bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic Review and Meta-analysis of Immunomodulator and Biologic Therapies for Treatment of Chronic Pouchitis
Authors: Khoo Emi , Lee Andrew , Neeman Teresa , An Yoon-Kyo , Begun Jakob
Published: January 2021

Background

Pouchitis is a common complication after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA). Although antibiotics are the primary therapy for acute pouchitis, a proportion of patients developed chronic antibiotic-dependent pouchitis (CADP) or antibiotic-refractory pouchitis (CARP). The efficacy of second line immunomodulator and biologic therapies for chronic pouchitis remain undefined. We performed a systematic review and metanalysis of published studies to assess their efficacy.

Method

The online EMBASE database was searched for full-text articles describing the treatment of chronic pouchitis meeting our criteria. Post-induction clinical and endoscopic response and remission rates were extracted and combined for meta-analyses. The rate of treatment discontinuation and safety profiles were also assessed.

Results

A total of 21 full-text articles were included in this meta-analysis representing 491 patients. The overall clinical response rate was 49% with clinical remission rate of 34%. The overall endoscopic response and remission rates were 53% and 36% respectively. The safety profile of individual agents was reassuring, but vedolizumab appears to have a more favorable safety profile.

Conclusion

This review and meta-analysis identified the effectiveness of vedolizumab and ustekinumab in achieving clinical and endoscopic response in chronic pouchitis, with a reassuring safety profile. There is limited data regarding use of immunomodulators and no conclusion can be drawn. Further studies are required to define the comparative effectiveness of available treatments of CADP or CARP.
Estimating dates of origin and end of COVID-19 epidemics
Authors: Beneteau Thomas , Elie Baptiste , Sofonea Mircea T. , Alizon Samuel
Published: January 2021

Estimating the date at which an epidemic started in a country and the date at which it can end depending on interventions intensity are important to guide public health responses. Both are potentially shaped by similar factors including stochasticity (due to small population sizes), superspreading events, and ‘memory effects’ (the fact that the occurrence of some events, e.g. recovering from an infection, depend on the past, e.g. the number of days since the infection). Focusing on COVID-19 epidemics, we develop and analyse mathematical models to explore how these three factors may affect early and final epidemic dynamics. Regarding the date of origin, we find limited effects on the mean estimates, but strong effects on their variances. Regarding the date of extinction following lockdown onset, mean values decrease with stochasticity or with the presence of superspreading events. These results underline the importance of accounting for heterogeneity in infection history and transmission patterns to accurately capture early and late epidemic dynamics.
Mobile microscopy and telemedicine platform assisted by deep learning for quantification ofTrichuris trichiurainfection
Authors: Dacal Elena , Bermejo-Peláez David , Lin Lin , Álamo Elisa , Cuadrado Daniel , Martínez Álvaro , Mousa Adriana , Postigo María , Soto Alicia , Sukosd Endre , Vladimirov Alexander , Mwandawiro Charles , Gichuki Paul , Williams Nana Aba , Muñoz José , Kepha Stella , Luengo-Oroz Miguel
Published: January 2021

Soil-transmitted helminths (STH) are the most prevalent pathogens among the group of neglected tropical diseases (NTDs). Kato-Katz technique is the diagnosis method recommended by WHO and although is generally more sensitive than other microscopic methods in high transmission settings, it often presents a decreased sensitivity in low transmission settings and it is labour intensive. Digitizing the samples could provide a solution which allows to store the samples in a digital database and perform remote analysis. Artificial intelligence methods based on digitized samples can support diagnostics efforts by support diagnostics efforts by performing an automatic and objective quantification of disease infection.

In this work, we propose an end-to-end pipeline for microscopy image digitization and automatic analysis of digitized images of soil-transmitted helminths. Our solution includes (1) a digitalization system based on a mobile app that digitizes the microscope samples using a low-cost 3D-printed microscope adapter, (2) a telemedicine platform for remote analysis and labelling and (3) novel deep learning algorithms for automatic assessment and quantification of parasitological infection of STH.

This work has been evaluated by comparing the STH quantification using both a manual remote analysis based on the digitized images and the AI-assisted quantification against the reference method based on conventional microscopy. The deep learning algorithm has been trained and tested on 41 slides of stool samples containing 949 eggs from 6 different subjects using a cross-validation strategy obtaining a mean precision of 98,44% and mean recall of 80,94%. The results also proved the potential of generalization capability of the method at identifying different types of helminth eggs.

