bluuebunny/crossref_metadata_2025 huggingface dataset:
Pressure Injury Prevention Knowledge Among Family Caregivers of Patients Needing Home Care
Authors: Jafari Mojtaba , Nassehi Asra , Rafiei Hossein , Taqavi Sara , Karimi Yeganeh , Bardsiri Tayebeh Ilaghinezhad , Bellón Josefina Arboledas
Published: June 2021

One of the complications that patients in need of home healthcare might experience is pressure injury. Given that a significant part of the care of these patients is performed by their family caregivers, they must have sufficient knowledge about prevention and treatment of pressure injuries. We investigated the knowledge related to pressure injuries among family caregivers of patients needing home care who were at risk of pressure injury. Family caregivers of patients in Iran who needed home care services and were at risk of developing pressure injuries based on the Braden scale were invited to participate. A special questionnaire designed by Arboledas and Pancorbo-Hidalgo was used to assess the caregivers' level of knowledge. This questionnaire consists of 23 items, and with total scores between 23 and 46. A higher score indicates a higher level of knowledge about pressure injuries. A total of 323 family caregivers participated, most of whom were female. The mean total score of caregivers' knowledge about pressure injuries was 34.5 ± 3.4 (ranging 23 to 42). Most of the participants (n = 290) stated they did not receive adequate education related to pressure injuries. Among the demographic variables, a significant relationship was observed between the level of caregivers' knowledge with the level of education, younger age, offspring, admission in intensive care units, and male sex (p < 0.005). Family caregivers did not have sufficient knowledge about pressure injuries. Most of them did not receive the necessary education during the time of their patient's hospitalization. This issue should be considered by healthcare providers, and the necessary interventions should be considered to improve the situation.
Vasculitis Presenting as Autonomic Failure
Authors: Blech Benzion , Meyer Megan , Goodman Brent , Knox Molly , Aslam Fawad , Schmitt Alessandra , Grill Marie
Published: June 2021

Introduction:

Granulomatosis with polyangiitis (GPA) is a vasculitic process that can cause neurological dysfunction in addition to characteristic sinus and pulmonary manifestations. This case report highlights the spectrum of nervous system manifestations and includes rarely reported autonomic and pituitary involvement.

Case Report:

A 62-year-old woman presented with orthostatic intolerance, tachycardia, dry mouth, and temperature sensitivity; subsequent autonomic reflex study demonstrated widespread postganglionic sympathetic sudomotor, cardiovagal, and cardiovascular adrenergic impairment reflective of autonomic neuropathy and overall autonomic failure. Additional progressive symptoms included dysarthria, dysphagia, bilateral hearing loss, voice hoarseness, and right-sided facial numbness with multiple cranial neuropathies identified on neurological examination. The diagnosis of central diabetes insipidus was also confirmed. Pachymeningitis was present on brain magnetic resonance imaging. Pathologic review of the dural biopsy specimen revealed necrotizing granulomatous vasculitis consistent with GPA. She was treated with intravenous methylprednisolone and rituximab. Over the next 2 months, she had near-complete resolution of her symptoms with normalization on repeat autonomic testing.

Conclusions:

This is a unique GPA case presenting with autonomic failure and pituitary dysfunction with conclusive objective findings of autonomic dysfunction. Autonomic dysfunction and other disease manifestations were responsive to immunosuppressive therapy.
Hemorrhage Into a Subependymal Giant Cell Astrocytoma in an Adult With Tuberous Sclerosis
Authors: Barbiero Frank J. , Huttner Anita J. , Fulbright Robert K. , Baehring Joachim M.
Published: June 2021

Background:

We present an uncommon cause of intracranial hemorrhage in a young adult. Tuberous sclerosis complex is a rare genetic disorder characterized by skin changes, benign systemic or central nervous system tumors [subependymal giant cell astrocytoma (SEGA)], mental retardation, or epilepsy. Hemorrhage into SEGA is exceedingly rare.

Case Presentation:

We evaluated a 21-year-old college student with migraine. Biopsy of numerous popular skin lesions on his nose revealed adenoma sebaceum. Magnetic resonance imaging brain showed a subependymal nodule near the foramen of Monro suspected to be SEGA. Genetic analysis identified a tuberous sclerosis complex-1 germ line mutation. Surveillance imaging was recommended for the subependymal tumor. Fourteen months later, he presented with spontaneous hemorrhage into the tumor. Hematoma evacuation and tumor resection revealed SEGA. The college graduate was able to return to full-time work.

Conclusions:

We present an unusual cause of intracranial hemorrhage in a young adult. Thorough work-up and recognition of an underlying genetic predisposition can curtails diagnostic delay when life-threatening complications occur.
Intraosseous Venous Malformation of the Zygomatic Bone: Virtual Surgical Planning and Reconstruction With Customized CAD-CAM Titanium Implant
Authors: Antúnez-Conde Raúl , Salmerón José Ignacio , Navarro Carlos
Published: June 2021

Zygomatic intraosseous vascular anomalies are uncommon. Most cases have been reported without a precise diagnosis. The prevalence is 3:1 women during the fourth decade of life. The study of these lesions includes clinical findings, radiological studies, such as computed tomography and magnetic resonance imaging scans, and a postoperative histological study of the specimen. Biopsy is not recommended because of the risk of bleeding. Complete surgical resection remains the gold standard elective treatment.

