bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a Training Curriculum for Hospital Security About Autism Spectrum Disorder
Authors: Christiansen Audrey , Harstad Elizabeth , Sideridis Georgios , Weissman Laura
Published: December 2020

Objective:

To evaluate whether a newly developed autism spectrum disorder (ASD)-training curriculum for hospital security officers improves comfort, knowledge, and practice.

Methods:

Participants were security officers. The ASD-training curriculum was a 45-minute interactive session, adapted from trainings developed for other types of hospital providers. The curriculum included information regarding the presentation of, and challenges faced by, children with ASD in the hospital setting. Officers completed surveys before (T1), immediately after (T2), and 3 months after (T3) the training to assess comfort, knowledge, and practice. Comfort (Likert scale 1–5; 5 = highest) and knowledge (11 yes/no questions) questions were adapted from previous measures. Application of skills was assessed using case scenarios (at T1, T2, and T3) and with officers' report of using various strategies (at T1 and T3; Likert scale 1–5; 5 = always). Data were analyzed using repeated-measures analysis of variance and a series of paired contrast.

Results:

For the 114 officers who completed surveys, mean comfort scores significantly increased from T1 to T2 (3.48 vs 3.9; p < 0.05), and these gains were maintained at T3 (4.1). Mean percent correct on knowledge questions significantly increased from T1 to T2 (74.6% vs 84.0%; p < 0.05) and was maintained at T3 (82.9%). Officers reported using 2 ASD-supportive strategies significantly more between T1 and T3: using pictures and written communication and asking the caregivers for advice.

Conclusion:

This newly developed ASD-training curriculum for hospital security officers resulted in an immediate increase of self-reported comfort and demonstrated knowledge with continued gains 3 months after training.
Femtosecond Laser-Assisted Cataract Surgery: Does It Improve Outcomes in Fuchs Endothelial Corneal Dystrophy?
Authors: Koo Ellen H.
Published: December 2020

The role of femtosecond laser -assisted cataract surgery in patients with Fuchs endothelial corneal dystrophy remains poorly defined. This invited commentary examines the current evidence surrounding this often-debated topic.
Field Notes From the Frontline of a COVID-19 Outbreak
Authors: Pavlu Dawn , DeMarco Katherine , Sobrino-Bonilla Yusimi
Published: December 2020

Northern New Jersey was inside one of the worst initial coronavirus disease 2019 pandemic epicenters in the United States. At the peak of the pandemic surge in mid-April 2020, New Jersey saw 8045 hospitalized patients with severe coronavirus disease 2019 symptoms, of which 2002 were in intensive care unit beds (86.3% of statewide capacity), including 1705 requiring mechanical ventilation. Because of the severity of pulmonary dysfunction/hypoxia, the unprecedented numbers of critically ill patients, the national opioid shortage, and transmission prevention measures for standard palliative care treatment protocols in place for refractory and/or end-of-life dyspnea were found to be ineffective in providing adequate symptom relief. The aim of the following Notes From the Field is to provide concise, pragmatic, and experiential reflection by 3 palliative care advanced practice nurses from 3 different hospital systems within the pandemic epicenter. The novel methods and opioid strategies implemented by their respective palliative care teams to ensure continued effective and appropriate treatment for end-of-life dyspnea are described. These accounts include Lessons Learned in order to assist others who may need to quickly implement changes in the future due to pandemic resurgence or second-wave events.
Applying Computational Ethnography to Examine Nurses’ Workflow Within Electronic Health Records
Authors: Tolentino Dante Anthony , Subbian Vignesh , Gephart Sheila M.
Published: December 2020

Background

Many existing electronic health record (EHR) workflow studies report conflicting results in time spent in the record, documentation demand, and usability and often do not explore the time-based navigation patterns of nurses.

Objective

The aim of this study was to describe computational ethnography as a contemporary and supplemental methodology in EHR workflow analysis and the relevance of this method to nursing research.

Methods

We explore the use of audit logs as a computational ethnographic data source and the utility of data mining techniques, including sequential pattern mining (SPM) and Markov chain analysis (MCA), to analyze nurses’ workflow within the EHRs. SPM extracts frequent patterns in a given transactional database (e.g., audit logs from the record). MCA is a stochastic process that models a sequence of states and allows for calculating the probability of moving from one state to the next. These methods can help uncover nurses’ global navigational patterns (i.e., how nurses navigate within the record) and enable robust workflow analyses.

Results

We demonstrate hypothetical examples from SPM and MCA, such as (a) the most frequent sequential pattern of nurses’ workflow when navigating the EHR using SPM and (b) transition probability from one record screen to the next using MCA. These examples demonstrate new methods to address the inflexibility of current approaches used to examine nursing EHR workflow.

Discussion

Within a clinical context, the use of computational ethnographic data and data mining techniques can inform the optimization of the EHR. Results from these analyses can be used to supplement the data needed in redesigning the EHR, such as organizing and combining features within a screen or predicting future navigation to improve the record that nurses use.
Positive MITF and NKI/C3 Expression in Cellular Neurothekeoma and Dermatofibroma
Authors: Abdaljaleel Maram , North Jeffrey P.
Published: December 2020

Background:

Cellular neurothekeoma (CNT) is a benign mesenchymal tumor with uncertain cellular differentiation. Studies have found evidence of myofibroblastic differentiation and possible relation to dermatofibromas (DFs). As microphthalmia transcription factor (MITF) and NKI/C3 stains are routinely positive in CNT, we compared expression patterns of both markers in CNT and DF to assess their relationship.