In conclusion, this work has presented a comprehensive pipeline using smartphone-based microscopy integrated with a telemedicine platform for automatic image analysis and quantification of STH infection using artificial intelligence models.
Fibrillar Aβ causes profound microglial metabolic perturbations in a novel APP knock-in mouse model
Authors: Xia Dan , Lianoglou Steve , Sandmann Thomas , Calvert Meredith , Suh Jung H. , Thomsen Elliot , Dugas Jason , Pizzo Michelle E. , DeVos Sarah L. , Earr Timothy K. , Lin Chia-Ching , Davis Sonnet , Ha Connie , Nguyen Hoang , Chau Roni , Yulyaningsih Ernie , Solanoy Hilda , Masoud Shababa T. , Liang Richard , Lin Karin , Thorne Robert G. , Garceau Dylan , Whitesell Jennifer D. , Sasner Michael , Harris Julie A. , Scearce-Levie Kimberly , Lewcock Joseph W. , Di Paolo Gilbert , Sanchez Pascal E.
Published: January 2021

Microglial dysfunction is believed to play a pathogenic role in Alzheimer’s disease (AD). Here, we characterize the amyloid-β related pathology and microglial responses in an engineered APP knock-in mouse model of familial AD. This model recapitulates key pathological features of AD such as a progressive accumulation of parenchymal amyloid plaques and vascular amyloid deposits, altered glial responses and neurodegeneration. Leveraging multi-omics approaches, we found lipid accumulation and an exacerbated disease-associated transcriptomic response in methoxy-X04-positive, phagocytic microglia. Together, these findings highlight the potential of this novel, open-access mouse model to investigate AD pathogenesis and demonstrate that fibrillar Aβ triggers lipid dysregulation and immuno-metabolic perturbations in phagocytic microglia.

Highlights

Novel open-access APP KI mouse model shows salient AD pathological features

Deep phenotyping of sorted microglia reveals profound lipidomic perturbations in line with Alois Alzheimer’s original descriptions of glial adipose inclusions

Immunometabolic perturbations are exacerbated in microglia accumulating fibrillar Aβ
The neuroprotective effects of Sonic hedgehog pathway agonist SAG in a rat model of neonatal stroke
Authors: Nguyen Vien , Chavali Manideep , Larpthaveesarp Amara , Kodali Srikirti , Gonzalez Ginez , Franklin Robin J.M. , Rowitch David H. , Gonzalez Fernando
Published: January 2021

Objective

Neonatal stroke affects 1 in 2800 live births and is a major cause of neurological injury. The Sonic Hedgehog (Shh) signaling pathway is critical for central nervous system (CNS) development and has neuroprotective and reparative effects in different CNS injury models. Previous studies have demonstrated beneficial effects of small molecule Shh-Smoothened-agonist (SAG) against neonatal cerebellar injury and it improves Down syndrome-related brain structural deficits in mice. Here, we investigated SAG neuroprotection in rat models of neonatal ischemia-reperfusion (stroke) and adult focal white matter injury.

Methods

We used transient middle cerebral artery occlusion at P10 and ethidium bromide injection in adult rats to induce damage. Following surgery and SAG or vehicle treatment we analyzed tissue loss, cell proliferation and fate, and behavioral outcome.

Results

We report that a single dose of SAG administered following neonatal stroke preserved brain volume, reduced inflammation, enhanced oligodendrocyte progenitor cell (OPC) and EC proliferation, and resulted in long-term cognitive improvement. Single-dose SAG also promoted proliferation of OPCs following focal demyelination in the adult rat.

Conclusion

These findings indicate benefit of one-time SAG treatment post-insult in reducing brain injury and improving behavioral outcome after experimental neonatal stroke.
Ectopic FVIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma
Authors: Kapelanski-Lamoureux Audrey , Chen Zhouji , Gao Zu-Hua , Deng Ruishu , Lazaris Anthoula , Lebeaupin Cynthia , Giles Lisa , Malhotra Jyoti , Yong Jing , Zou Chenhui , de Jong Ype P. , Metrakos Peter , Herzog Roland W. , Kaufman Randal J.
Published: January 2021