The case of a patient with an intraosseous venous malformation of the zygomatic bone is presented, detailing the clinical, histological, and radiological characteristics and the surgical treatment with a primary reconstruction through Computer-Aided Design/Computer-Aided Manufacturing customized titanium implant guided by virtual surgical planning with a reduction of surgical time and morbidity in the donor area with optimal functional and aesthetic results.
John Marion Thoday. 30 August 1916—25 August 2008
Authors: MacDonald D. W. , Thompson J. N.
Published: June 2021

Professor John M. Thoday, ScD, FRS, was Arthur Balfour Professor of Genetics at the University of Cambridge from 1959 until 1983. In that position, he was influential in establishing genetics as an integral part of the undergraduate programme in biology at Cambridge, and he developed an active research programme that explored genetic processes underlying quantitative genetic traits, natural selection in sympatric populations and genetic variation in human and other populations. In more than 125 publications, he brought insightful attention to questions that had often been overlooked by others. Some of his most significant work explored the genetic basis of quantitative traits and thus pioneered approaches to understanding the mechanisms behind responses to selection. This helped set the stage to uncovering genes in the multiple-gene systems that determine polygenic characters in fields from medicine to agriculture. Other key work focused on disruptive, or diversifying, selection as a potential mechanism for populations to respond to adaptive challenges in nature. When his study of disruptive selection began, many in the field believed it was not even a possible process. In his many roles, John Thoday was a mentor who stimulated an open, respectful and intellectually rich academic environment for the Department of Genetics at Cambridge and for his field of creative activity.
Quantifying the differences incall detail records
Authors: Botta Federico
Published: June 2021

The increasing availability of mobile phone data has attracted the attention of several researchers interested in studying our collective behaviour. Our interactions with the phone network can take several forms, from SMS messages to phone calls and data usage. Typically, mobile phone data are released to researchers in the form ofcall detail records, which contain records of different types of interactions, and can be used to analyse various aspects of our behaviour. However, the inherently behavioural nature of these interactions may result in differences between how we make phone calls and receive text messages. Studies which rely on data derived from these interactions, therefore, need to carefully consider these differences. Here, we aim to investigate differences and limitations of different types of mobile phone interactions data by analysing a large mobile phone dataset. We study the relationship between different types of interactions and show how it changes over time. We anticipate our findings to be of interest to all researchers working in the area of computational social science.
Land use and social-ecological legacies of Rio de Janeiro's Atlantic urban forests: from charcoal production to novel ecosystems
Authors: Solórzano Alexandro , Brasil-Machado Ana , Ribeiro de Oliveira Rogério
Published: June 2021

Historical ecology is an important tool in deciphering human–environment interactions imprinted on landscapes throughout time. However, gaps of knowledge still remain regarding the land use legacies hidden in the current Atlantic Forest landscape; and also regarding how this information can help management of the remaining forest cover. The social-ecological systems framework was applied to understand charcoal production in the urban forests of Rio de Janeiro, from the nineteenth to mid-twentieth century, and their current social-ecological legacies. Charcoal production carried out by former enslaved populations, allowed for rapid forest regeneration. Forest thinning instead of forest felling was carried out by small groups in these urban remnant forests, sparing large native trees and facilitating natural regeneration. Currently, more than one thousand former charcoal production sites are accounted for hidden underneath the forest cover. The forest landscape of today is a result of novel forest successional trajectories that recovered structural and functional attributes of the forest ecosystem. However, this came at the cost of social invisibility and marginalization of these populations. The management practices of charcoal production dispersed in the landscape is one of Rio de Janeiro's most important, albeit hidden, land use legacies. Currently, the forested landscape is comprised of regenerated forests, both structurally and functionally sound, though with significant changes in species composition including the introduction of exotic species throughout recent centuries. These urban forests are today a complex mosaic of novel ecosystems, with rich biocultural diversity, and together with managed lands and well conserved forest tracts, provide not only livelihood and sustenance for forest dwelling families, but also important ecosystem services for the entire population of Rio de Janeiro. We believe that these concepts and frameworks can offer practical solutions for urban forest management, taking into account the biocultural diversity of Rio de Janeiro, increasing awareness of sustainability and promoting food security.
Wild jackdaws respond to their partner's distress, but not with consolation
Authors: Hooper Rebecca , Meekins Ella , McIvor Guillam E. , Thornton Alex
Published: June 2021