Materials and Methods:

We assessed cases of CNT (n=25) and DFs (n=35) for histopathologic characteristics and MITF and NKI/C3 expression. Immunostaining results were classified as negative, focally positive (<50%), and diffusely positive (>50%). At least 1 additional melanocytic marker was assessed in each case of CNT.

Results:

Both DFs and CNTs showed a female predilection and a wide age range. Immunostaining in CNTs for MITF was positive in the vast majority (focal 68%, diffuse 24%), as was NKI/C3 (focal 72%, diffuse 24%). All DFs were MITF positive (diffuse 74%, focal 26%), and most DFs were NKI/C3 positive (focal 57%, diffuse 3%).

Conclusion:

CNT and DF share demographic, histopathologic, and immunohistochemical features, including shared expression of MITF and NKI/C3, especially cellular DF.
New Clinicopathologic Scenarios of EBV+ Inflammatory Follicular Dendritic Cell Sarcoma
Authors: Jiang Xiang-Nan , Zhang Yan , Xue Tian , Chen Jie-Yu , Chan Alex C.L. , Cheuk Wah , Chan John K.C. , Li Xiao-Qiu
Published: December 2020

EBV+ inflammatory follicular dendritic cell (FDC) sarcoma is an indolent malignant neoplasm of spindled FDCs with a rich lymphoplasmacytic infiltrate and a consistent association with Epstein-Barr virus (EBV). It occurs exclusively in the liver and spleen, with the exception of a few colonic examples. In this study, we report 9 extrahepatosplenic cases, including 4 occurring in previously undescribed sites, but all apparently anatomically related to the aerodigestive tract. The cases included 5 gastrointestinal tumors all presenting as colonic pedunculated polyps, 2 presenting as mesocolon mass, and 2 involving the palatine or nasopharyngeal tonsils. One patient with a colonic tumor was complicated by paraneoplastic pemphigus. The patients had a median age of 58 years, with female predominance (female:male=7:2). A favorable outcome was observed in 7 patients. Histologically, EBV+ inflammatory FDC sarcomas arising from these anatomic sites were similar to their hepatosplenic counterparts. Spindled to oval neoplastic cells with ill-defined cell borders were dispersed or formed loose whorled fascicles in a dense lymphoplasmacytic background. They had vesicular nuclei with distinct nucleoli and typically exhibited a range of nuclear atypia in the same case. The neoplastic cells showed variable expression of FDC markers and were labeled for Epstein-Barr virus–encoded RNA on in situ hybridization. These 9 cases thus broaden the clinicopathologic scenarios of EBV+ inflammatory FDC sarcoma. Recognition of the potential existence of this tumor type in extrahepatosplenic sites permits a correct diagnosis to be made.
NLRP3 and IL-1β Gene Expression Is Elevated in Monocytes From HIV-Treated Patients With Neurocognitive Disorders
Authors: Mazaheri-Tehrani Elham , Mohraz Minoo , Nasi Milena , Chester Johanna , De Gaetano Anna , Lo Tartaro Domenico , SeyedAlinaghi SeyedAhmad , Gholami Mohammad , De Biasi Sara , Gibellini Lara , Mattioli Anna Vittoria , Pinti Marcello , Mussini Cristina , Cossarizza Andrea
Published: December 2020

Background:

Systemic immune activation and inflammation in chronic HIV infection are driving factors of non–AIDS-related events, including neurocognitive impairment. The role of inflammasome in monocytes from patients with HIV infection has been extensively studied, but its association with the extent of neurocognitive dysfunction has been poorly investigated.

Methods:

We enrolled 79 HIV-positive patients; 44 with varying levels of HIV-associated neurocognitive disorder (HAND) and 35 without and 8 healthy donors. HAND subtypes included asymptomatic neurocognitive impairment (asymptomatic neurocognitive impairment; n = 19), mild neurocognitive disorder (MND; n = 17), and HIV-associated dementia (n = 8). We quantified plasmatic concentrations of proinflammatory cytokines (TNF-α, IL-6, IL-17A, IL-1β, and IFN-γ) for all HIV patients, and the mRNA expression of genes involved in the inflammasome activity (NLRP3, PYCARD, NAIP, AIM2, IL-1β, and IL-18) in monocytes of a subgroup of 28 HIV patients and 8 healthy donors.

Results:

HIV patients' plasma concentrations of IFN-γ, IL-1β, and IL-17A were undetectable. Levels of TNF-α and IL-6 were similar among the HIV patient groups. A trend toward an increased expression of inflammasome genes according to neurocognitive disorder severity was observed. Of note, the NLRP3 mRNA relative expression was higher in MND compared with other groups, and IL-1β was lower in MND than HIV-associated dementia patients.

