major1007fsvariant.

In brief

This work reveals a mechanism by which macrophages use their innate immune sensor, NOD2, to protect the host against overzealous inflammation during bacterial infections, and the consequences of its loss, as occurs in the most important Crohn’s disease-risk variant.

GRAPHIC ABSTRACT

HIGHLIGHTS

GIV is a functional and direct interactor of the terminal LRR repeat of NOD2

Mice lacking MФ GIV develop dysbiosis, protracted ileocolitis and sepsis

MDP/NOD2-dependent protective host responses require GIV

CD-risk NOD21007fsvariant lacking the terminal LRR#10 cannot bind GIV
Effectiveness of influenza vaccination against SARS-CoV-2 infection among healthcare workers in Qatar
Authors: Tayar Elias , Abdeen Sami , Alah Muna Abed , Chemaitelly Hiam , Bougmiza Iheb , Ayoub Houssein H. , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Al-Romaihi Hamad Eid , Al-Thani Mohamed H. , Bertollini Roberto , Abu-Raddad Laith J. , Al-Khal Abdullatif
Published: May 2022

A number of studies reported that influenza vaccination is associated with lower risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or coronavirus disease 2019 (COVID-19) morbidity and mortality. We conducted a matched, test-negative, case-control study to estimate effectiveness of influenza vaccination, using Abbott’s quadrivalent Influvac Tetra vaccine, against SARS-CoV-2 infection and against severe COVID-19. The study was implemented on a population of 30,774 healthcare workers (HCWs) in Qatar during the 2020 annual influenza vaccination campaign, between September 17, 2020 and December 31, 2020, before introduction of COVID-19 vaccination. The median age in the matched samples was 36 years (interquartile range (IQR), 32-44) for cases and 35 years (IQR, 32-42) for controls. The median duration between influenza vaccination and the PCR test was 43 days (IQR, 29-62). The estimated effectiveness of influenza vaccination against SARS-CoV-2 infection >14 days after receiving the vaccine was 29.7% (95% CI: 5.5-47.7%). The estimated effectiveness of influenza vaccination against any severe, critical, or fatal COVID-19 was 88.9% (95% CI: 4.1-98.7%). Sensitivity analyses confirmed main analysis results. Recent influenza vaccination is associated with an appreciable reduction in the risk of SARS-CoV-2 infection and COVID-19 severity.
Smoking trajectories over the first year of the pandemic in UK middle-aged adults: evidence from the UKHLS COVID-19 study
Authors: Gagné Thierry
Published: May 2022

Background

The COVID-19 pandemic has altered the conditions leading people to smoke. Multiple studies have examined changes in population levels of smoking at the start of the pandemic. However, conclusions remain mixed due to the high proportion of studies with poor methods and short follow-up periods.

Methods

This study used longitudinal data from the UKHLS COVID-19 study to derive smoking trajectories among 4,130 UK adults aged 35-64 across four time points over the first year of the pandemic (2018-19, April 2020, September 2020, and January 2021). Random-effects models were used to examine subject-specific changes across time points.

Results

Between the pre-pandemic estimate and January 2021, there was a significant decline in smoking from 14.8% to 13.1% (PR = 0.89, 95%CI 0.83-0.95). The number of cigarettes smoked per day among smokers increased in April 2020 (B = 0.5, 95%CI 0.0, 1.0) and September 2020 (B = 1.0, 95%CI 0.4, 1.5), but declined back to pre-pandemic levels in January 2021 (B = 0.3, 95%CI -0.3, 0.8). These changes did not vary by sex, ethnicity, relationship status, education, occupation, or household income.

Conclusion

Among UK adults aged 35-64, there has been a slight decrease in smoking which was maintained up to January 2021. Whereas there was an increase in cigarette consumption among smokers at the start of the pandemic, this was no longer observable in January 2021. The findings support the argument that the first year of the pandemic is unlikely to have had a negative effect of most middle-aged adult smokers’ trajectory.
Physical activity, respiratory physiotherapy practices, and nutrition among people with primary ciliary dyskinesia in Switzerland
Authors: Lam Yin Ting , Pedersen Eva SL , Schreck Leonie D , Hüsler Leonie , Koppe Helena , Belle Fabiën N , Clarenbach Christian , Latzin Philipp ,   Swiss PCD research group, Kuehni Claudia E , Goutaki Myrofora
Published: May 2022

Aims of the study

We know little about the level of physical activity, respiratory physiotherapy practices, and nutritional status of people with primary ciliary dyskinesia (PCD), although these are important aspects of patients with chronic respiratory disease. We assessed physical activity, respiratory physiotherapy practices, and nutritional status among people with PCD in Switzerland, investigated how these vary by age, and identified factors associated with regular physical activity.