Individuals are expected to manage their social relationships to maximize fitness returns. For example, reports of some mammals and birds offering unsolicited affiliation to distressed social partners (commonly termed ‘consolation’) are argued to illustrate convergent evolution of prosocial traits across divergent taxa. However, most studies cannot discriminate between consolation and alternative explanations such as self-soothing. Crucially, no study that controls for key confounds has examined consolation in the wild, where individuals face more complex and dangerous environments than in captivity. Controlling for common confounds, we find that male jackdaws (
Corvus monedula
) respond to their mate's stress-states, but not with consolation. Instead, they tended to decrease affiliation and partner visit rate in both experimental and natural contexts. This is striking because jackdaws have long-term monogamous relationships with highly interdependent fitness outcomes, which is precisely where theory predicts consolation should occur. Our findings challenge common conceptions about where consolation should evolve, and chime with concerns that current theory may be influenced by anthropomorphic expectations of how social relationships should be managed. To further our understanding of the evolution of such traits, we highlight the need for our current predictive frameworks to incorporate the behavioural trade-offs inherent to life in the wild.
Effects of uniform vertical inflow perturbations on the performance of flapping wings
Authors: Mazharmanesh Soudeh , Stallard Jace , Medina Albert , Fisher Alex , Ando Noriyasu , Tian Fang-Bao , Young John , Ravi Sridhar
Published: June 2021

Flapping wings have attracted significant interest for use in miniature unmanned flying vehicles. Although numerous studies have investigated the performance of flapping wings under quiescent conditions, effects of freestream disturbances on their performance remain under-explored. In this study, we experimentally investigated the effects of uniform vertical inflows on flapping wings using a Reynolds-scaled apparatus operating in water at Reynolds number ≈ 3600. The overall lift and drag produced by a flapping wing were measured by varying the magnitude of inflow perturbation from
J
Vert
= −1 (downward inflow) to
J
Vert
= 1 (upward inflow), where
J
Vert
is the ratio of the inflow velocity to the wing's velocity. The interaction between flapping wing and downward-oriented inflows resulted in a steady linear reduction in mean lift and drag coefficients,

C
¯

L

and

C
¯

D

, with increasing inflow magnitude. While a steady linear increase in

C
¯

L

and

C
¯

D

was noted for upward-oriented inflows between 0 <
J
Vert
< 0.3 and
J
Vert
> 0.7, a significant unsteady wing–wake interaction occurred when 0.3 ≤
J
Vert
< 0.7, which caused large variations in instantaneous forces over the wing and led to a reduction in mean performance. These findings highlight asymmetrical effects of vertically oriented perturbations on the performance of flapping wings and pave the way for development of suitable control strategies.
What constrains adaptive radiation? Documentation and explanation of under-evolved morphologies in
Anolis
lizards
Authors: Poe Steven , Donald Lorenzo A. H. , Anderson Christopher
Published: June 2021

Adaptive radiations fill ecological and morphological space during evolutionary diversification. Why do some trait combinations evolve during such radiations, whereas others do not? ‘Required’ constraints of pleiotropy and developmental interaction frequently are implicated in explanations for such patterns, but selective forces also may discourage particular trait combinations. Here, we use a dataset of 351 species to demonstrate the dearth of some theoretically plausible trait combinations of limb, toe and tail length in
Anolis
lizards. For example, disproportionately few
Anolis
species display long limbs and short toes. We evaluate recovered patterns within three species of
Anolis
, and find that cladewide patterns are not evident at intraspecific levels. For example, within species, the combination of long limbs and short toes is not significantly rarer than long limbs and long toes. Differences in scale complicate inter- and intraspecific comparisons and disallow concrete conclusions of cause. However, the absence of the interspecific pattern at the intraspecific level is more compatible with selection favouring particular trait combinations than with ‘required’ forces dictating which trait combinations are available for selection. We also demonstrate the isometry of toe, tail and hindlimb length relative to body length between species but allometry in four of nine trait–body comparisons within species.
Phenotypic plasticity can reverse the relative extent of intra- and interspecific variability across a thermal gradient
Authors: Jacob Staffan , Legrand Delphine
Published: June 2021

Intra- and interspecific variability can both ensure ecosystem functions. Generalizing the effects of individual and species assemblages requires understanding how much within and between species trait variation is genetically based or results from phenotypic plasticity. Phenotypic plasticity can indeed lead to rapid and important changes of trait distributions, and in turn community functionality, depending on environmental conditions, which raises a crucial question: could phenotypic plasticity modify the relative importance of intra- and interspecific variability along environmental gradients? We quantified the fundamental niche of five genotypes in monocultures for each of five ciliate species along a wide thermal gradient in standardized conditions to assess the importance of phenotypic plasticity for the level of intraspecific variability compared to differences between species. We showed that phenotypic plasticity strongly influences trait variability and reverses the relative extent of intra- and interspecific variability along the thermal gradient. Our results show that phenotypic plasticity may lead to either increase or decrease of functional trait variability along environmental gradients, making intra- and interspecific variability highly dynamic components of ecological systems.
Supplemental forage ameliorates the negative impact of insecticides on bumblebees in a pollinator-dependent crop
Authors: Ingwell Laura L. , Ternest John J. , Pecenka Jacob R. , Kaplan Ian
Published: June 2021