Conclusions:

Changes in inflammasome components in circulating monocytes according to different HAND severity suggest that NLRP3 may be a possible biomarker or target to better understand and treat the link between systemic inflammation and neurocognitive impairment in HIV infection.
Roadway features associated with elderly drivers in motor vehicle crashes
Authors: Presser Maxwell , Nwabuo Adaobi , Soltani Shamsi , Morris Devan , Wier Megan , Plevin Rebecca E.
Published: December 2020

BACKGROUND

As the number of older US drivers has increased over the past decades, so has the number of injuries, hospitalizations, and deaths from motor vehicle crashes (MVCs) involving elderly drivers. We seek to identify personal, environmental, and roadway features associated with increased crashes involving elderly drivers. We hypothesize that elderly drivers are more likely to be involved in MVCs at intersections with more complex signage and traffic flow.

METHODS

This is a retrospective observational study using 2015 to 2019 police traffic crash reports and a Department of Public Health database of built-environment variables from a single urban center. Demographics and environmental/road features were compared for vehicle-only MVCs involving elderly (≥65 years) and younger drivers. χ2 and nonparametric tests were used to analyze 36,168 drivers involved in MVCs.

RESULTS

There were 2,575 (7.1%) elderly drivers involved in MVCs during the study period. Left turns and all-way stop signs were associated with increased crash risk among elderly drivers compared with younger drivers. Elderly-involved MVCs were less likely to occur at intersections with left-turn restrictions, traffic lights, only one-way streets, and bike lanes compared with MVCs with younger drivers. Elderly drivers were more likely to be involved in MVCs on weekdays, less often intoxicated at the time of the crash, and less frequently involved in fatal MVCs compared with younger drivers. However, elderly drivers were more frequently the at-fault party, especially after the age of 75 years.

CONCLUSION

Updates to roadway features have potential to decrease injury and death from MVCs involving elderly adults. Left turn restrictions or other innovative safety treatments at all-way stops or where left turns are permitted may mitigate road crashes involving older adults. Education may increase awareness of higher-risk driving tasks such as turning left, and driving alternatives including public transportation/paratransit may offer alternate means to maintain activities of daily living.

LEVEL OF EVIDENCE

Prognostic/Epidemiological, level IV.
A Systematic Review of Cognitive Functioning After Traumatic Brain Injury in Individuals Aged 10–30 Years
Authors: Kohler Mark J. , Hendrickx Matthew D. , Powell-Jones Alycia , Bryan-Hancock Claire
Published: December 2020

Given the importance of the period of life from 10 to 30 years in terms of cognitive development and education, combined with the high incidence of traumatic brain injury (TBI) during this period, and limited consensus as to the pattern and degree of cognitive impairment post TBI during this period, we conducted a systematic review to investigate cognitive performance across a range of domains among individuals between the ages of 10 and 30 years who had sustained a TBI. We searched five databases and identified 799 unique records; 52 met our inclusion criteria. These studies reported cognitive function for intelligence, attention, memory, processing speed, and executive function. The majority of the studies reported significant effects, suggesting that TBI is associated with cognitive impairments in these domains. Nine of the studies used physiological tests (EEG and fMRI), the outcomes of which supported behaviorally demonstrated cognitive deficits. In the studies we reviewed, individuals aged 10–30 years who had experienced a TBI performed worse than healthy controls on cognitive function measures—specifically for attention, memory, processing speed, and executive function. In the studies that subjected the individuals with TBI to EEG and fMRI, atypical activation in associated brain regions was demonstrated while the individuals were undergoing cognitive tasks. However, caution should be taken when interpreting the overall results due to the high risk of bias across the majority of the studies. The broader implications of reduced cognitive performance after TBI across this age range are yet to be fully understood.
Biomimetic six-axis robots replicate human cardiac papillary muscle motion: pioneering the next generation of biomechanical heart simulator technology
Authors: Imbrie-Moore Annabel M. , Park Matthew H. , Paulsen Michael J. , Sellke Mark , Kulkami Rohun , Wang Hanjay , Zhu Yuanjia , Farry Justin M. , Bourdillon Alexandra T. , Callinan Christine , Lucian Haley J. , Hironaka Camille E. , Deschamps Daniela , Joseph Woo Y.
Published: December 2020

Papillary muscles serve as attachment points for chordae tendineae which anchor and position mitral valve leaflets for proper coaptation. As the ventricle contracts, the papillary muscles translate and rotate, impacting chordae and leaflet kinematics; this motion can be significantly affected in a diseased heart. In
ex vivo
heart simulation, an explanted valve is subjected to physiologic conditions and can be adapted to mimic a disease state, thus providing a valuable tool to quantitatively analyse biomechanics and optimize surgical valve repair. However, without the inclusion of papillary muscle motion, current simulators are limited in their ability to accurately replicate cardiac biomechanics. We developed and implemented image-guided papillary muscle (IPM) robots to mimic the precise motion of papillary muscles. The IPM robotic system was designed with six degrees of freedom to fully capture the native motion. Mathematical analysis was used to avoid singularity conditions, and a supercomputing cluster enabled the calculation of the system's reachable workspace. The IPM robots were implemented in our heart simulator with motion prescribed by high-resolution human computed tomography images, revealing that papillary muscle motion significantly impacts the chordae force profile. Our IPM robotic system represents a significant advancement for
ex vivo
simulation, enabling more reliable cardiac simulations and repair optimizations.
Electrochemistry as a surrogate for protein phosphorylation: voltage-controlled assembly of reflectin A1
Authors: Liang Sheng-Ping , Levenson Robert , Malady Brandon , Gordon Michael J. , Morse Daniel E. , Sepunaru Lior
Published: December 2020