Methods

We sent a postal questionnaire survey to people with PCD enrolled in the Swiss PCD registry (CH-PCD), based on the standardised FOLLOW-PCD patient questionnaire. We collected information about physical activity, physiotherapy, respiratory symptoms, and nutritional status. We calculated the metabolic equivalent (MET) to better reflect the intensity of the reported physical activities. To assess nutritional status, we extracted information from CH-PCD and calculated participants’ body mass index (BMI).

Results

Of the 86 questionnaires we sent, 74 (86% response rate) were returned from 24 children and 50 adults. The median age at survey completion was 23 years [IQR (interquartile range) 15–51], and 51% were female. Among all 74 participants, 48 (65%) performed sports regularly. Children were vigorously active (median MET 9.1; IQR 7.9–9.6) and adults were moderately active (median MET 5.5; IQR 4.3-6.9). 59 participants (80%) reported performing some type of respiratory physiotherapy. However, only 30% of adults saw a professional physiotherapist compared with 75% of children. Half of the participants had normal BMI; one child (4%) and two adults (4%) were underweight. People who were regularly physically active reported seeing a physiotherapist more often.

Conclusions

Our study is the first to provide patient-reported data about physical activity, respiratory physiotherapy, and nutrition among people with PCD. Our results highlight that professional respiratory physiotherapy, exercise recommendations, and nutritional advice are often not implemented in the care of people with PCD in Switzerland. Multidisciplinary care in specialised centres by teams including physiotherapists and nutrition consultants could improve the quality of life of people with PCD.
A systematic review of ontology-based clinical decision support system rules: usage, management, and interoperability
Authors: Jing Xia , Min Hua , Gong Yang , Sittig Dean F. , Biondich Paul , Robinson David , Law Tim , Wright Adam , Nøhr Christian , Faxvaag Arild , Rennert Lior , Hubig Nina , Gimbel Ronald
Published: May 2022

Objective

Clinical decision support systems (CDSS) have a critical role in improving the quality and safety of health care delivery. CDSS rules direct the behavior of CDSS. However, the CDSS rules have not been routinely shared and reused, and ontology can promote the reusing of CDSS rules. We systematically screened literature to elaborate on the current status of ontology applied in CDSS rule management.

Methods

We searched PubMed, the Association for Computing Machinery (ACM) Digital Library, and the Nursing & Allied Health Database for publications focusing on ontology, clinical decision support, and rules. Grounded theory and PRISMA 2020 guidelines were followed. One author started the screening and literature analysis, and two authors validated the processes and results. Inclusion and exclusion criteria were developed and refined iteratively.

Results

Among 81 included publications, the identified CDSS were mainly applied to managing chronic conditions, alerts for medication prescriptions, reminders for immunizations and preventive services, diagnoses, and treatment recommendations. The CDSS rules were presented in Semantic Web Rule Language, Jess, or Jena formats. Despite ontology was used to supply medical knowledge, CDSS rules, and terminologies to CDSS, ontology has not been used in CDSS rule management.

Conclusions

Although ontology can facilitate the reuse, management, and maintenance of CDSS rules, CDSS ontology remains unavailable indicating that more efforts are needed to improve the reusability and interoperability of CDSS rules.
High-speed MRI recordings of eyeball lifting, retraction and compression during blinks
Authors: Kirchner Johannes , Watson Tamara , Bauer Jochen , Lappe Markus
Published: May 2022

Blinks occur frequently in normal life and have increasingly been linked to perceptual and cognitive effects. However, the oculomechanics of blink-related eye movements are much less researched than other types of eye movements. While it has been observed that the eye is being pulled back into its socket during a blink, possibly due to co-contraction of extraocular muscles, this elusive eye motion has not been studied in detail due to the technical difficulties that go along with a closed eyelid. Here we use dynamic magnetic resonance imaging (MRI) to obtain videos of this motion and analyse the kinematics with the recently developed MREyeTrack algorithm. We show that the eye is not only retracted but also lifted up during a blink. For some participants we observed eyeball lifting by up to 3 mm, far exceeding the amount of translation believed to occur during natural eye movements. Slow blinks can be accompanied by large tonic rotations of up to 15°. Furthermore, we collected evidence that the co-contraction of extraocular muscles leads to a slight compression of the eyeball. These findings demonstrate the surprising complexity of ocular motility and offer new opportunities to study orbital mechanics in health and disease.
Phenotypic and genetic factors are associated with absence of cardiomyopathy symptoms in PLN c.40_42delAGA carriers
Authors: Lopera-Maya Esteban A. , Li Shuang , de Brouwer Remco , Nolte Ilja M. , van Breen Justin ,   The Netherlands ACM registry,   Lifelines Cohort study, Jongbloed Jan D.H. , Swertz Morris A. , Snieder Harold , Franke Lude , Wijmenga Cisca , de Boer Rudolf A. , Deelen Patrick , van der Zwaag Paul A. , Sanna Serena
Published: May 2022