Insecticide use and insufficient forage are two of the leading stressors to pollinators in agroecosystems. While these factors have been well studied individually, the experimental designs do not reflect real-world conditions where insecticide exposure and lack of forage occur simultaneously and could interactively suppress pollinator health. Using outdoor enclosures, we tested the effects of insecticides (imidacloprid + lambda-cyhalothrin) and non-crop forage (clover) in a factorial design, measuring the survival, behaviour and performance of bumblebees (
Bombus impatiens
), as well as pollination of the focal crop, watermelon. Colony survival was synergistically reduced to 17% in watermelon alone + insecticides (survival was 100% in all other treatments). However, behavioural shifts in foraging were mainly owing to insecticides (e.g. 95% reduced visitation rate to watermelon flowers), while impacts on hive performance were primarily driven by clover presence (e.g. 374% increase in the number of live eggs). Insecticide-mediated reductions in foraging decreased crop pollination (fruit set) by 32%. Altogether, these data indicate that both insecticides and non-crop forage play integral roles in shaping pollinator health in agricultural landscapes, but the relative importance and interaction of these two factors depend on which aspect of ‘health’ is being considered.
Self and non-self recognition affects clonal reproduction and competition in the pea aphid
Authors: Li Yang , Akimoto Shin-ichi
Published: June 2021

The spatial interaction of clonal organisms is an unsolved but crucial topic in evolutionary biology. We evaluated the interactions between aphid clones using a colour mutant (yellow) and an original (green) clone. Colonies founded by two aphids of the same clone and mixed colonies, founded by a green aphid and a yellow aphid, were set up to observe population growth for 15 days. We confirmed positive competition effects, with mixed colonies increasing in size more rapidly than clonal colonies. In mixed colonies where reproduction started simultaneously, green aphids overwhelmed yellow aphids in number, and yellow aphids restrained reproduction. However, when yellow aphids started to reproduce earlier, they outnumbered the green aphids. To test whether aphids have the ability to control reproduction according to the densities of self and non-self clones, one yellow aphid or one antennae-excised yellow aphid was transferred into a highly dense green clone colony. Intact yellow aphids produced fewer nymphs in crowded green colonies, whereas the fecundity of antennae-excised aphids did not change. Thus, we conclude that aphid clones can discriminate between self and non-self clones, and can regulate their reproduction, depending on whether they are superior or inferior in number to their competitors.
Introgression dynamics from invasive pigs into wild boar following the March 2011 natural and anthropogenic disasters at Fukushima
Authors: Anderson Donovan , Negishi Yuki , Ishiniwa Hiroko , Okuda Kei , Hinton Thomas G. , Toma Rio , Nagata Junco , Tamate Hidetoshi B. , Kaneko Shingo
Published: June 2021

Natural and anthropogenic disasters have the capability to cause sudden extrinsic environmental changes and long-lasting perturbations including invasive species, species expansion and influence evolution as selective pressures force adaption. Such disasters occurred on 11 March 2011, in Fukushima, Japan, when an earthquake, tsunami and meltdown of a nuclear power plant all drastically reformed anthropogenic land use. Using genetic data, we demonstrate how wild boar (
Sus scrofa leucomystax
) have persevered against these environmental changes, including an invasion of escaped domestic pigs (
Sus scrofa domesticus
). Concurrently, we show evidence of successful hybridization between pigs and native wild boar in this area; however in future offspring, the pig legacy has been diluted through time. We speculate that the range expansion dynamics inhibit long-term introgression and introgressed alleles will continue to decrease at each generation while only maternally inherited organelles will persist. Using the gene flow data among wild boar, we assume that offspring from hybrid lineages will continue dispersal north at low frequencies as climates warm. We conclude that future risks for wild boar in this area include intraspecies competition, revitalization of human-related disruptions and disease outbreaks.
Insect flight metabolic rate revealed by bolus injection of the stable isotope
13
C
Authors: Urca Tomer , Levin Eran , Ribak Gal
Published: June 2021

Measuring metabolic rate (MR) poses a formidable challenge in free-flying insects who cannot breathe into masks or be trained to fly in controlled settings. Consequently, flight MR has been predominantly measured on hovering or tethered insects flying in closed systems. Stable isotopes such as labelled water allow measurement of MR in free-flying animals but integrates the measurement over long periods exceeding the average flight duration of insects. Here, we applied the ‘bolus injection of isotopic
13
C Na-bicarbonate’ method to insects to measure their flight MR and report a 90% accuracy compared to respirometry. We applied the method on two beetle species, measuring MR during free flight and tethered flight in a wind tunnel. We also demonstrate the ability to repeatedly use the technique on the same individual. Therefore, the method provides a simple, reliable and accurate tool that solves a long-lasting limitation on insect flight research by enabling the measurement of MR during free flight.
Novelty-induced frontal-STN networks in Parkinson’s disease
Authors: Cole Rachel C , Espinoza Arturo I , Singh Arun , Berger Joel I , Cavanagh James F , Wessel Jan R , Greenlee Jeremy D , Narayanan Nandakumar S
Published: June 2021