Phosphorylation is among the most widely distributed mechanisms regulating the tunable structure and function of proteins in response to neuronal, hormonal and environmental signals. We demonstrate here that the low-voltage electrochemical reduction of histidine residues in reflectin A1, a protein that mediates the neuronal fine-tuning of colour reflected from skin cells for camouflage and communication in squids, acts as an
in vitro
surrogate for phosphorylation
in vivo
, driving the assembly previously shown to regulate its function. Using micro-drop voltammetry and a newly designed electrochemical cell integrated with an instrument measuring dynamic light scattering, we demonstrate selective reduction of the imidazolium side chains of histidine in monomers, oligopeptides and this complex protein in solution. The formal reduction potential of imidazolium proves readily distinguishable from those of hydronium and primary amines, allowing unequivocal confirmation of the direct and energetically selective deprotonation of histidine in the protein. The resulting ‘electro-assembly’ provides a new approach to probe, understand, and control the mechanisms that dynamically tune protein structure and function in normal physiology and disease. With its abilities to serve as a surrogate for phosphorylation and other mechanisms of charge neutralization, and to potentially isolate early intermediates in protein assembly, this method may be useful for analysing never-before-seen early intermediates in the phosphorylation-driven assembly of other proteins in normal physiology and disease.
Bronchoconstriction: a potential missing link in airway remodelling
Authors: O'Sullivan Michael J. , Phung Thien-Khoi N. , Park Jin-Ah
Published: December 2020

In asthma, progressive structural changes of the airway wall are collectively termed airway remodelling. Despite its deleterious effect on lung function, airway remodelling is incompletely understood. As one of the important causes leading to airway remodelling, here we discuss the significance of mechanical forces that are produced in the narrowed airway during asthma exacerbation, as a driving force of airway remodelling. We cover
in vitro
,
ex vivo
and
in vivo
work in this field, and discuss up-to-date literature supporting the idea that bronchoconstriction may be the missing link in a comprehensive understanding of airway remodelling in asthma.
Habitat loss alters effects of intransitive higher-order competition on biodiversity: a new metapopulation framework
Authors: Li Yinglin , Bearup Daniel , Liao Jinbao
Published: December 2020

Recent studies have suggested that intransitive competition, as opposed to hierarchical competition, allows more species to coexist. Furthermore, it is recognized that the prevalent paradigm, which assumes that species interactions are exclusively pairwise, may be insufficient. More importantly, whether and how habitat loss, a key driver of biodiversity loss, can alter these complex competition structures (and therefore species coexistence) remain unclear. We thus present a new, simple yet comprehensive metapopulation framework that can account for any competition pattern and more complex higher-order interactions (HOIs) among species. We find that competitive intransitivity increases community diversity and that HOIs generally enhance this effect. Essentially, intransitivity promotes species richness by preventing the dominance of a few species, unlike the hierarchical competition, while HOIs facilitate species coexistence through stabilizing community fluctuations. However, variation in species’ vital rates and habitat loss can weaken or even reverse such higher-order effects, as their interaction can lead to a more rapid decline in competitive intransitivity under HOIs. Thus, it is essential to correctly identify the most appropriate interaction model for a given system before models are used to inform conservation efforts. Overall, our simple model framework provides a more parsimonious explanation for biodiversity maintenance than the existing theory.
Follow the straggler: zebrafish use a simple heuristic for collective decision-making
Authors: Kadak Kevin , Miller Noam
Published: December 2020

Animal groups often make decisions sequentially, from the front to the back of the group. In such cases, individuals can use the choices made by earlier ranks, a form of social information, to inform their own choice. The optimal strategy for such decisions has been explored in models which differ on, for example, whether or not agents take into account the sequence of observed choices. The models demonstrate that choices made later in a sequence are more informative, but it is not clear if animals use this information or rely instead on simpler heuristics, such as quorum rules. We show that a simple rule ‘copy the last observed choice', gives similar predictions to those of optimal models for most likely sequences. We trained groups of zebrafish to choose one arm of a Y-maze and used them to demonstrate various sequences to naive fish. We show that the naive fish appear to use a simple rule, most often copying the choice of the last demonstrator, which results in near-optimal choices at a fraction of the computational cost.
Occipital gamma-aminobutyric acid and glutamate-glutamine alterations in major depressive disorder: An MRS study and meta-analysis
Authors: Truong Vuong , Cheng Paul Z. , Lee Hsin-Chien , Lane Timothy J. , Hsu Tzu-Yu , Duncan Niall W.
Published: December 2020

