bluuebunny/crossref_metadata_2025 huggingface dataset:
Sweetpotato Root Development Influences Susceptibility to Black Rot Caused by the Fungal Pathogen Ceratocystis fimbriata
Authors: Parada-Rojas C. H. , Pecota Kenneth , Almeyda C. , Yencho G. Craig , Quesada-Ocampo L. M.
Published: February 2021

Black rot of sweetpotato, caused by Ceratocystis fimbriata, is an important reemerging disease threatening sweetpotato production in the United States. This study assessed disease susceptibility of the storage root surface, storage root cambium, and slips (vine cuttings) of 48 sweetpotato cultivars, advanced breeding lines, and wild relative accessions. We also characterized the effect of storage root development on susceptibility to C. fimbriata. None of the cultivars examined at the storage root level were resistant, with most cultivars exhibiting similar levels of susceptibility. In storage roots, Jewel and Covington were the least susceptible and significantly different from White Bonita, the most susceptible cultivar. In the slip, significant differences in disease incidence were observed for above- and below-ground plant structures among cultivars, advanced breeding lines, and wild relative accessions. Burgundy and Ipomoea littoralis displayed less below-ground disease incidence compared with NASPOT 8, Sunnyside, and LSU-417, the most susceptible cultivars. Correlation of black rot susceptibility between storage roots and slips was not significant, suggesting that slip assays are not useful to predict resistance in storage roots. Immature, early-developing storage roots were comparatively more susceptible than older, fully developed storage roots. The high significant correlation between the storage root cross-section area and the cross-sectional lesion ratio suggests the presence of an unfavorable environment for C. fimbriata as the storage root develops. Incorporating applications of effective fungicides at transplanting and during early-storage root development when sweetpotato tissues are most susceptible to black rot infection may improve disease management efforts.
Cerebellum size is related to fear memory and domestication of chickens
Authors: Katajamaa Rebecca , Wright Dominic , Henriksen Rie , Jensen Per
Published: February 2021

Red Junglefowl (
Gallus gallus
) were selected for divergent levels of fear of humans during eight generations, causing the selection lines to differ in fear levels as well as in the proportional brain and cerebellum masses. Birds from the two lines were then crossed to obtain an F3 intercross in order to study the correlations between brain mass and fear learning. We exposed 105 F3-animals individually to a fear habituation and memory test at 8 days of age, where the reactions to repeated light flashes were assessed on 2 consecutive days. After culling, the absolute and relative sizes of each of four brain regions were measured. Stepwise regression was used to analyse the effects of the size of each brain region on habituation and memory. There were no effects of any brain region on the habituation on day one. However, birds with a larger absolute size of cerebellum had significantly reduced reactions to the fearful stimuli on day two, indicating a better memory of the stimuli. No other regions had significant effects. We conclude that increased cerebellum size may have been important in facilitating chicken domestication, allowing them to adapt to a life with humans.
Leon Mestel. 5 August 1927—15 September 2017
Authors: Smith Robert Connon , Weiss Nigel
Published: February 2021

Leon Mestel was best known for his wide-ranging work on cosmic magnetism, but he also worked on an equally wide range of non-magnetic problems in astrophysics, from star and galaxy formation to white dwarf cooling. Despite his work being primarily theoretical and highly mathematical, he was always aware of all the relevant observational data that both needed to be explained and also provided constraints for his theoretical models. He was internationally recognized as an authority on the influence of magnetic fields in astronomy, receiving a number of significant honours. He also had a deserved reputation for scrupulous honesty and integrity in his work. His life's work culminated in the publication of two editions of a magisterial monograph on stellar magnetism. He collaborated widely, influenced many other researchers and was in great demand as a conference speaker. He was also a conscientious academic, taking his full part in departmental teaching and administration, and a delightful companion and friend to all who knew him. He was well known for his many stories and jokes, which were widely enjoyed. His outside interests included being a long-standing member of the Editorial Board of this publication,
Biographical Memoirs of Fellows of the Royal Society
.
Integrating blood cell mechanics, platelet adhesive dynamics and coagulation cascade for modelling thrombus formation in normal and diabetic blood
Authors: Yazdani Alireza , Deng Yixiang , Li He , Javadi Elahe , Li Zhen , Jamali Safa , Lin Chensen , Humphrey Jay D. , Mantzoros Christos S. , Em Karniadakis George
Published: February 2021

Normal haemostasis is an important physiological mechanism that prevents excessive bleeding during trauma, whereas the pathological thrombosis especially in diabetics leads to increased incidence of heart attacks and strokes as well as peripheral vascular events. In this work, we propose a new multiscale framework that integrates seamlessly four key components of blood clotting, namely transport of coagulation factors, coagulation kinetics, blood cell mechanics and platelet adhesive dynamics, to model the development of thrombi under physiological and pathological conditions. We implement this framework to simulate platelet adhesion due to the exposure of tissue factor in a three-dimensional microchannel. Our results show that our model can simulate thrombin-mediated platelet activation in the flowing blood, resulting in platelet adhesion to the injury site of the channel wall. Furthermore, we simulate platelet adhesion in diabetic blood, and our results show that both the pathological alterations in the biomechanics of blood cells and changes in the amount of coagulation factors contribute to the excessive platelet adhesion and aggregation in diabetic blood. Taken together, this new framework can be used to probe synergistic mechanisms of thrombus formation under physiological and pathological conditions, and open new directions in modelling complex biological problems that involve several multiscale processes.
Experimental evaluation of the viscoelasticity of porcine vitreous
Authors: Aboulatta Ali , Abass Ahmed , Makarem Ahmed , Eliasy Ashkan , Zhou Dong , Chen Duo , Liu Xiaoyu , Elsheikh Ahmed
Published: February 2021