Novelty detection is a primitive subcomponent of cognitive control that is deficient in Parkinson’s disease (PD) patients with cognitive dysfunction. Here, we studied novelty-response mechanisms in PD. In participants with PD, we recorded from cortical circuits with scalp-based electroencephalography (EEG) and from subcortical circuits using intraoperative neurophysiology during surgeries for implantation of deep-brain stimulation (DBS) electrodes. We report three major results. First, novel auditory stimuli triggered midfrontal low-frequency rhythms; of these, 1-4 Hz “delta” rhythms were linked to novelty-associated slowing whereas 4-7 Hz “theta” rhythms were specifically attenuated in PD. Second, 32% of subthalamic nucleus (STN) neurons were response-modulated; nearly all (94%) of these were also modulated by novel stimuli. Third, response-modulated STN neurons were coherent with midfrontal 1-4 Hz activity. These findings link scalp-based measurements of neural activity with neuronal activity in the STN. Our results provide insight into midfrontal cognitive control mechanisms and how purported hyperdirect fronto-basal ganglia circuits evaluate new information.
Racial/ethnic-based spirometry reference equations: Are they accurate for admixed populations?
Authors: Witonsky Jonathan , Elhawary Jennifer R. , Eng Celeste , Rodríguez-Santana José R. , Borrell Luisa N. , Burchard Esteban G.
Published: June 2021

BACKGROUND

Variation in genetic ancestry among admixed racial/ethnic groups may influence the fit of guideline-recommended spirometry reference equations, which rely on self-identified race/ethnicity.

RESEARCH QUESTION

What is the influence of genetic ancestry on the fit of the guideline-recommended racial/ethnic-based spirometry reference equations in populations of genetically admixed children?

STUDY DESIGN AND METHODS

Cross-sectional fit of guideline-recommended racial/ethnic-based spirometry reference equations was evaluated in control subjects from case-control studies of asthma. Anthropometry, blood samples, and spirometric measurements were obtained in 599 healthy admixed children, aged 8 to 21-years. Genetic ancestry was estimated using genome-wide genotype data. Equation fit was determined as a mean z-score between -0.5 and 0.5 and assessed in self-identified African American (N = 275) and Puerto Rican (N = 324) children using the distribution to determine cut points of genetic ancestry.

RESULTS

For African American children, African American-derived equations fit for predicting FEV1 and FVC in those with an African ancestry above the median (81-100%), whereas composite equations for “other/mixed” populations fit for predicting FEV1 and FVC in those with an African ancestry below the median (31-81%). Among Puerto Rican children, White-derived equations fit for predicting FEV1, and the composite equations fit for predicting FVC for those with African ancestry above the median (21-88%). In contrast, in Puerto Rican children with African ancestry below the median (6-21%), only equations derived in Whites provide an adequate fit.

INTERPRETATION

Guideline-recommended spirometry reference equations yielded biased estimates of lung function in admixed populations with high variation of African ancestry. Spirometry is due for reference equations that incorporate genetic ancestry, either for more precise application of the current equations or the derivation and utilization of new equations.
Imaging cortical multiple sclerosis lesions with ultra-high field MRI
Authors: Madsen Mads A.J. , Wiggermann Vanessa , Bramow Stephan , Christensen Jeppe Romme , Sellebjerg Finn , Siebner Hartwig R.
Published: June 2021

Background

Cortical lesions are abundant in multiple sclerosis (MS), yet difficult to visualizein vivo. Ultra-high field (UHF) MRI at 7T and above provides technological advances suited to optimize the detection of cortical lesions in MS.

Purpose

To provide a narrative and quantitative systematic review of the literature on UHF MRI of cortical lesions in MS.

Methods

A systematic search of all literature on UHF MRI of cortical lesions in MS published before September 2020. Quantitative outcome measures included cortical lesion numbers reported using 3T and 7T MRI and between 7T MRI sequences, along with sensitivity of UHF MRI towards cortical lesions verified by histopathology.

Results

7T MRI detected on average 52±26% (mean ± 95% confidence interval) more cortical lesions than the best performing image contrast at 3T, with the largest increase in type II-IV intracortical lesion detection. Across all studies, the mean cortical lesion number was 17±6/patient. In progressive MS cohorts, approximately four times more cortical lesions were reported than in CIS/early RRMS, and RRMS. Superiority of one MRI sequence over another could not be established from available data.Post-mortemlesion detection with UHF MRI agreed only modestly with pathological examinations. Mean pro- and retrospective sensitivity was 33±6% and 71±10%, respectively, with the highest sensitivity towards type I and type IV lesions.

Conclusion

UHF MRI improves cortical lesion detection in MS considerably compared to 3T MRI, particularly for type II-IV lesions. Despite modest sensitivity, 7T MRI is still capable of visualizing all aspects of cortical lesion pathology and could potentially aid clinicians in diagnosing and monitoring MS, and progressive MS in particular. However, standardization of acquisition and segmentation protocols is needed.
Comparative evaluation of the transmissibility of SARS-CoV-2 variants of concern
Authors: Wang Liang , Didelot Xavier , Bi Yuhai , Gao George F
Published: June 2021