The neurotransmitters GABA and glutamate have been suggested to play a role in Major Depressive Disorder (MDD) through an imbalance between cortical inhibition and excitation. This effect has been highlighted in higher brain areas, such as the prefrontal cortex, but has also been posited in basic sensory cortices. Based on this, magnetic resonance spectroscopy (MRS) was used to investigate potential changes to GABA+ and glutamate+glutamine (Glx) concentrations within the occipital cortex in MDD patients (n = 25) and healthy controls (n = 25). No difference in occipital GABA+ or Glx concentrations, nor in the GABA+/Glx ratio, was found between groups. An analysis of an extended MDD patient and unmatched control dataset (n = 90) found no correlation between metabolite concentrations and depressive symptoms. These results were integrated with prior studies through metabolite-specific meta-analyses, revealing no difference in occipital GABA and Glx concentrations between patients and controls. An effect of publication year on GABA group differences was found, suggesting that previously reported results may have been artifacts of measurement accuracy. Taken together, our results suggest that, contrary to some prior reports, MRS measurements of occipital GABA and Glx do not differ between MDD patients and controls.
Modeling MRSA decolonization: Interactions between body sites and the impact of site-specific clearance
Authors: Poyraz Onur , Sater Mohamad R. A. , Miller Loren G. , McKinnell James A. , Huang Susan S. , Grad Yonatan H. , Marttinen Pekka
Published: December 2020

Methicillin-resistantStaphylococcus aureus(MRSA) can colonize multiple body sites, and carriage is a risk factor for infection. Successful decolonization protocols reduce disease incidence; however, multiple protocols exist, comprising diverse therapies targeting multiple body sites, and the optimal protocol is unclear. Standard methods are inadequate to infer the impact of site-specific components on successful decolonization. Here, we formulate a Bayesian coupled hidden Markov model (CHMM), which estimates interactions between body sites, quantifies the contribution of each therapy to successful decolonization, and enables predictions of the efficacy of therapy combinations. We applied the model to longitudinal data from a randomized controlled trial (RCT) of an MRSA decolonization protocol consisting of chlorhexidine body and mouthwash and nasal mupirocin. Our findings 1) confirmed nares as a central hub for MRSA colonization and nasal mupirocin as the most crucial therapy, and 2) demonstrated that all components contributed significantly to the efficacy of the protocol and the protocol reduced self-inoculation. Finally, we assessed the impact of hypothetical increases on the effectiveness of each therapyin silicoand found that enhancing MRSA clearance at the skin would yield the largest gains to the overall decolonization regimen. This study demonstrates the use of advanced modeling to go beyond what is typically achieved by RCTs, enabling evidence-based decision-making to streamline clinical protocols.
Transcriptional regulation profiling reveals disrupted lipid metabolism in failing hearts with a pathogenic phospholamban mutation
Authors: Pei Jiayi , Maas Renee G.C. , Nagyova Ema , Gho Johannes M.I.H. , Blok Christian Snijders , van Adrichem Iris , Calis Jorg J.A. , van Es René , Sepehrkhouy Shahrzad , Feyen Dries , van den Dungen Noortje , Lansu Nico , de Jonge Nicolaas , den Ruijter Hester M. , Huibers Manon M.H. , de Weger Roel A. , van Laake Linda W. , Verhaar Marianne C. , van Tintelen Peter , van Steenbeek Frank G. , van Mil Alain , Buikema Jan W. , Burgering Boudewijn , Kararikes Ioannis , Mercola Mark , Doevendans Pieter A. , Sluijter Joost , Vink Aryan , Cheng Caroline , Mokry Michal , Asselbergs Folkert W. , Harakalova Magdalena
Published: December 2020

Background

The R14del mutation in the phospholamban (PLN) gene is associated with various types of cardiomyopathies and increases the risk of developing life-threatening ventricular arrhythmias. In this study, we focused on a homogeneous Dutch founder cohort of genetic cardiomyopathy due to PLN R14del mutation and aimed to study the influence of epigenetic changes from a multi-dimensional perspective.

Results

Using cardiac tissue of PLN R14del patients and donors, we identified differentially acetylated promoters and enhancers (H3K27ac ChIPseq), annotated enriched transcription factor (TF) binding motifs located in those regions, and identified differentially expressed genes (RNA-seq). In line with the fibrofatty replacement in PLN R14del hearts at the histological level, our integrative analysis detected the downregulation of key TF regulators in fatty acid oxidation (FAO) metabolisms and their downstream target in PLN R14del hearts as compared to controls. We further examined heart tissue using immunofluorescence staining (IF) and to confirm the mitochondrial lipid abnormalities in the PLN R14del hearts. Furthermore, we observed the accumulation and deformation of lipid droplets and a disrupted morphology of mitochondria, the key organelle where FAO takes place, in PLN R14del heart using transmission electron microscopy (TEM).