This study aims to estimate the material properties of the porcine vitreous while
testing it in close to its natural physiological conditions. Eighteen porcine
eyes were tested within 48 h post-mortem. A custom-built computer-controlled
test rig was designed to support, load and monitor the behaviour of eye globes
while being subjected to dynamic rotation cycles mimicking saccade eye movement.
Specimens were glued to the base of a container, surrounded by gelatin, frozen
and cut in half to expose the vitreous. After thawing, the container was
subjected to concentric dynamic rotations of up to 5°, 10° or
15°, while taking 50 MP photos of the specimen every 2 ms. The images
were analysed by a digital image correlation algorithm to trace the movement of
marked points on the vitreous surface with different radii from the centre of
the posterior chamber. The initial camera image was used in building a
finite-element model of the test set-up, which was used in an inverse analysis
exercise to estimate the material properties of the vitreous. Angular
displacements of the monitored points were up to 3.3°, 4.1° and
3.9° in response to eye rotations of 5°, 10° and
15°, respectively. With the experimental relationships between eye
rotation and angular displacements used as target behaviour, the inverse
analysis exercise estimated the initial shear modulus, the long-term shear
modulus and the viscoelastic decay constant of the porcine vitreous as 2.10
± 0.15 Pa, 0.50 ± 0.04 Pa and 1.20 ± 0.09
s
−1
, respectively. Consideration of the viscoelasticity of
the vitreous was essential to represent its experimental behaviour. Testing the
vitreous in close to its normal physiological conditions produced estimations of
the initial shear modulus and long-term shear modulus that were, respectively,
smaller and larger than reported values (Zimberlin
et al
. 2010
Soft Matter
6, 3632–3635. (
doi:10.1039/b925407b
), Liu
et al
. 2013
J. Biomech.
46, 1321–7. (
doi:10.1016/j.jbiomech.2013.02.006)
, Rossi
et
al
. 2011
Invest. Ophthalmol. Vis. Sci.
52,
3994–4002. (
doi:10.1167/iovs.10-6477
)).
Meso-scale dislocations and friction of shape-complementary soft interfaces
Authors: He Zhenping , Liu Zezhou , Li Meng , Hui Chung-Yuen , Jagota Anand
Published: February 2021

The interface between two surfaces patterned with complementary shapes such as arrays of ridge–channel structures or pillars accommodates relative misorientation and lattice mismatch by spontaneous production of dislocation arrays. Here, we show that the relative sliding of such an interface is accomplished by dislocation glide on the interfacial plane. An exception is the singular case where the lattices are perfectly matched across the sample dimension, in which case sliding is accompanied by motion of edge-nucleated defects. These are meso-scale analogues of molecular sliding friction mechanisms between crystalline interfaces. The dislocations, in addition to the long-range elastic energy associated with their Burgers vectors, also cause significant out-of-plane dilation, which props open the interface locally. For this reason, the sliding friction is strongly pressure dependent; it also depends on the relative orientation of the patterns. Sliding friction can be strongly enhanced compared with a control, showing that shape-complementary interfaces can be engineered for strongly enhanced pressure- and orientation-dependent frictional properties in soft solids.
The plastic cell: mechanical deformation of cells and tissues
Authors: Molnar Kelly , Labouesse Michel
Published: February 2021

Epithelial cells possess the ability to change their shape in response to mechanical stress by remodelling their junctions and their cytoskeleton. This property lies at the heart of tissue morphogenesis in embryos. A key feature of embryonic cell shape changes is that they result from repeated mechanical inputs that make them partially irreversible at each step. Past work on cell rheology has rarely addressed how changes can become irreversible in a complex tissue. Here, we review new and exciting findings dissecting some of the physical principles and molecular mechanisms accounting for irreversible cell shape changes. We discuss concepts of mechanical ratchets and tension thresholds required to induce permanent cell deformations akin to mechanical plasticity. Work in different systems has highlighted the importance of actin remodelling and of E-cadherin endocytosis. We also list some novel experimental approaches to fine-tune mechanical tension, using optogenetics, magnetic beads or stretching of suspended epithelial tissues. Finally, we discuss some mathematical models that have been used to describe the quantitative aspects of accounting for mechanical cell plasticity and offer perspectives on this rapidly evolving field.
Consensus of travel direction is achieved by simple copying, not voting, in free-ranging goats
Authors: Sankey D. W. E. , O'Bryan L. R. , Garnier S. , Cowlishaw G. , Hopkins P. , Holton M. , Fürtbauer I. , King A. J.
Published: February 2021