Hemophilia A gene therapy targets hepatocytes to express B domain deleted-(BDD) clotting factor VIII (FVIII) to permit viral encapsidation. Since BDD is prone to misfolding in the endoplasmic reticulum (ER) and ER protein misfolding in hepatocytes followed by high fat diet (HFD) can cause hepatocellular carcinoma (HCC), we studied how FVIII misfolding impacts HCC development using hepatocyte DNA delivery to express three proteins from the same parental vector: 1) well-folded cytosolic dihydrofolate reductase (DHFR); 2) BDD-FVIII, which is prone to misfolding in the ER; and 3) N6-FVIII which folds more efficiently than BDD-FVIII. One week after DNA delivery, when FVIII expression was undetectable, mice were fed HFD for 65 weeks. Remarkably, all mice that received BDD-FVIII vector developed liver tumors, whereas only 58% of mice that received N6 and no mice that received DHFR vector developed liver tumors, suggesting that the degree of protein misfolding in the ER increases predisposition to HCC in the context of a HFD and in the absence of viral transduction. Our findings raise concerns of ectopic BDD-FVIII expression in hepatocytes in the clinic, which poses risks independent of viral vector integration. Limited expression per hepatocyte and/or use of proteins that avoid misfolding may enhance safety.

Graphical abstract
Development of larvae of the Australian blowfly,Calliphora augur(Diptera: Calliphoridae), at constant temperatures
Authors: Day Donnah M. , Butterworth Nathan J. , Tagat Anirudh , Markowsky Gregory , Wallman James F.
Published: January 2021

Calliphora augur(Diptera: Calliphoridae) is a common carrion-breeding blowfly of forensic, medical and agricultural importance in eastern Australia. Despite this, detailed information on the developmental biology ofC. auguris lacking. Here, we present the first comprehensive study on the development of all three larval instars ofC. augur, fed on sheep’s liver, at constant temperatures of 15, 20, 25, 30 and 35°C. We provide thermal summation models describing instar duration, as well as 95% prediction intervals for larval length at each constant temperature, enabling the age of larvae ofC. augurto be estimated from their developmental stage and their average length. These data provide a basis for the application of this species to forensic investigations.
Breeding seasonality generates reproductive trade-offs in a long-lived mammal
Authors: Dezeure Jules , Baniel Alice , Carter Alecia J. , Cowlishaw Guy , Godelle Bernard , Huchard Elise
Published: January 2021

The evolutionary benefits of reproductive seasonality are usually measured by a single fitness component, namely offspring survival to nutritional independence (Bronson, 2009). Yet different fitness components may be maximised by dissimilar birth timings. This may generate fitness trade-offs that could be critical to understanding variation in reproductive timing across individuals, populations and species. Here, we use long-term demographic and behavioural data from wild chacma baboons (Papio ursinus) living in a seasonal environment to test the adaptive significance of seasonal variation in birth frequencies. Like humans, baboons are eclectic omnivores, give birth every 1-3 years to a single offspring that develops slowly, and typically breed year-round. We identify two distinct optimal birth timings in the annual cycle, located 4-months apart, which maximize offspring survival or minimize maternal interbirth intervals (IBIs), by respectively matching the annual food peak with late or early weaning. Observed births are the most frequent between these optima, supporting an adaptive trade-off between current and future reproduction. Furthermore, infants born closer to the optimal timing favouring maternal IBIs (instead of offspring survival) throw more tantrums, a typical manifestation of mother-offspring conflict (Maestripieri, 2002). Maternal trade-offs over birth timing, which extend into mother-offspring conflict after birth, may commonly occur in long-lived species where development from birth to independence spans multiple seasons. Such trade-offs may substantially weaken the benefits of seasonal reproduction, and our findings therefore open new avenues to understanding the evolution of breeding phenology in long-lived animals, including humans.

SIGNIFICANCE STATEMENT

Why some species breed seasonally and others do not remain unclear. The fitness consequences of birth timing have traditionally been measured on offspring survival, ignoring other fitness components. We investigated the effects of birth timing on two fitness components in wild baboons, who breed year-round despite living in a seasonal savannah. Birth timing generates a trade-off between offspring survival and future maternal reproductive pace, meaning that mothers cannot maximize both. When birth timing favours maternal reproductive pace (instead of offspring survival), behavioural manifestations of mother-offspring conflict around weaning are intense. These results open new avenues to understand the evolution of reproductive timings in long-lived animals including humans, where such reproductive trade-offs may commonly weaken the intensity of reproductive seasonality.
Architecture of the Neuro-Glia-Vascular System
Authors: Zisis Eleftherios , Keller Daniel , Kanari Lida , Arnaudon Alexis , Gevaert Michael , Delemontex Thomas , Coste Benoît , Foni Alessandro , Abdellah Marwan , Calì Corrado , Hess Kathryn , Magistretti Pierre Julius , Schürmann Felix , Markram Henry
Published: January 2021