Conclusion

Using multi-omics approaches, we successfully obtained a unique list of chromatin regions and genes, including TF-coding genes, which played important roles in the metabolism-related signalling in PLN R14del hearts.
Large uncertainty in individual PRS estimation impacts PRS-based risk stratification
Authors: Ding Yi , Hou Kangcheng , Burch Kathryn S. , Lapinska Sandra , Privé Florian , Vilhjálmsson Bjarni , Sankararaman Sriram , Pasaniuc Bogdan
Published: December 2020

Large-scale genome-wide association studies have enabled polygenic risk scores (PRS), which estimate the genetic value of an individual for a given trait. Since PRS accuracy is typically assessed using cohort-level metrics (e.g., R2), uncertainty in PRS estimates at individual level remains underexplored. Here we show that Bayesian PRS methods can estimate the variance of an individual’s PRS and can yield well-calibrated credible intervals for the genetic value of a single individual. For real traits in the UK Biobank (N=291,273 unrelated “white British”) we observe large variance in individual PRS estimates which impacts interpretation of PRS-based stratification; for example, averaging across 13 traits, only 0.8% (s.d. 1.6%) of individuals with PRS point estimates in the top decile have their entire 95% credible intervals fully contained in the top decile. We provide an analytical estimator for individual PRS variance—a function of SNP-heritability, number of causal SNPs, and sample size—and observe high concordance with individual variances estimated via posterior sampling. Finally as an example of the utility of individual PRS uncertainties, we explore a probabilistic approach to PRS-based stratification that estimates the probability of an individual’s genetic value to be above a prespecified threshold. Our results showcase the importance of incorporating uncertainty in individual PRS estimates into subsequent analyses.
Optimized chemogenomic library design strategies for precision oncology
Authors: Athanasiadis Paschalis , Ravikumar Balaguru , Carragher Neil O. , Clemons Paul A. , Johanssen Timothy , Ebner Daniel , Aittokallio Tero
Published: December 2020

Designing a focused compound screening library of bioactive small molecules is a challenging task since many compounds modulate their effects through multiple protein targets with various degrees of potency and selectivity. We describe here several analytic procedures with adjustable cut-off parameters that enable one to design anticancer target-focused compound libraries optimized for library size, cellular activity, biological and chemical diversity and target selectivity. Even though our focus was on designing compound libraries to enable a comprehensive investigation of the target biology of glioblastoma (GBM), the compound collections cover a wide range of protein targets and biological pathways implicated in various types of cancers, making the libraries widely applicable in precision oncology studies. We published the final screening set library, called theComprehensive anti-Cancer small-CompoundLibrary, orC3L.We hope these general library design principles and the current, widely annotated small molecule libraries will prove useful for the community in various phenotypic screening experiments in GBM and other cancers.
On the permeability of cell membranes subjected to lipid oxidation
Authors: Wiczew Daniel , Szulc Natalia , Tarek Mounir
Published: December 2020

The formation of transient hydrophilic pores in their membranes is a well-recognized mechanism of permeabilization of cells exposed to high-intensity electric pulses. However, the formation of such pores alone is not able to explain all aspects of the so-called electroporation phenomenon. In particular, the reasons for the sustained permeability of cell membranes, which persist long after the pulses’ application, remain elusive. The complete resealing of the cell membranes takes indeed orders of magnitude longer than the time of electropore closure as reported from molecular modelling investigations. A possible alternative mechanism to explain the observed long-lived permeability of cell membranes, lipid peroxidation, has been previously suggested but the theoretical investigations of membrane lesions, containing excess amounts of hydroperoxides, have shown that the conductivities of such lesions were not high enough to reasonably explain the entire range of experimental measurements. Here, we expand on these studies and investigate the permeability of cell membrane lesions that underwent secondary oxidation. Molecular dynamics simulations and free energy calculations on lipid bilayers in different states show that such lesions provide a better model for post-pulsed permeable and conductive electropermeabilized cells. These results are further discussed in context of sonoporation and ferroptosis, respectively a procedure and a phenomena, among others, in which alike electroporation substantial lipid oxidation might be triggered.

Highlights

The contribution of secondary lipids’ oxidation to the permeabilization of model membranes is quantitatively assessed

Small patches of secondary lipids’ oxidation cause formation long-lived pores in lipid bilayers.

The cholesterol content of membranes enhances the life-time of the formed pores.

A single pore accounts for the measured post-pulse electropermeabilization of cells.

The diffusion of the secondary oxidation lipids, even after pores closure leads to permeability of lipid membrane.
Heterochromatin flexibility contributes to chromosome segregation in the cell nucleus
Authors: Girard Martin , Olvera de la Cruz Monica , Marko John F. , Erbaş Aykut
Published: December 2020

While there is a prevalent genome organization in eukaryotic cells, with heterochromatin concentrated at the nuclear periphery, anomalous cases do occur. Deviations of chromatin distribution are frequent, for example, upon aging, under malignant diseases, or even naturally in rod cells of nocturnal mammals. Using molecular dynamic simulations, we study the segregation of heterochromatin in the cell nucleus by modeling interphase chromosomes as diblock ring copolymers confined in a rigid spherical shell. In our model, heterochromatin and euchromatin are distinguished by their bending stiffnesses, while an interaction potential between the spherical shell and chromatin is used as a proxy for lamin-associated proteins. Our simulations indicate that in the absence of attractive interactions between the nuclear shell and the chromatin, the majority of heterochromatin segregates towards the nuclear interior due to depletion of less flexible heterochromatin segments from the nuclear periphery. This inverted chromatin distribution is in accord with experimental observations in rod cells. This “inversion” is also found to be independent of the heterochromatin concentration and chromosome number, and is further enhanced by additional attractive interactions between heterochromatin segments. as well as by allowing bond-crossing to emulate topoisomerase activity. The usual chromatin distribution, with heterochromatin at the periphery, can be recovered by further increasing the bending stiffness of heterochromatin segments or by turning on attractive interactions between the nuclear shell and heterochromatin. Overall, our results indicate that bending stiffness of chromatin could be a contributor to chromosome organization along with differential effects of HP1α-driven phase segregation and of loop extruders, and interactions with the nuclear envelope and topological constraints.
Interactive Web-based Annotation of Plant MicroRNAs with iwa-miRNA
Authors: Zhang Ting , Zhai Jingjing , Zhang Xiaorong , Ling Lei , Li Menghan , Xie Shang , Song Minggui , Ma Chuang
Published: December 2020