For group-living animals to remain cohesive they must agree on where to travel. Theoretical models predict shared group decisions should be favoured, and a number of empirical examples support this. However, the behavioural mechanisms that underpin shared decision-making are not fully understood. Groups may achieve consensus of direction by active communication of individual preferences (i.e. voting), or by responding to each other's orientation and movement (i.e. copying). For example, African buffalo (
Syncerus caffer
) are reported to use body orientation to vote and indicate their preferred direction to achieve a consensus on travel direction, while golden shiners (
Notemigonus crysoleucas
) achieve consensus of direction by responding to the movement cues of their neighbours. Here, we present a conceptual model (supported by agent-based simulations) that allows us to distinguish patterns of motion that represent voting or copying. We test our model predictions using high-resolution GPS and magnetometer data collected from a herd of free-ranging goats (
Capra aegagrus hircus
) in the Namib Desert, Namibia. We find that decisions concerning travel direction were more consistent with individuals copying one another's motion and find no evidence to support the use of voting with body orientation. Our findings highlight the role of simple behavioural rules for collective decision-making by animal groups.
Juvenile hormone III skipped bisepoxide is widespread in true bugs (Hemiptera: Heteroptera)
Authors: Matsumoto Keiji , Kotaki Toyomi , Numata Hideharu , Shinada Tetsuro , Goto Shin G.
Published: February 2021

Juvenile hormone (JH) plays important roles in almost every aspect of insect development and reproduction. JHs are a group of acyclic sesquiterpenoids, and their farnesol backbone has been chemically modified to generate a homologous series of hormones in some insect lineages. JH III (methyl farnesoate, 10,11-epoxide) is the most common JH in insects, but Lepidoptera (butterflies and moths) and ‘higher’ Diptera (suborder: Brachycera; flies) have developed their own unique JHs. Although JH was first proposed in the hemipteran suborder Heteroptera (true bugs), the chemical identity of the heteropteran JH was only recently determined. Furthermore, recent studies revealed the presence of a novel JH, JH III skipped bisepoxide (JHSB3), in some heteropterans, but its taxonomic distribution remains largely unknown. In the present study, we investigated JHSB3production in 31 heteropteran species, covering almost all heteropteran lineages, through ultra-performance liquid chromatography coupled with tandem mass spectrometry. We found that all of the focal species produced JHSB3, indicating that JHSB3is widespread in heteropteran bugs and the evolutionary occurrence of JHSB3ascends to the common ancestor of Heteroptera.
High proportion of genome-wide homology and increased basal pvcrt levels in Plasmodium vivax late recurrences: a chloroquine therapeutic efficacy study
Authors: Rovira-Vallbona Eduard , Van Hong Nguyen , Kattenberg Johanna H. , Huan Ro Mah , Binh Nguyen Thi Huong , Ngọc Nguyen Thi Hong , Guetens Pieter , Hieu Nguyen Luong , Thị Thu Hien Nguyen , Sang Vu Thi , Long Nguyen Duc , Sauve Erin , Duong Tran Thanh , Xa Nguyen Xuan , Erhart Annette , Rosanas-Urgell Anna
Published: February 2021

Chloroquine (CQ) is the first-line treatment for Plasmodium vivax malaria in most endemic countries. Monitoring P.vivax CQ resistance (CQR) is critical but remains challenged by the difficulty to distinguish real treatment failure from reinfection or liver relapse. Therapeutic efficacy of CQ against uncomplicated P.vivax malaria was evaluated in Gia Lai province, Vietnam. Sixty-seven patients were enrolled and followed-up for 42 days using microscopy and (RT)qPCR. Adequate clinical and parasitological response (ACPR) was 100% (66/66) on Day 28, but 75.4% (49/65) on Day 42. Eighteen recurrences (27.7%) were detected with a median time-to-recurrence of 42 days (IQR 35, 42) and blood CQ concentration <100ng/ml. Parasite genotyping by microsatellites, SNP-barcoding and whole-genome sequencing (WGS) identified a majority of homologous recurrences, with 80% (8/10) showing >98% identity-by-descent to paired Day 0 samples. Primary infections leading to recurrence occurred in younger individuals (median age for ACPR=25 years [IQR 20, 28]; recurrences=18 [16, 21]; p=0.002), had a longer parasite clearance time (PCT for ACPR=47.5h [IQR 36.2, 59.8]; recurrences=54.2h [48.4, 62.0]; p=0.035) and higher pvcrt gene expression (median relative expression ratio for ACPR=0.09 [IQR 0.05, 0.22]; recurrences=0.20 [0.15, 0.56]; p=0.002), but there was no difference in ex vivo CQ sensitivity. This study shows that CQ remained largely efficacious to treat P.vivax in Gia Lai, i.e. recurrences occurred late (>Day 28) and in the presence of low blood CQ concentrations. However, the combination of WGS and gene expression analysis (pvcrt) with clinical data (PCT) allowed to identify potential emergence of low-grade CQR that should be closely monitored.
A Molecular network approach reveals shared cellular and molecular signatures between chronic fatigue syndrome and other fatiguing illnesses
Authors: Comella Phillip H. , Gonzalez-Kozlova Edgar , Kosoy Roman , Charney Alexander W. , Peradejordi Irene Font , Chandrasekar Shreya , Tyler Scott R. , Wang Wenhui , Losic Bojan , Zhu Jun , Hoffman Gabriel E. , Kim-Schulze Seunghee , Qi Jingjing , Patel Manishkumar , Kasarskis Andrew , Suarez-Farinas Mayte , Gümüş Zeynep H. , Argmann Carmen , Merad Miriam , Becker Christian , Beckmann Noam D. , Schadt Eric E.
Published: February 2021