Since the start of the SARS-CoV-2 pandemic in late 2019, several variants of concern (VOC) have been reported, such as B.1.1.7, B.1.351, P.1, and B.1.617.2. The exact reproduction number Rt for these VOCs is important to determine appropriate control measures. Here, we estimated the transmissibility for VOCs and lineages of SAR-CoV-2 based on genomic data and Bayesian inference under an epidemiological model to infer the reproduction number (Rt). We analyzed data for multiple VOCs from the same time period and countries, in order to compare their transmissibility while controlling for geographical and temporal factors. The lineage B had a significantly higher transmissibility than lineage A, and contributed to the global pandemic to a large extent. In addition, all VOCs had increased transmissibility when compared with other lineages in each country, indicating they are harder to control and present a high risk to public health. All countries should formulate specific prevention and control policies for these VOCs when they are detected to curve their potential for large-scale spread.
Truncated RNA-binding protein production by DUX4-induced systemic inhibition of nonsense-mediated RNA decay
Authors: Campbell Amy E. , Dyle Michael C. , Calviello Lorenzo , Matheny Tyler , Sudheendran Kavitha , Cortazar Michael A. , Forman Thomas , Fu Rui , Gillen Austin E. , Caruthers Marvin H. , Floor Stephen N. , Jagannathan Sujatha
Published: June 2021

Nonsense-mediated RNA decay (NMD) is a surveillance mechanism that degrades both canonical and aberrant transcripts carrying premature translation termination codons. NMD is thought to have evolved to prevent the synthesis of toxic truncated proteins. However, whether global inhibition of NMD results in widespread production of truncated proteins is unknown. A human genetic disease, facioscapulohumeral muscular dystrophy (FSHD) features acute inhibition of NMD upon expression of the disease-causing transcription factor, DUX4. Here, using a cell-based model of FSHD, we show the production of hundreds of truncated proteins from physiological NMD targets. Using ribosome profiling, we map the precise C-terminal end of these aberrant truncated proteins and find that RNA-binding proteins are especially enriched for aberrant truncations. The stabilized NMD isoform of one RNA-binding protein, SRSF3, is robustly translated to produce a stable truncated protein, which can also be detected in FSHD patient-derived myotubes. Notably, ectopic expression of truncated SRSF3 alone confers toxicity and its downregulation is cytoprotective. Our results demonstrate the genome-scale impact of NMD inhibition. This widespread production of potentially deleterious truncated proteins has implications for FSHD biology as well as other genetic diseases where NMD is therapeutically modulated.
SenseNet, a tool for analysis of protein structure networks obtained from molecular dynamics simulations
Authors: Schneider Markus , Antes Iris
Published: June 2021

Computational methods play a key role for investigating allosteric mechanisms in proteins, with the potential of generating valuable insights for innovative drug design. Here we present the SenseNet (“Structure ENSEmble NETworks”) framework for analysis of protein structure networks, which differs from established network models by focusing on interaction timelines obtained by molecular dynamics simulations. This approach is evaluated by predicting allosteric residues reported by NMR experiments in the PDZ2 domain of hPTP1e, a reference system for which previous computational predictions have shown considerable variance. We applied two models based on the mutual information between interaction timelines to estimate the conformational influence of each residue on its local environment. In terms of accuracy our prediction model is comparable to the top performing model published for this system, but by contrast benefits from its independence from NMR structures. Our results are complementary to experimental data and the consensus of previous predictions, demonstrating the potential of our new analysis tool SenseNet. Biochemical interpretation of our model suggests that allosteric residues in the PDZ2 domain form two distinct clusters of contiguous sidechain surfaces. SenseNet is provided as a plugin for the network analysis software Cytoscape, allowing for ease of future application and contributing to a system of compatible tools bridging the fields of system and structural biology.

Author Summary

Regulation and signal transduction processes in proteins are often correlated to structural changes induced by ligand binding, which can lead to suppression or enhancement of protein function. A common method to investigate such changes are numerical simulations of protein dynamics. We developed the analysis software SenseNet for predicting how protein dynamics and function is affected by e.g. ligand binding events based on molecular dynamics simulations. Our model estimates which structural elements of the protein confer the most information about their local environment, reasoning that these elements are essential for signal propagation. Applying this method on the PDZ2 domain of the hPTP1e protein, we were able to accurately predict structure elements with known signaling roles as determined by previous experiments. Integrating these experimental data with the consensus of other computational models and our predictions, we find two separate pathways which may transmit information through the PDZ2 protein structure. In addition to deepening our insight into the behavior of this particular protein, these results demonstrate the usefulness of our methods for other systems, such as potential drug targets. To make this analysis available to a broad audience, we implemented it as a plugin for the popular network analysis software Cytoscape.
Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients
Authors: Nguyen Bastien , Fong Christopher , Luthra Anisha , Smith Shaleigh A. , DiNatale Renzo G. , Nandakumar Subhiksha , Walch Henry , Chatila Walid K. , Madupuri Ramyasree , Kundra Ritika , Bielski Craig M. , Mastrogiacomo Brooke , Boire Adrienne , Chandarlapaty Sarat , Ganesh Karuna , Harding James J. , lacobuzio-Donahue Christine A. , Razavi Pedram , Reznik Ed , Rudin Charles M. , Zamarin Dmitriy , Abida Wassim , Abou-Alfa Ghassan K. , Aghajanian Carol , Cercek Andrea , Chi Ping , Feldman Darren , Ho Alan L. , Iyer Gopakumar , Janjigian Yelena Y. , Morris Michael , Motzer Robert J. , O’Reilly Eileen M. , Postow Michael A. , Raj Nitya P. , Riely Gregory J. , Robson Mark E. , Rosenberg Jonathan E. , Safonov Anton , Shoushtari Alexander N. , Tap William , Teo Min Yuen , Varghese Anna M. , Voss Martin , Yaeger Rona , Zauderer Marjorie G. , Abu-Rustum Nadeem , Garcia-Aguilar Julio , Bochner Bernard , Hakimi Abraham , Jarnagin William R. , Jones David R. , Molena Daniela , Morris Luc , Rios-Doria Eric , Russo Paul , Singer Samuel , Strong Vivian E. , Chakravarty Debyani , Ellenson Lora H. , Gopalan Anuradha , Reis-Filho Jorge S. , Weigelt Britta , Ladanyi Marc , Gonen Mithat , Shah Sohrab P. , Massague Joan , Gao Jianjiong , Zehir Ahmet , Berger Michael F. , Solit David B. , Bakhoum Samuel F. , Sanchez-Vega Francisco , Schultz Nikolaus
Published: June 2021