The c.40_42delAGA variant in the phospholamban gene (PLN) has been associated with dilated and arrhythmogenic cardiomyopathy, with up to 70% of carriers experiencing a major cardiac event by age 70. However, other carriers remain asymptomatic or show only mild symptoms in old age. To understand the mechanisms behind this incomplete penetrance, we evaluated potential phenotypic and genetic modifiers in 74 PLN c.40_42delAGA carriers identified in 36,339 participants of the Lifelines population cohort. Asymptomatic carriers (N=48) showed shorter QRS duration (−5.73 ms, p-value=0.001) compared to asymptomatic non-carriers and symptomatic carriers (N=26), and we replicated this in different subset of 21,771 participants from the Lifelines cohort (−3.87 ms, p-value=0.028) and in 592 carriers from the Arrhythmogenic Cardiomyopathy (ACM) patient registry (−6.91 ms, p-value=0.0002). Furthermore, symptomatic carriers showed a higher correlation between genetic predisposition to higher QRS duration (PGSQRS) and QRS (p-value=1.98×10-8), suggesting that symptomatic PLN c.40_42delAGA carriers may have an increased sensitivity to the effect of genetic variation in cardiac rhythm. Our results may help improve risk prediction models for cardiac outcomes for future studies, while our approach could guide studies on genetic diseases with incomplete penetrance.
Sociodemographic inequalities and excess non-COVID-19 mortality during the COVID-19 pandemic: A data-driven analysis of 1,069,174 death certificates in Mexico
Authors: Antonio-Villa Neftali Eduardo , Fermín-Martínez Carlos A. , Aburto José Manuel , Fernández-Chirino Luisa , Ramírez-García Daniel , Pisanty-Alatorre Julio , González-Díaz Armando , Vargas-Vázquez Arsenio , Seiglie Jacqueline A. , Barquera Simón , Gutiérrez-Robledo Luis Miguel , Bello-Chavolla Omar Yaxmehen
Published: May 2022

BACKGROUND

In 2020, Mexico experienced one of the highest rates of excess mortality globally. However, the extent to which non-COVID deaths contributed to excess mortality, its regional characterization, and the association between municipal-and individual-level sociodemographic inequality has not been characterized.

METHODS

We conducted a retrospective municipal an individual-level study using death certificate data in Mexico from 2016-2020. We analyzed mortality related to COVID-19 and to non-COVID-19 causes using ICD-10 codes to identify cause-specific mortality. Excess mortality was estimated as the increase in deaths in 2020 compared to the average of 2016-2019, disaggregated by primary cause of death, death setting (in-hospital and out-of-hospital) and geographical location. We evaluated correlates of non-COVID-19 mortality at the individual level using mixed effects logistic regression and correlates of non-COVID-19 excess mortality in 2020 at the municipal level using negative binomial regression.

RESULTS

We identified 1,069,174 deaths in 2020 (833.5 per 100,000 inhabitants), which was 49% higher compared to the 2016-2019 average (557.38 per 100,000 inhabitants). Overall excess mortality (276.11 deaths per 100,000 inhabitants) was attributable in 76.1% to COVID-19; however, non-COVID-19 causes comprised one-fifth of excess deaths. COVID-19 deaths occurred primarily in-hospital, while excess non-COVID-19 deaths decreased in this setting and increased out-of-hospital. Excess non-COVID-19 mortality displayed geographical heterogeneity linked to sociodemographic inequalities with clustering in states in southern Mexico. Municipal-level predictors of non-COVID-19 excess mortality included levels of social security coverage, higher rates of COVID-19 hospitalization, and social marginalization. At the individual level, lower educational attainment, blue collar workers, and lack of medical care assistance were associated with non-COVID-19 mortality during 2020.