Intro

The molecular mechanisms of chronic fatigue syndrome (CFS, or Myalgic encephalomyelitis), a disease defined by extreme, long-term fatigue, remain largely uncharacterized, and presently no molecular diagnostic test and no specific treatments exist to diagnose and treat CFS patients. While CFS has historically had an estimated prevalence of 0.1-0.5% [1], concerns of a “long hauler” version of Coronavirus disease 2019 (COVID-19) that symptomatically overlaps CFS to a significant degree(Supplemental Table-1)and appears to occur in 10% of COVID-19 patients[2], has raised concerns of a larger spike in CFS [3]. Here, we established molecular signatures of CFS and a corresponding network-based disease context from RNA-sequencing data generated on whole blood and FACs sorted specific peripheral blood mononuclear cells (PBMCs) isolated from CFS cases and non-CFS controls. The immune cell type specific molecular signatures of CFS we identified, overlapped molecular signatures from other fatiguing illnesses, demonstrating a common molecular etiology. Further, after constructing a probabilistic causal model of the CFS gene expression data, we identified master regulator genes modulating network states associated with CFS, suggesting potential therapeutic targets for CFS.
COVID-19 risk perceptions of social interaction and essential activities and inequity in the United States: Results from a nationally representative survey
Authors: Erchick Daniel J. , Zapf Alexander J. , Baral Prativa , Edwards Jeffrey , Mehta Shruti H. , Solomon Sunil S. , Gibson Dustin G. , Agarwal Smisha , Labrique Alain B.
Published: February 2021

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) related diagnoses, hospitalizations, and deaths have disproportionately affected disadvantaged communities across the United States. Few studies have sought to understand how risk perceptions related to social interaction and essential activities during the COVID-19 pandemic vary by sociodemographic factors, information that could inform targeted interventions to reduce inequities in access to care and information.

Methods

We conducted a nationally representative online survey of 1,592 adults in the United States to understand risk perceptions related to transmission of COVID-19 for various social and essential activities. We assessed relationships for each activity, after weighting to adjust for the survey design, using bivariate comparisons and multivariable logistic regression modeling, between responses of safe and unsafe, and participant characteristics, including age, gender, race, education, income, and political affiliation.

Results

Half of participants were younger than 45 years (n=844, 53.0%), female (n=800, 50.3%), and White/Caucasian (n=685, 43.0%), Black/African American (n=410, 25.8%), or Hispanic/Latino (n=382, 24.0%). Risk perceptions of unsafe for 13 activities ranged from 29.2% to 73.5%. Large gatherings, indoor dining, and visits with elderly relatives had the highest proportion of unsafe responses (>58%) while activities outdoor, visiting the doctor or dentist, and going to the grocery store had the lowest (<36%). Older respondents were more likely to view social gatherings and indoor activities as unsafe, yet more likely to view activities such as going to the grocery store, participating in outdoor activities, visiting elderly relatives, and visiting the doctor or emergency room as safe. Compared to White/Caucasian respondents, Black/African American and Hispanic/Latino respondents were more likely to view activities such as dining and visiting friends outdoor as unsafe. Generally, men vs. women, Republicans vs. Democrats and independents, and individuals with higher vs. lower income were more likely to view activities as safe.

Conclusions

These findings suggest the importance of sociodemographic differences in risk perception, health behaviors, and access to information and health care when implementing efforts to control the COVID-19 pandemic. Further research should address how evidence-based interventions can be tailored considering these differences with a goal of increased health equity in the pandemic response.
Genetic determination of regional connectivity in modelling the spread of COVID-19 outbreak for improved mitigation strategies
Authors: Salichos Leonidas , Warrell Jonathan , Cevasco Hannah , Chung Alvin , Gerstein Mark
Published: February 2021

Covid-19 has resulted in the death of more than 1,500,000 individuals. Due to the pandemic’s severity, thousands of genomes have been sequenced and publicly stored with extensive records, an unprecedented amount of data for an outbreak in a single year. Simultaneously, prediction models offered region-specific and often contradicting results, while states or countries implemented mitigation strategies with little information on success, precision, or agreement with neighboring regions. Even though viral transmissions have been already documented in a historical and geographical context, few studies aimed to model geographic and temporal flow from viral sequence information. Here, using a case study of 7 states, we model the flow of the Covid-19 outbreak with respect to phylogenetic information, viral migration, inter- and intra- regional connectivity, epidemiologic and demographic characteristics. By assessing regional connectivity from genomic variants, we can significantly improve predictions in modeling the viral spread and intensity.