MicroRNAs (miRNAs) are important regulators of gene expression. The large-scale detection and profiling of miRNAs has accelerated with the development of high-throughput small RNA sequencing (sRNA-Seq) techniques and bioinformatics tools. However, generating high-quality comprehensive miRNA annotations remains challenging, due to the intrinsic complexity of sRNA-Seq data and inherent limitations of existing miRNA predictions. Here, we present iwa-miRNA, a Galaxy-based framework that can facilitate miRNA annotation in plant species by combining computational analysis and manual curation. iwa-miRNA is specifically designed to generate a comprehensive list of miRNA candidates, bridging the gap between already annotated miRNAs provided by public miRNA databases and new predictions from sRNA-Seq datasets. It can also assist users to select promising miRNA candidates in an interactive mode through the automated and manual steps, contributing to the accessibility and reproducibility of genome-wide miRNA annotation. iwa-miRNA is user-friendly and can be easily deployed as a web application for researchers without programming experience. With flexible, interactive, and easy-to-use features, iwa-miRNA is a valuable tool for annotation of miRNAs in plant species with reference genomes. We illustrated the application of iwa-miRNA for miRNA annotation of plant species with varying complexity. The sources codes and web server of iwa-miRNA is freely accessible at:http://iwa-miRNA.omicstudio.cloud/.
Hierarchical development of dominance through the winner-loser effect and socio-spatial structure
Authors: van Haeringen E.S. , Hemelrijk C.K.
Published: December 2020

In many groups of animals the dominance hierarchy is linear. What mechanisms underlie this linearity of the dominance hierarchy is under debate. Linearity is often attributed to cognitively sophisticated processes, such as transitive inference and eavesdropping. An alternative explanation is that it develops via the winner-loser effect. This effect implies that after a fight has been decided the winner is more likely to win again, and the loser is more likely to lose again. Although it has been shown that dominance hierarchies may develop via the winner-loser effect, the degree of linearity of such hierarchies is unknown.

The aim of the present study is to investigate whether a similar degree of linearity, like in real animals, may emerge as a consequence of the winner-loser effect and the socio-spatial structure of group members. For this purpose, we use the model DomWorld, in which agents group and compete and the outcome of conflicts are self-reinforcing. Here dominance hierarchies are shown to emerge. In the model, we apply analytical methods previously used in a study on dominance in real hens including an analysis of behaviourial dynamics and network triad motifs.

We show that when in the complete model one parameter, representing the intensity of aggression, was set high, the model reproduced the high linearity and many patterns of hierarchical development typical of groups of hens. Yet, when omitting from the model the winner-loser effect or spatial location of individuals, this resemblance decreased markedly.

Our results demonstrate that the spatial structure and the winner-loser effect provide a plausible alternative for hierarchical linearity to processes that are cognitively more sophisticated. Further research should determine whether the winner-loser effect and spatial structure of group members also explains the characteristics of hierarchical development in other species.
Modeling of Internal and External Factors affecting a Complex Dengue Network
Authors: Malik Hafiz Abid Mahmood , Abid Faiza , Wahiddin Mohamed Ridza , Waqas Ahmad
Published: December 2020

There are different factors that are the cause of abrupt spread of arbovirus. We modelled the factors (internal & external) that can increase the diffusion of dengue virus and observed their effects. These factors have influenced on theAedes aegypti(a dengue virus carrier); factors which increase the dengue transmission. Interestingly, there are some factors that can suppress theAedes aegypti. The species ofAedes aegyptiformalizes its own network by which dengue virus is spread. Internal & external exposures of the dengue epidemic complex network have been modelled and analyzed. Influence of internal and external diffusion with two scenarios has been discussed. ‘Genetically modified mosquito’ technique has been applied and its associated simulated results are discussed. From the outcomes, the best time duration to contain the spread of dengue virus has been proposed, and our simulation model showed the possibility of suppressing theAedes aegyptinetwork.
Viral Packaging ATPases Utilize a Glutamate Switch to Couple ATPase Activity and DNA Translocation
Authors: Pajak Joshua , Atz Rockney , Hilbert Brendan J. , Morais Marc C. , Kelch Brian A. , Jardine Paul , Arya Gaurav
Published: December 2020