Astrocytes connect the vasculature to neurons and mediate the supply of nutrients and biochemicals. They also remove metabolites from the neurons and extracellular environment. They are involved in a growing number of physiological and pathophysiological processes. Understanding the biophysical, physiological, and molecular interactions in this neuro-glia-vascular ensemble (NGV) and how they support brain function is severely restricted by the lack of detailed cytoarchitecture. To address this problem, we used data from multiple sources to create a data-driven digital reconstruction of the NGV at micrometer anatomical resolution. We reconstructed 0.2 mm3of rat somatosensory cortical tissue with approximately 16000 morphologically detailed neurons, its microvasculature, and approximately 2500 morphologically detailed protoplasmic astrocytes. The consistency of the reconstruction with a wide array of experimental measurements allows novel predictions of the numbers and locations of astrocytes and astrocytic processes that support different types of neurons. This allows anatomical reconstruction of the spatial microdomains of astrocytes and their overlapping regions. The number and locations of end-feet connecting each astrocyte to the vasculature can be determined as well as the extent to which they cover the microvasculature. The structural analysis of the NGV circuit showed that astrocytic shape and numbers are constrained by vasculature’s spatial occupancy and their functional role to form NGV connections. The digital reconstruction of the NGV is a resource that will enable a better understanding of the anatomical principles and geometric constraints which govern how astrocytes support brain function.

Table of contents

Main points

The Blue Brain Project digitally reconstructs a part of neocortical Neuro-Glia-Vascular organization

Interdependencies and topological methods allow dense in silico reconstruction from sparse experimental data

The polarized role of protoplasmic astrocytes constrains their shapes and numbers

Table of contents image
In vivo proximity labeling identifies cardiomyocyte protein networks during zebrafish heart regeneration
Authors: Pronobis Mira I. , Zheng Susan , Singh Sumeet P. , Poss Kenneth D.
Published: January 2021

Strategies have not been available until recently to uncover interacting protein networks specific to key cell types, their subcellular compartments, and their major regulators during complexin vivoevents. Here we apply BioID2 proximity labeling to capture protein networks acting within cardiomyocytes during a key model of innate heart regeneration in zebrafish. Transgenic zebrafish expressing a promiscuous BirA2 localized to the entire myocardial cell or membrane compartment were generated, each identifying unique proteomes in adult cardiomyocytes that became altered during regeneration. BioID2 profiling for interactors with ErbB2, a co-receptor for the cardiomyocyte mitogen Nrg1, implicated Rho A as a target of ErbB2 signaling in cardiomyocytes. Blockade of Rho A during heart regeneration, or during cardiogenic stimulation by the mitogenic influences Nrg1, Vegfaa or Vitamin D, disrupted muscle creation. Our findings reveal proximity labeling as a useful resource to interrogate cell proteomes and signaling networks during tissue regeneration in zebrafish.
COVID-19 Knowledge, Attitudes, and Practices of United Arab Emirates Medical and Health Sciences Students: A Cross Sectional Study
Authors: Baniyas Noura , Sheek-Hussein Mohamud , Al Kaabi Nouf , Al Shamsi Maitha , Al Neyadi Maitha , Al Khoori Rauda , Ajab Suad , Abid Muhammad , Grivna Michael , Abu Zidan Fikri M.
Published: January 2021

COVID-19 pandemic is the largest unprecedented viral pandemic of the 21st century. We aimed to study the COVID-19 knowledge, attitudes, and practices (KAP) among medical and health sciences students in the United Arab Emirates (UAE). We performed a cross-sectional study between 2nd June and 19th August 2020. The survey was developed using online Survey Monkey. The link was distributed via UAE University to all students and via WhatsApp© groups. The self-administered questionnaire was conducted in English and comprised of two parts: socio-demographic characteristics and KAP towards COVID-19. A total of 712 responses to the questionnaire were collected. 90% (n=695) were under-graduate, while 10% (n=81) were post-graduate students. Majority (87%, n=647) stated that they obtained COVID-19 information from multiple reliable sources. They were highly knowledgeable about COVID-19 pandemic but 76% (n=539) did not recognize its routes of transmission. 63% (n=431) were worried of getting COVID-19, while 92% (n=633)) were worried that a family member could get infected with the virus. 97% (n=655) took precautions when accepting home deliveries, 94% (n=637) had been washing their hands more frequently, and 95% (n=643) had been wearing face masks. In conclusion, participants showed high levels of knowledge and awareness about COVID-19. They were worried about getting infected themselves or their family members, and had good practices against COVID-19.
Metabolic regulation of ILC2 differentiation into ILC1-like cells duringMycobacterium tuberculosisinfection
Authors: Corral Dan , Charton Alison , Krauss Maria Z , Blanquart Eve , Levillain Florence , Lefrançais Emma , Sneperger Tamara , Girard Jean-Philippe , Eberl Gérard , Poquet Yannick , Guéry Jean-Charles , Arguello Rafael J , Hepworth Matthew R , Neyrolles Olivier , Hudrisier Denis
Published: January 2021