Contrary to previous results, our study shows that the vast majority of the first outbreak can be traced to very few lineages, despite the existence of multiple worldwide transmissions. Moreover, our results show that while the distance from hotspots is initially important, connectivity becomes increasingly significant as the virus establishes itself. Similarly, isolated local strategies-such as relying on herd immunity-can negatively impact neighboring states. Our work suggests that we can achieve more efficient unified mitigation strategies with selective interventions.
A specific agonist of the orphan nuclear receptor NR2F1 suppresses metastasis through the induction of cancer cell dormancy
Authors: Khalil Bassem D. , Sanchez Roberto , Rahman Tasrina , Rodriguez-Tirado Carolina , Moritsch Stefan , Martinez Alba Rodriguez , Miles Brett , Farias Eduardo , Mezei Mihaly , Cheung Julie F. , Nobre Ana Rita , Kale Nupura , Sproll Karl Christoph , Sosa Maria Soledad , Aguirre-Ghiso Julio A.
Published: February 2021

Abstract

Disseminated tumor cells (DTCs) in secondary organs often remain dormant for a long period of time before re-awakening and growing into overt metastases. We have previously identified NR2F1/COUP-TF1, an orphan nuclear receptor, as a master regulator of tumor cell dormancy in head and neck squamous cell carcinoma (HNSCC) and other cancer types. Here we describe the identification and function of a novel NR2F1 agonist herein referred to as compound 26 (C26). C26 was found to specifically activate NR2F1 in HNSCC cells, leading to increased NR2F1 transcription and nuclear protein accumulation. C26-mediated activation of NR2F1 induced growth arrest of HNSCC PDX line and cell lines in 3D culturesin vitroand on chicken embryo chorioallantoic membrane (CAM)in vivo. The effect of C26 on growth arrest was lost when NR2F1 was knocked out by CRISPR/Cas9. C26-induced growth arrest was mediated by activation of an NR2F1-regulated dormancy program, including upregulation of cyclin-dependent kinase (CDK) inhibitor p27 and the transcription factors retinoic acid receptor β (RARβ) and Sox9. In mice bearing HNSCC PDX tumors, combined adjuvant and neo-adjuvant treatment with C26 resulted in complete inhibition of lethal lung metastasis. Mechanistic analysis showed that lung DTCs in C26-treated mice displayed an NR2F1hi/p27hi/Ki-67lophenotype, which kept them dormant in a single-cell state preventing their outgrowth into overt metastases. Our work reveals a novel NR2F1 agonist and provides a proof of principle strategy supporting that inducing DTC dormancy using NR2F1 agonists could be used as a therapeutic strategy to prevent metastasis.
Non-invasively measured brain activity and radiological progression in diffuse glioma
Authors: Numan T. , Kulik S.D. , Moraal B. , Reijneveld J.C. , Stam CJ. , de Witt Hamer P.C. , Derks J. , Bruynzeel A.M.E. , van Linde M.E. , Wesseling P. , Kouwenhoven M.C.M. , Klein M. , Würdinger T. , Barkhof F. , Geurts J.J.G. , Hillebrand A. , Douw L.
Published: February 2021

Non-invasively measured brain activity is related to progression-free survival in glioma patients, suggesting its potential as a marker of glioma progression. We therefore assessed the relationship between brain activity and increasing tumor volumes on routine clinical magnetic resonance imaging (MRI) in glioma patients. Postoperative magnetoencephalography (MEG) was recorded in 45 diffuse glioma patients. Brain activity was estimated using three measures (absolute broadband power, offset and slope) calculated at three spatial levels: global average, averaged across the peritumoral areas, and averaged across the homologues of these peritumoral areas in the contralateral hemisphere. Tumors were segmented on MRI. Changes in tumor volume between the two scans surrounding the MEG were calculated and correlated with brain activity. Brain activity was compared between patient groups classified into having increasing or stable tumor volume. Results show that brain activity was significantly increased in the tumor hemisphere in general, and in peritumoral regions specifically. However, none of the measures and spatial levels of brain activity correlated with changes in tumor volume, nor did they differ between patients with increasing versus stable tumor volumes. Longitudinal studies in more homogeneous subgroups of glioma patients are necessary to further explore the clinical potential of non-invasively measured brain activity.
Extracellular matrix stiffness regulates degradation of the Hippo kinase MST2 via SCFβTrCP
Authors: Fiore Ana Paula Zen Petisco , da Silva Ana Maria Rodrigues , Filho Helder Veras Ribeiro , Manucci Antonio Carlos , de Freitas Ribeiro Pedro , Botelho Mayara Carolinne Silva , de Oliveira Paulo Sergio Lopes , Pagano Michele , Bruni-Cardoso Alexandre
Published: February 2021

Tumor microenvironments display disrupted mechanical properties, including altered extracellular matrix (ECM) rigidity. ECM stiffening perturbs cell tensional homeostasis resulting in activation of mechanosensing transcriptional co-activators, such as the Hippo pathway effectors YAP and TAZ. The Hippo pathway plays central roles in development and tumorigenesis, but how the proteostasis of the Hippo kinase MST2 is regulated remains unknown. Here, we show that ECM stiffness induces MST2 degradation via proteasome degradation. MST2 degradation is enhanced in human breast epithelial cells (HMEC) that are cultured in stiffer microenvironments due to integrin and integrin-linked kinase activation. MST2 knockdown resulted in increased nucleus-to-cytoplasm ratio of YAP in physiological and breast tumor rigidities and altered mechanoregulated cellular processes in HMEC. We found that MST2 is ubiquitinated by the SCFβTrCPubiquitin ligase. Site-directed mutagenesis combined with computational molecular dynamics studies revealed that βTrCP binds MST2 via a noncanonical degradation motif. Our study uncovers the underlying biochemical mechanisms controlling MST2 degradation and demonstrates how changes in the microenvironment rigidity regulate the proteostasis of a central Hippo pathway component.
Neonatal-onset autoinflammation and immunodeficiency caused by heterozygous missense mutation of the proteasome subunit β-type 9
Authors: Kanazawa Nobuo , Hemmi Hiroaki , Kinjo Noriko , Ohnishi Hidenori , Hamazaki Jun , Mishima Hiroyuki , Kinoshita Akira , Mizushima Tsunehiro , Hamada Satoru , Hamada Kazuya , Kawamoto Norio , Kadowaki Saori , Honda Yoshitaka , Izawa Kazushi , Nishikomori Ryuta , Tsumura Miyuki , Yamashita Yusuke , Tamura Shinobu , Orimo Takashi , Ozasa Toshiya , Kato Takashi , Sasaki Izumi , Fukuda-Ohta Yuri , Wakaki-Nishiyama Naoko , Inaba Yutaka , Kunimoto Kayo , Okada Satoshi , Taketani Takeshi , Nakanishi Koichi , Murata Shigeo , Yoshiura Koh-ichiro , Kaisho Tsuneyasu
Published: February 2021