Progression to metastatic disease remains the main cause of cancer death. Yet, the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we present MSK-MET, an integrated pan-cancer cohort of tumor genomic and clinical outcome data from more than 25,000 patients. We analyzed this dataset to identify associations between tumor genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma and HR-positive breast ductal carcinoma, but not in others, such as colorectal adenocarcinoma, pancreatic adenocarcinoma and high-grade serous ovarian cancer. We also identified specific somatic alterations associated with increased metastatic burden and specific routes of metastatic spread. Our data offer a unique resource for the investigation of the biological basis for metastatic spread and highlight the crucial role of chromosomal instability in cancer progression.
Lack of Host Reproductive Trade-offs Associated with Fecundity Compensation Response to Parasitic Castration
Authors: Davis Annabell A. , Vannatta J. Trevor , Gutierrez Stephanie O. , Minchella Dennis J.
Published: June 2021

Host-parasite coevolution may result in life-history changes in hosts that can limit the detrimental effects of parasitism. Fecundity compensation is one such life-history response, occurring when hosts increase their current reproductive output to make up for expected losses in future reproduction due to parasitic infection. However, the potential trade-offs between quantity and quality of offspring produced during fecundity compensation are relatively unexplored. This study uses the trematode, Schistosoma mansoni, and its snail intermediate host, Biomphalaria glabrata, to better understand the impacts of this host life-history response. Measures of host reproductive output as well as offspring hatching success and survival were collected to assess the reproductive consequences of infection. Infected snails exhibited fecundity compensation (increase in the number of eggs laid compared to controls) and had a higher probability of laying any eggs at all. Infection status did not play a significant role in hatching or offspring survival to maturity. However, the age of the parental snail had a significant impact on hatching success, as offspring from older parents demonstrated a higher hatching success rate. Overall, the lack of an apparent trade-off between quantity and quality of offspring suggests that infected parental snails invest more resources towards reproduction in order to maintain the fitness of their offspring, possibly at the expense of their own longevity.
Systematic genome-scale identification of host factors for SARS-CoV-2 infection across models yields a core single gene dependency; ACE2
Authors: Chan Katherine , Farias Adrian Granda , Lee Hunsang , Guvenc Furkan , Mero Patricia , Aulakh Kamaldeep , Brown Kevin R. , Haider Shahan , Marcon Edyta , Braunschweig Ulrich , Yan Tong Amy Hin , Pu Shuye , Habsid Andrea , Christie-Holmes Natasha , Budylowski Patrick , Astori Audrey , Ghalami Ayoob , Mubareka Samira , Banerjee Arinjay , Mossman Karen L. , Greenblatt Jack , Gray-Owen Scott D. , Raught Brian , Blencowe Benjamin J. , Taipale Mikko , Moffat Jason
Published: June 2021

SARS-CoV-2, depends on host cell components for replication, therefore the identification of virus-host dependencies offers an effective way to elucidate mechanisms involved in viral infection. Such host factors may be necessary for infection and replication of SARS-CoV-2 and, if druggable, presents an attractive strategy for anti-viral therapy. We performed genome wide CRISPR knockout screens in Vero E6 cells and 4 human cell lines including Calu-3, Caco-2, Hek293 and Huh7 to identify genetic regulators of SARS-CoV-2 infection. Our findings identified only ACE2, the cognate SARS-CoV-2 entry receptor, as a common host dependency factor across all cell lines, while all other host genes identified were cell line specific including known factors TMPRSS2 and CTSL. Several of the discovered host-dependency factors converged on pathways involved in cell signalling, lipid metabolism, immune pathways and chromatin modulation. Notably, chromatin modulator genes KMT2C and KDM6A in Calu-3 cells had the strongest impact in preventing SARS-CoV-2 infection when perturbed. Overall, the network of host factors that have been identified will be broadly applicable to understanding the impact of SARS-CoV-2 on human cells and facilitate the development of host-directed therapies.

IN BRIEF

SARS-CoV-2, depends on host cell components for infection and replication. Genome-wide CRISPR screens were performed in multiple human cell lines to elucidate common host dependencies required for SARS-CoV-2 infection. Only ACE2, the cognate SARS-CoV-2 entry receptor, was common amongst cell lines, while all other host genes identified were cell line specific, several of which converged on pathways involved in cell signalling, lipid metabolism, immune pathways, and chromatin modulation. Overall, a network of host factors was identified that will be broadly applicable to understanding the impact of SARS-CoV-2 on human cells and facilitate productive targeting of host genes and pathways.