CONCLUSION

Non-COVID-19 causes of death, largely chronic cardiometabolic conditions, comprised up to one-fifth of excess deaths in Mexico during 2020. Non-COVID-19 excess deaths occurred disproportionately out-of-hospital and were associated with both individual-and municipal-level sociodemographic inequalities. These findings should prompt an urgent call to action to improve healthcare coverage and access to reduce health and sociodemographic inequalities in Mexico to reduce preventable mortality in situations which increase the stress of healthcare systems, including the ongoing COVID-19 pandemic.
Post COVID-19 condition of the Omicron variant of SARS-CoV-2
Authors: Morioka Shinichiro , Tsuzuki Shinya , Suzuki Michiyo , Terada Mari , Akashi Masako , Osanai Yasuyo , Kuge Chika , Sanada Mio , Tanaka Keiko , Maruki Taketomo , Takahashi Kozue , Saito Sho , Hayakawa Kayoko , Teruya Katsuji , Hojo Masayuki , Ohmagari Norio
Published: May 2022

Background

No epidemiological data on post coronavirus disease (COVID-19) condition due to Omicron variant has been reported yet.

Methods

This was as a single-center, cross-sectional study, that interviewed via telephone the patients who recovered from Omicron COVID-19 infection (Omicron group), and surveyed via self-reporting questionnaire those patients infected with other strains (control group). Data on patients’ characteristics, information regarding the acute-phase COVID-19, as well as presence and duration of COVID-19-related symptoms were obtained. Post COVID-19 condition in this study was defined as a symptom that lasted at least 2 months within 3 months since the onset of COVID-19. We investigated and compared the prevalence of post COVID-19 condition in both groups after performing propensity score matching.

Results

We conducted interviews for 53 out of 128 patients with Omicron, and obtained 502 responses in the control group. After matching, 18 patients each in Omicron and control group had improved covariate balance of the older adult, female sex, obese patients, and vaccination status. There were no significant differences in the prevalence of each post-acute COVID-19 symptoms between the two groups. The numbers of patients with at least one post-acute COVID-19 symptom in the Omicron and the control group were 1 (5.6%) and 10 (55.6%) (p=0.003), respectively.

Conclusion

The prevalence of post Omicron COVID-19 conditions was less than that of the other strains. Further research with more participants is needed to investigate the precise epidemiology of post COVID-19 condition of Omicron, and its impact on health-related quality of life and social productivity.
Lack of the human choline transporter-like protein CTL2 causes hearing impairment and a rare red blood cell phenotype
Authors: Koehl Bérengère , Vrignaud Cédric , Mikdar Mahmoud , Nair Thankam S. , Yang Lucy , Laiguillon Guy , Anselme-Martin Sophie , Giroux-Lathuile Claudine , Kenz Hanane El , Hermine Olivier , Mohandas Narla , Cartron Jean Pierre , Colin Yves , Detante Olivier , Le Van Kim Caroline , Carey Thomas E. , Azouzi Slim , Peyrard Thierry
Published: May 2022

Recent genome-wide association and murine studies identified the human neutrophil antigen -3a/b polymorphism (HNA-3a/b) in SLC44A2 (rs2288904-G/A) as a risk factor in venous thromboembolism (VTE). The choline transporter-like protein CTL2 encoded by the SLC44A2 gene plays an important role in platelet aggregation and neutrophil interaction with the von Willebrand factor. By investigating alloantibodies to a high-prevalence antigen of unknown specificity, found in patients with a rare blood type, we showed that CTL2 is also expressed in red blood cells and carries a new blood group system. Furthermore, we identified three siblings of European ancestry who are homozygous for a large deletion in SLC44A2, resulting in complete CTL2 deficiency. Interestingly, the first-ever reported CTL2-deficient individuals suffer from progressive hearing impairment, recurrent arterial aneurysms and epilepsy. In contrast to Slc44a2-/- mice, CTL2null individuals showed normal platelet aggregation and do not suffer from any apparent hematological disorders. In addition, CD34+ cells from CTL2null patients undergo normal ex vivo erythropoiesis, indicating that CTL2 is not essential for erythroid proliferation and differentiation. Overall, our findings confirm the function of CTL2 in hearing preservation and provide new insights into the possible role of this protein in maintaining cerebrovascular homeostasis.
A meta-analysis of structural MRI studies of the brain in systemic lupus erythematosus (SLE)
Authors: Cox Jennifer G. , de Groot Marius , Cole James H. , Williams Steven C. R. , Kempton Matthew J.
Published: May 2022

Objective

A comprehensive search of published literature in brain volumetry was conducted in three autoimmune diseases – Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), and Ulcerative Colitis (UC) with the intention of performing a meta-analysis of published data. Due to lack of data in RA and UC the reported meta-analysis was limited to SLE.