BACKGROUND

Defective proteasome activities due to genetic mutations lead to an autoinflammatory disease, termed as proteasome-associated autoinflammatory syndromes (PRAAS). In PRAAS relapsing inflammations and progressive wasting are common, but immunodeficiency has not been reported.

METHODS

We studied two unrelated Japanese infants with PRAAS-like manifestations. We have also generated and analyzed the mice carrying the candidate mutation found in the patients.

RESULTS

Both patients showed neonatal-onset skin rash, myositis and basal ganglia calcification, similar to PRAAS patients. Meanwhile, they manifested distinct phenotypes, including pulmonary hypertension and immunodeficiency without lipoatrophy. We identified a novel de novo heterozygous missense mutation, G156D, in a proteasome subunit gene, PSMB9, encoding β1i, in the two patients. Maturation and activity of the immunoproteasome were impaired, but ubiquitin accumulation was hardly detected not only in patient-derived cells and samples but also in Psmb9G156D/+ mice. As an immunodeficient phenotype, one patient showed decrease of B cells and increase of monocytes, while the other patient showed decrease of CD8 T cells. The proteasome defects and immunodeficient phenotypes were recapitulated in Psmb9G156D/+ mice.

CONCLUSIONS

The PSMB9 G156D is a unique mutation in proteasome subunits in causing defects by its heterozygosity, affecting two β rings interaction and leading to immunodeficiency. The mutant mice are the first mice model for analyzing proteasome dysfunctions in PRAAS. We here propose the term, proteasome-associated autoinflammation and immunodeficiency disease (PRAID), as an umbrella name for our cases, PRAAS with immunodeficiency, as well as PRAAS described so far.
Comparing effect estimates in randomized trials and observational studies from the same population: an application to percutaneous coronary intervention
Authors: Matthews Anthony A , Szummer Karolina , Dahabreh Issa J , Lindahl Bertil , Erlinge David , Feychting Maria , Jernberg Tomas , Berglund Anita , Hernán Miguel A
Published: February 2021

Background

The ability for real world data to deliver similar results as a trial that asks the same question about the risks or benefits of a clinical intervention can be restricted not only by lack of randomization, but also limited information on eligibility criteria and outcomes. To understand when results from observational studies and randomized trials are comparable, we carried out an observational emulation of a target trial designed to ask similar questions as the VALIDATE randomized trial. VALIDATE compared the effect of bivalirudin and heparin during percutaneous coronary intervention on the risk of death, myocardial infarction, and bleeding across Sweden.

Methods

We specified the protocol of a target trial similar to the VALIDATE trial protocol, then emulated the target trial in the period before the trial took place using data from the SWEDEHEART registry; the same registry in which the trial was undertaken.

Results

The target trial emulation and the VALIDATE trial both estimated no difference in the effect of bivalirudin and heparin on the risk of death or myocardial infarction by 180 days: emulation risk ratio for death 1.21 (0.88, 1.54); VALIDATE hazard ratio for death 1.05 (0.78, 1.41). The observational data, however, could not capture less severe cases of bleeding, resulting in an inability to define a bleeding outcome like the trial, and could not account for intractable confounding early in follow-up (risk ratio for death by 14 days 1.85 (0.95, 3.63)).

Conclusion

Using real world data to emulate a target trial can deliver accurate long-term effect estimates. Yet, even with rich observational data, it is not always possible to estimate the short-term effect of interventions, or the effect on outcomes for which data are not routinely collected. If registries included information on reasons for treatment decisions, researchers may be better positioned to identify important confounders.
A Rapid Realist Review of the Role of Community Pharmacy in the Public Health Response to COVID-19
Authors: Maidment Ian , Young Emma , MacPhee Maura , Booth Andrew , Zaman Hadar , Breen Juanita , Hilton Andrea , Kelly Tony , Wong Geoff
Published: February 2021

Introduction

Community pharmacists and their teams have remained accessible to the public providing essential services despite immense pressures during the COVID-19 pandemic. They have successfully expanded the influenza vaccination programme and are now supporting the delivery of the COVID-19 vaccination roll-out.

Aim

This rapid realist review aims to understand how community pharmacy can most effectively deliver essential and advanced services, with a focus on vaccination, during the pandemic and in the future.