HIGHLIGHTS

- Genome-wide CRISPR screens for SARS-CoV-2 in multiple human cell lines

- Identification of wide-ranging cell-type dependent genetic dependencies for SARS-CoV-2 infection

- ACE2 is the only common host factor identified across different cell types
Deciphering the landscape of phosphorylated HLA-II ligands
Authors: Solleder Marthe , Racle Julien , Guillaume Philippe , Coukos George , Bassani-Sternberg Michal , Gfeller David
Published: June 2021

CD4+ T-cell activation in infectious diseases and cancer is governed by the recognition of peptides presented on class II human leukocyte antigen (HLA-II) molecules. Therefore, HLA-II ligands represent promising targets for vaccine design and personalized cancer immunotherapy. Much work has been done to identify and predict unmodified peptides presented on HLA-II molecules. However, little is known about the presentation of phosphorylated HLA-II ligands. Here, we analyzed Mass Spectrometry HLA-II peptidomics data and identified 1,113 unique phosphorylated HLA-II ligands. This enabled us to precisely define phosphorylated binding motifs for more than 30 common HLA-II alleles and to explore various molecular properties of phosphorylated peptides. Our data were further used to develop the first predictor of phosphorylated peptide presentation on HLA-II molecules.
Analysis of expression Quantitative Trait Loci for NLGN4X in relation to language and neurodevelopmental function: an exploratory analysis using FUSION and GTEx workflows
Authors: Simpson Nuala H. , Bishop Dorothy V.M. , Newbury Dianne F.
Published: June 2021

Language disorders in children are highly heritable, but progress in identifying genetic variants that contribute to language phenotypes has been slow. Here we applied a novel approach by identifying SNPs that are associated with gene expression in the brain, taking as our focus a gene on the X chromosome, NLGN4X, which has been postulated to play a role in neurodevelopmental disorders affecting language and communication. We found no significant associations between expression quantitative trait loci (eQTLs) and phenotypes of nonword repetition, general language ability or neurodevelopmental disorder in two samples of twin children, who had been selected for a relatively high rate of language problems. We report here our experiences with two methods, FUSION and GTEx, for eQTL analysis. It is likely that our null result represents a true negative, but for the interest of others interested in using these methods, we note specific challenges encountered in applying this approach to our data: a) complications associated with studying a gene on the X chromosome; b) lack of agreement between expression estimates from FUSION and GTEx; c) software compatibility issues with different versions of the R programming language.
Functional control of a 0.5 MDa TET aminopeptidase by a flexible loop revealed by MAS NMR
Authors: Gauto Diego F. , Macek Pavel , Malinverni Duccio , Fraga Hugo , Paloni Matteo , Sučec Iva , Hessel Audrey , Bustamante Juan Pablo , Barducci Alessandro , Schanda Paul
Published: June 2021

Large oligomeric enzymes control a myriad of cellular processes, from protein synthesis and degradation to metabolism. The 0.5 MDa large TET2 aminopeptidase, a prototypical protease important for cellular homeostasis, degrades peptides within a ca. 60 Å wide tetrahedral chamber with four lateral openings. The mechanisms of substrate trafficking and processing remain debated. Here, we integrate magic-angle spinning (MAS) NMR, mutagenesis, co-evolution analysis and molecular dynamics simulations and reveal that a loop in the catalytic chamber is a key element for enzymatic function. The loop is able to stabilize ligands in the active site and may additionally have a direct role in activating the catalytic water molecule whereby a conserved histidine plays a key role. Our data provide a strong case for the functional importance of highly dynamic - and often overlooked - parts of an enzyme, and the potential of MAS NMR to investigate their dynamics at atomic resolution.
Genetic diversity and evolution of SARS-CoV-2 in Belgium during the first wave outbreak
Authors: Wawina-Bokalanga Tony , Martí-Carreras Joan , Vanmechelen Bert , Bloemen Mandy , Wollants Elke , Laenen Lies , Cuypers Lize , Beuselinck Kurt , Lagrou Katrien , André Emmanuel , Van Ranst Marc , Maes Piet
Published: June 2021

SARS-CoV-2, the causative agent of COVID-19 was first detected in Belgium on 3rd February 2020, albeit the first epidemiological wave started in March and ended in June 2020. One year after the first epidemiological wave hit the country data analyses reveled the temporal and variant distribution of SARS-CoV-2 and its implication with Belgian epidemiological measures. In this study, 766 complete SARS-CoV-2 genomes of samples originating from the first epidemiological were sequenced to characterize the temporal and geographic distribution of the COVID-19 pandemic in Belgium through phylogenetic and variant analysis. Our analysis reveals the presence of the major circulating SARS-CoV-2 clades (G, GH and GR) and lineages circulating in Belgium at that time. Moreover, it contextualizes the density of SARS-CoV-2 cases over time with non-intervention measures taken to prevent the spread of SARS-CoV-2 in Belgium, specific international case imports and the functional implications of the most representative non-synonymous mutations present in Belgium between February to June 2020.