Methods

The MEDLINE database was searched for studies from 1988 through March 2022. A total of 175 papers met the initial inclusion criteria and 16 were included in a random effects meta-analysis. The reduction in the number of papers included in the final analysis is primarily due to the lack of overlap in measured and reported brain regions.

Results

A significantly lower volume was seen in patients with SLE in the hippocampus, corpus callosum and total gray matter volume measurements as compared to age and sex matched controls. There were not enough studies to perform a meta-analysis for RA and UC; instead we include a summary of published volumetric studies.

Conclusions

The meta-analyses revealed structural brain abnormalities in patients with SLE suggesting that lower global brain volumes are associated with disease status. This volumetric difference was seen in both the hippocampus and corpus callosum and total gray matter volume measurements. These results indicate both gray and white matter involvement in SLE and suggest there may be both localised and global reductions in brain volume.

KEY MESSAGES

What’s already known on this topic

Central nervous system effects of lupus are common, however, agreement on principally affected neuroanatomical regions is lacking.

What this study adds

This study combines the volumetric neuroimaging data from previously published SLE literature in a meta-analysis. The hippocampus, corpus callosum and total gray matter volume in patients with SLE is smaller than in age and sex matched controls. Additionally, a summary of published data in RA and UC is provided.

How this study might affect research, practice or policy

This is the first meta-analysis on neuroimaging studies of volume differences in SLE. The regions identified can inform further research on disease progression and therapy evaluation targeted at brain volumetric changes in SLE.

These results provide specific regions of interest to further explore in the central treatment and management of SLE. While these regions are shown to be directly affected, additional brain regions may be implicated. Further research to understand the potential link between these volumetric measurements and behavioural/cognitive changes observed in patients with lupus is warranted.
Implication of Hepsin from primary tumor in the prognosis of colorectal cancer patients
Authors: Zaragoza-Huesca David , Nieto-Olivares Andrés , García-Molina Francisco , Ricote Guillermo , Montenegro Sofía , Sánchez-Cánovas Manuel , Garrido-Rodríguez Pedro , Peñas-Martínez Julia , Vicente Vicente , Martínez Francisco , Luisa-Lozano María , Carmona-Bayonas Alberto , Martínez-Martínez Irene
Published: May 2022

Background

Hepsin is a type II transmembrane serine protease whose functions include degradation of the extracellular matrix and activation of factor VII. In many tumors, hepsin dysregulation leads to tumor invasion by proteolysis of pericellular components. Colorectal cancer is a tumor with high thrombotic and metastatic risk, but the role of hepsin is unknown.

Objectives

To study the correlations between hepsin expression in the primary tumor and different clinical-histopathological variables in patients with localized and metastatic colorectal cancer.

Methods

A cohort of 287 patients, 169 with localized colorectal cancer and 118 with metastases at diagnosis, was recruited. Tissue microarrays were made from samples at diagnosis of primary tumors and stained with an anti-hepsin antibody. Hepsin levels were determined and the association with clinical-histopathological variables was evaluated using the chi-square and Kruskal-Wallis tests. Time-to-event results and cumulative incidence functions were calculated using Kaplan-Meier and Aalen-Johansen estimators, in combination with Cox and Fine&Gray multivariate models.

Results

In patients with localized colorectal cancer, high intensity hepsin staining was associated with reduced 5-year disease-free survival (p-value = 0.16). In this context, according to multivariable Cox regression, medium and high intensity of hepsin expression versus low intensity was associated with an increased risk of metastatic relapse (hazard ratio 2.83, p-value=0.035, and hazard ratio 3.30, p-value=0.012, respectively), being a more accurate prognostic factor than classic histological variables. Also, in patients with localized colorectal cancer, the cumulative incidence of thrombosis at 5 years increased significantly with higher hepsin levels (p-value = 0.038). According to the multivariate Fine&Gray regression, the medium and high intensity of hepsin with respect to the low intensity, was associated with an increase in thrombotic risk (hazard ratio 7.71, p-value=0.043 and hazard ratio 9.02, p-value=0.028, respectively). This relationship between hepsin and thrombosis was independent of previous tumor relapse (p-value = 0.036). In patients with metastatic colorectal cancer, low intensity of hepsin was associated with a low degree of tumor differentiation (p-value <0.001) and spread to more than one metastatic site (p-value = 0.023).