Method

An embryonic programme theory was generated using four diverse and complementary documents along with the expertise of the project team. Academic databases, preprint services and grey literature were searched and screened for documents meeting our inclusion criteria. The data was extracted from 103 documents to develop and refine a programme theory using a realist logic of analysis. Our analysis generated 13 context-mechanism-outcome configurations explaining when, why and how community pharmacy can support public health vaccination campaigns, maintain essential services during pandemics, and capitalise on opportunities for expanded, sustainable public health service roles. The views of stakeholders including pharmacy users, pharmacists, pharmacy teams and other healthcare professionals were sought throughout to refine the 13 explanatory configurations.

Results

The 13 context-mechanism-outcome configurations are organised according to decision makers, community pharmacy teams and community pharmacy users as key actors. Review findings include: supporting a clear role for community pharmacies in public health; clarifying pharmacists’ legal and professional liabilities; involving pharmacy teams in service specification design; providing suitable guidance, adequate compensation and resources; and leveraging accessible, convenient locations of community pharmacy.

Discussion

Community pharmacy has been able to offer key services during the pandemic. Decision makers must endorse, articulate and support a clear public health role for community pharmacy. We provide key recommendations for decision makers to optimise such a role during these unprecedented times and in the future.
IN-HOSPITAL CONTINUATION WITH ANGIOTENSIN RECEPTOR BLOCKERS IS ASSOCIATED WITH A LOWER MORTALITY RATE THAN CONTINUATION WITH ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN COVID-19 PATIENTS: A RETROSPECTIVE COHORT STUDY
Authors: de Abajo Francisco J. , Rodríguez-Miguel Antonio , Rodríguez-Martín Sara , Lerma Victoria , García-Lledó Alberto
Published: February 2021

Background

Several studies have reported a reduced risk of death associated with the inpatient use of angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) in COVID-19 patients, but have been criticized for incurring in several types of bias. Also, most studies have pooled ACEIs and ARBs as if they were a unique group, overlooking their pharmacological differences. We aimed to assess whether the in-hospital continuation of ARBs and ACEIs, in regular users of these drugs, was associated with a reduced risk of death as compared to their discontinuation and also to compare head-to-head ARBs with ACEIs.

Methods

Adult patients with a PCR-confirmed diagnosis of COVID-19 requiring admission during March, 2020 were consecutively selected from 7 hospitals in Madrid, Spain. Among them, we identified outpatient users of ACEIs/ARBs and divided them in two cohorts depending on treatment discontinuation/continuation at admission. Then, they were followed-up until discharge or in-hospital death. An intention-to-treat survival analysis was carried out and hazard ratios (HRs) and their 95%CI were computed through a Cox regression model adjusted for propensity scores of discontinuation and controlled by potential mediators.

Results

Out of 625 ACEI/ARB users, 340(54.4%) discontinued treatment. The in-hospital mortality rates were 27.6% and 27.7% in discontinuation and continuation cohorts, respectively (HR=1.01; 95%CI:0.70-1.46). No difference in mortality was observed between ARB and ACEI discontinuation (28.6% vs. 27.1%, respectively), while a significantly lower mortality rate was found among patients who continued with ARBs (20.8%,N=125) as compared to those who continued with ACEIs (33.1%,N=136; p=0.03). The head-to-head comparison (ARB vs. ACEI continuation) yielded an adjusted HR of 0.52 (95%CI:0.29-0.93), being especially notorious among males (HR=0.34; 95%CI:0.12-0.93), subjects older than 74 years (HR=0.46; 95%CI:0.25-0.85), and patients with obesity (HR=0.22; 95%CI:0.05-0.94), diabetes (HR=0.36; 95%CI:0.13-0.97) and heart failure (HR=0.12; 95%CI:0.03-0.97).

Conclusions

Among regular users of ARBs admitted for COVID-19, the in-hospital continuation with them was associated with an improved survival, while this was not observed with ACEIs. Regular users of ARBs should continue with this treatment if admitted for COVID-19, unless medically contraindicated. In admitted ACEI users, a switching to ARBs should be considered, especially among high-risk patients.

GRAPHICAL ABSTRACT
Metabolic subgroups and cardiometabolic multimorbidity in the UK Biobank
Authors: Mulugeta Anwar , Hypponen Elina , Ala-Korpela Mika , Makinen Ville-Petteri
Published: February 2021

Background: Ischemic heart disease (IHD), diabetes, cancer and dementia share features of age-associated metabolic dysfunction. We hypothesized that metabolic diversity explains the diversity of morbidity later in life.
Methods: We analyzed data from the UK Biobank (N = 329,908). A self-organizing map (SOM, an artificial neural network) was trained with 51 metabolic traits adjusted for age and sex. The SOM analyses produced six subgroups that summarized the multi-variable metabolic diversity. The subgroup with the lowest adiposity and disease burden was chosen as the reference. Hazard ratios (HR) were modeled by Cox regression (P < 0.0001 unless otherwise indicated). Enrichment of multi-morbidity over random expectation was tested by permutation analysis.
Results: The subgroup with the highest sex hormones was not associated with IHD (HR = 1.04, P = 0.14). The subgroup with high urinary excretion without kidney stress (HR = 1.24) and the subgroup with the highest apolipoprotein B and blood pressure (HR = 1.52) were associated with IHD. The subgroup with high adiposity, inflammation and kidney stress was associated with IHD (HR = 2.11), cancer (HR= 1.29), dementia (HR = 1.70) and mortality (HR = 2.12). The subgroup with high triglycerides and liver enzymes was at risk of diabetes (HR = 15.6). Paradoxical enrichment of multimorbidity in young individuals and in favorable subgroups was observed.
Conclusions: These results support metabolic diversity as an explanation to diverging morbidity and demonstrate the potential value of population-based metabolic subgroups as public health targets for reducing aggregate burden of chronic diseases in ageing populations.
RAY: CRISPR diagnostic for rapid and accurate detection of SARS-CoV2 variants on a paper strip
Authors: Kumar Manoj , Gulati Sneha , Ansari Asgar Hussain , Phutela Rhythm , Acharya Sundaram , Kathpalia Poorti , Kanakan Akshay , Maurya Ranjeet , Vasudevan Janani Srinivasa , Murali Aparna , Pandey Rajesh , Maiti Souvik , Chakraborty Debojyoti
Published: February 2021