Many viruses utilize ringed packaging ATPases to translocate double-stranded DNA into procapsids during replication. A critical step in the mechanochemical cycle of such ATPases is ATP binding, which causes a subunit within the motor to grip DNA tightly. Here, we probe the underlying molecular mechanism by which ATP binding is coupled to DNA gripping and show that a glutamate switch residue found in AAA+ enzymes is central to this coupling in viral packaging ATPases. Using free energy landscapes computed through molecular dynamics simulations, we determined the stable conformational state of the ATPase active site in apo, ATP-bound, and ADP-bound states. Our results show that the catalytic glutamate residue transitions from an inactive to an active pose upon ATP binding, and that a residue assigned as the glutamate switch is necessary for regulating the transition. Further, we identifiedviamutual information analyses the intramolecular signaling pathway mediated by the glutamate switch that is responsible for coupling ATP binding to conformational transitions of DNA-gripping motifs. We corroborated these predictions with both structural and functional experimental data. Specifically, we showed that the crystal structure of the ADP-bound P74-26 packaging ATPase is consistent with the predicted structural coupling from simulations, and we further showed that disrupting the predicted signaling pathway indeed decouples ATPase activity from DNA translocation activity in the φ29 DNA packaging motor. Our work thus establishes a signaling pathway in viral DNA packaging motors that ensures coordination between chemical and mechanical events involved in viral DNA packaging.
Designed proteins assemble antibodies into modular nanocages
Authors: Divine Robby , Dang Ha V. , Ueda George , Fallas Jorge A. , Vulovic Ivan , Sheffler William , Saini Shally , Zhao Yan Ting , Raj Infencia Xavier , Morawski Peter A. , Jennewein Madeleine F. , Homad Leah J. , Wan Yu-Hsin , Tooley Marti R. , Seeger Franzika , Etemadi Ali , Fahning Mitchell L. , Lazarovits James , Roederer Alex , Walls Alexandra C. , Stewart Lance , Mazloomi Mohammadali , King Neil P. , Campbell Daniel J. , McGuire Andrew T. , Stamatatos Leonidas , Ruohola-Baker Hannele , Mathieu Julie , Veesler David , Baker David
Published: December 2020

Antibodies are widely used in biology and medicine, and there has been considerable interest in multivalent antibody formats to increase binding avidity and enhance signaling pathway agonism. However, there are currently no general approaches for forming precisely oriented antibody assemblies with controlled valency. We describe the computational design of two-component nanocages that overcome this limitation by uniting form and function. One structural component is any antibody or Fc fusion and the second is a designed Fc-binding homo-oligomer that drives nanocage assembly. Structures of 8 antibody nanocages determined by electron microscopy spanning dihedral, tetrahedral, octahedral, and icosahedral architectures with 2, 6, 12, and 30 antibodies per nanocage match the corresponding computational models. Antibody nanocages targeting cell-surface receptors enhance signaling compared to free antibodies or Fc-fusions in DR5-mediated apoptosis, Tie2-mediated angiogenesis, CD40 activation, and T cell proliferation; nanocage assembly also increases SARS-CoV-2 pseudovirus neutralization by α-SARS-CoV-2 monoclonal antibodies and Fc-ACE2 fusion proteins. We anticipate that the ability to assemble arbitrary antibodies without need for covalent modification into highly ordered assemblies with different geometries and valencies will have broad impact in biology and medicine.
Considerations and principles for conducting a participatory capacity and vulnerability analysis (PCVA) for disaster risk reduction and climate change adaptation
Authors: Ahmed Iftekhar
Published: December 2020

Purpose

While there are many such toolkits on community-based participatory methods, the key considerations and principles of conducting a participatory capacity and vulnerability analysis (PCVA) are less covered, yet they are central to the effective conduct of a PCVA, the reason why this paper focuses on such issues.

Design/methodology/approach

This paper is derived from a toolkit that was produced for Oxfam Australia. Disasters and climate change are major drivers of poverty and significantly affect the communities that development programs of Oxfam Australia aim to assist. Recognising the importance of building its organisational capacity to address these risks, Oxfam Australia initiated and commissioned the production of a PCVA toolkit to support disaster risk reduction and climate change adaptation programs; the production of the toolkit was led by the author. The methodology of producing the toolkit consisted of discussions with experts and a review of similar toolkits.

Findings

Details of the PCVA process and how to conduct one in a community setting are provided including PCVA concepts, briefing, logistics and management and principles of working with communities. Importantly, the different stages of conducting a PCVA are explained, and some selected tools are presented as illustrative examples. In conclusion, the importance of the PCVA considerations and principles are reaffirmed vis-à-vis the sensitivity and soft skills required in a low-income developing country setting.

Originality/value

The participatory development approach, which the toolkit follows, has been widely advocated for the past few decades and most non-governmental organisations involved in community development espouse this approach. Consequently, a wide range of participatory development toolkits have been developed, many of which relate to disasters and climate change. The PCVA toolkit discussed in this paper draws on the repertoire of toolkits already available and used over a long time. Nonetheless, effort was given to assembling a range of tools that were most suitable for the purpose of this particular PCVA toolkit. Instead of focussing on the tools, which are available from the freely downloadable toolkit and available in the public domain, in this paper, the PCVA process and its main principles are explained, and the key considerations to carry out an effective PCVA is discussed. Perhaps even more than the actual tools, these considerations and an understanding of the PCVA principles are significant because they underpin the utilisation of the toolkit.