Conclusion

Hepsin is a potential biomarker of thrombosis and metastasis in patients with localized colorectal cancer. Validation in a larger series and clarification of the underlying mechanism may be helpful in evaluating these patients. In metastatic patients, Hepsin behaves in a paradoxical way with respect to differentiation and invasion processes.
Clinical Performance of Direct RT-PCR Testing of Raw Saliva for Detection of SARS-CoV-2 in Symptomatic and Asymptomatic Individuals
Authors: Castillo-Bravo Rosa , Lucca Noel , Lai Linyi , Marlborough Killian , Brychkova Galina , Lonergan Charlie , O’Grady Justin , Alikhan Nabil-Fareed , Trotter Alexander J. , Page Andrew J. , Smyth Breda , McKeown Peter C. , Feenstra Jelena D. M. , Ulekleiv Camilla , Sorel Oceane , Gandhi Manoj , Spillane Charles
Published: May 2022

RT-qPCR tests based on RNA extraction from nasopharyngeal swab samples are promoted as the “gold standard” for SARS-CoV-2 detection. However, self-collected saliva samples offer a non-invasive alternative more suited to high-throughput testing. This study evaluated the performance of TaqPath COVID-19 Fast PCR Combo Kit 2.0 assay for detection of SARS-CoV-2 in raw saliva relative to a lab-developed direct RT-qPCR test (SalivaDirect-based PCR) and a RT-qPCR test based on RNA extraction from NPS samples. Both samples were collected from symptomatic and asymptomatic individuals (N=615). Saliva samples were tested for SARS-CoV-2 using the TaqPath COVID-19 Fast PCR Combo Kit 2.0 and the SalivaDirect-based PCR, while RNA extracts from NPS samples were tested by RT-qPCR according to the Irish national testing system. The TaqPath™ COVID-19 Fast PCR detected SARS-CoV-2 in 52 saliva samples, of which 51 were also positive with the SalivaDirect-based PCR. 49 samples displayed concordant results with the NPS extraction-based method, while three samples were positive on raw saliva. Among the negative samples, 10 discordant cases were found with the TaqPath COVID-19 Fast PCR (PPA–85.7%; NPA–99.5%), when compared to the RNA extraction-based NPS method, performing similarly to the SalivaDirect-based PCR (PPA-87.5%; NPA-99.5%). The direct RT-qPCR testing of saliva samples shows high concordance with NPS extraction-based method for SARS-CoV-2 detection, providing a cost-effective and highly-scalable system for high-throughput COVID-19 rapid-testing.
Common Genetic Risk Factors in ASD and ADHD Co-occurring Families
Authors: Zhou Anbo , Cao Xiaolong , Mahaganapathy Vaidhyanathan , Azaro Marco , Gwin Christine , Wilson Sherri , Buyske Steven , Bartlett Christopher W. , Flax Judy F. , Brzustowicz Linda M. , Xing Jinchuan
Published: May 2022

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are two major neurodevelopmental disorders that frequently co-occur. However, the genetic mechanism of the co-occurrence remains unclear. The New Jersey Language and Autism Genetics Study (NJLAGS) collected more than 100 families with at least one member affected by ASD. NJLAGS families show a high prevalence of ADHD and provide a good opportunity to study shared genetic risk factors for ASD and ADHD. The linkage study of the NJLAGS families revealed regions on chromosomes 12 and 17 that are significantly associated with ADHD. Using whole genome sequencing data on 272 samples from 73 NJLAGS families, we identified potential risk genes for ASD and ADHD. Within the linkage regions, we identified 36 genes that are associated with ADHD using a pedigree-based gene prioritization approach.KDM6B(Lysine Demethylase 6B) is the highest-ranking gene, which is a known risk gene for neurodevelopmental disorders, including ASD and ADHD. At the whole genome level, we identified 207 candidate genes from the analysis of both small variants and structure variants, including both known and novel genes. Using enrichment and protein-protein interaction network analyses, we identified gene ontology terms and pathways enriched for ASD and ADHD candidate genes, such as cilia function and cation channel activity. Candidate genes and pathways identified in our study provide a better understanding of the genetic etiology of ASD and ADHD and will lead to new diagnostic or therapeutic interventions for ASD and ADHD in the future.