The COVID-19 pandemic originating in the Wuhan province of China in late 2019 has impacted global health, causing increased mortality among elderly patients and individuals with comorbid conditions. During the passage of the virus through affected populations, it has undergone mutations- some of which have recently been linked with increased viral load and prognostic complexities. Interestingly, several of these variants are point mutations that are difficult to diagnose using the gold standard quantitative real-time PCR (qPCR) method. This necessitates widespread sequencing which is expensive, has long turn-around times, and requires high viral load for calling mutations accurately. In this study, we show that the high specificity of Francisella novicida Cas9 (FnCas9) to point mismatches can be successfully adapted for the simultaneous detection of SARS-CoV2 infection as well as for detecting point mutations in the sequence of the virus obtained from patient samples. We report the detection of the mutation N501Y (earlier shown to be present in the British N501Y.V1, South African N501Y.V2, and Brazilian N501Y.V3 variants of SARS-CoV2) within an hour using paper strip chemistry. The results were corroborated using deep sequencing. Our design principle can be rapidly adapted for other mutations, highlighting the advantages of quick optimization and roll-out of CRISPR diagnostics (CRISPRDx) for disease surveillance even beyond COVID-19.
Change in cognition and body mass index in relation to preclinical dementia
Authors: Karlsson Ida K , Zhan Yiqiang , Gatz Margaret , Reynolds Chandra A , Dahl Aslan Anna K
Published: February 2021

INTRODUCTION: To study if declining cognition drives weight loss in preclinical dementia, we examined the longitudinal association between body mass index (BMI) and cognitive abilities in those who did or did not later develop dementia.
METHODS: Using data from individuals spanning age 50-89, we applied dual change score models separately in individuals who remained cognitively intact (n=1,498) and those who were diagnosed with dementia within five years of last assessment (n=459).
RESULTS: Among the cognitively intact, there was a bidirectional association: stable BMI predicted stable cognition and vice versa. Among those subsequently diagnosed with dementia, the association was unidirectional: higher BMI predicted declining cognition, but cognition did not predict change in BMI.
DISCUSSION: While BMI and cognition stabilized each other when cognitive functioning was intact, this buffering effect was missing in the preclinical dementia phase. This finding indicates that weight loss in preclinical dementia is not driven by declining cognition.
Inference on the dynamics of the COVID pandemic from observational data
Authors: Bhattacharjee Satarupa , Liao Shuting , Paul Debashis , Chaudhuri Sanjay
Published: February 2021

Abstract

We describe a time dependent stochastic dynamic model in discrete time for the evolution of the COVID-19 pandemic in various states of USA. The proposed multi-compartment model is expressed through a system of difference equations that describe their temporal dynamics. Various compartments in our model is connected to the social distancing measures and diagnostic testing rates. A nonparametric estimation strategy is employed for obtaining estimates of interpretable temporally static and dynamic epidemiological rate parameters. The confidence bands of the parameters are obtained using a residual bootstrap procedure. A key feature of the methodology is its ability to estimate latent compartments such as the trajectory of the number of asymptomatic but infected individuals which are the key vectors of COVID-19 spread. The nature of the disease dynamics is further quantified by the proposed epidemiological markers, which use estimates of such key latent compartments.
Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes
Authors: Saad-Roy Chadi M. , Morris Sinead E. , Metcalf C. Jessica E. , Mina Michael J. , Baker Rachel E. , Farrar Jeremy , Holmes Edward C. , Pybus Oliver G. , Graham Andrea L. , Levin Simon A. , Grenfell Bryan T. , Wagner Caroline E.
Published: February 2021

As the threat of Covid-19 continues and in the face of vaccine dose shortages and logistical challenges, various deployment strategies are being proposed to increase population immunity levels. How timing of delivery of the second dose affects infection burden but also prospects for the evolution of viral immune escape are critical questions. Both hinge on the strength and duration (i.e. robustness) of the immune response elicited by a single dose, compared to natural and two-dose immunity. Building on an existing immuno-epidemiological model, we find that in the short-term, focusing on one dose generally decreases infections, but longer-term outcomes depend on this relative immune robustness. We then explore three scenarios of selection, evaluating how different second dose delays might drive immune escape via a build-up of partially immune individuals. Under certain scenarios, we find that a one-dose policy may increase the potential for antigenic evolution. We highlight the critical need to test viral loads and quantify immune responses after one vaccine dose, and to ramp up vaccination efforts throughout the world.