Tissue-resident innate lymphoid cells (ILCs) regulate tissue homeostasis, protect against pathogens at mucosal surfaces and are key players at the interface of innate and adaptive immunity. How ILCs adapt their phenotype and function to environmental cues within tissues remains to be fully understood. Here, we show thatMycobacterium tuberculosisinfection alters the phenotype and function of immature lung ILC2 toward a protective interferon-γ-producing ILC1-like population. This differentiation is controlled by type 1 cytokines and is associated with a glycolytic program involving the transcription factor HIF1α. Collectively, our data reveal how tissue-resident ILCs adapt to type 1 inflammation toward a pathogen tailored immune response.
VISUAL network analysis reveals the role of BEH3 as a stabilizer in the secondary vascular development in Arabidopsis
Authors: Furuya Tomoyuki , Saito Masato , Uchimura Haruka , Satake Akiko , Nosaki Shohei , Miyakawa Takuya , Shimadzu Shunji , Yamori Wataru , Tanokura Masaru , Fukuda Hiroo , Kondo Yuki
Published: January 2021

During secondary growth in plants, vascular stem cells located in the cambium continuously undergo self-renewal and differentiation throughout the lifetime. Recent cell-sorting technique enables to uncover transcriptional regulatory framework for cambial cells. However, the mechanisms underlying the robust control of vascular stem cells have not been understood yet. By coexpression network analysis using multiple transcriptome datasets of an ectopic vascular cell transdifferentiation system using Arabidopsis cotyledons, VISUAL, we newly identified a cambium-specific gene module from an alternative approach. The cambium gene list included a transcription factor BES1/BZR1 homolog 3 (BEH3), whose homolog BES1 is known to control vascular stem cell maintenance negatively. Interestingly, the vascular size of thebeh3mutants showed a large variation, implying the role of BEH3 as a stabilizer. BEH3 almost lost the transcriptional repressor activity and functioned antagonistically with other BES/BZR members via competitive binding to the same motif BRRE. Indeed, mathematical modeling suggests that the competitive relationship among BES/BZRs leads to the robust regulation of vascular stem cells.
Mechanosensitive remodeling of the bacterial flagellar motor is independent of direction of rotation
Authors: Wadhwa Navish , Tu Yuhai , Berg Howard C.
Published: January 2021

Motility is critical for the survival and dispersal of bacteria, and it plays an important role during infection. How bacteria regulate motility is thus a question of broad interest. Regulation of bacterial motility by chemical stimuli is well studied, but recent work has added a new dimension to the problem of motility control. The bidirectional flagellar motor of the bacteriumEscherichia colirecruits or releases torque-generating units (stator units) in response to changes in load. Here, we show that this mechanosensitive remodeling of the flagellar motor is independent of direction of rotation. Remodeling rate constants in clockwise rotating motors and in counterclockwise rotating motors, measured previously, fall on the same curve if plotted against torque. Increased torque decreases the off rate of stator units from the motor, thereby increasing the number of active stator units at steady state. A simple mathematical model based on observed dynamics provides quantitative insight into the underlying molecular interactions. The torque-dependent remodeling mechanism represents a robust strategy to quickly regulate output (torque) in response to changes in demand (load).

Significance

Macromolecular machines carry out most of the biological functions in living organisms. Despite their significance, we do not yet understand the rules that govern the self-assembly of large multi-protein complexes. The bacterial flagellar motor tunes the assembly of its torque-generating stator complex with changes in external load. Here, we report that clockwise and counterclockwise rotating motors have identical remodeling response to changes in the external load, suggesting a purely mechanical mechanism for this regulation. Autonomous control of self-assembly may be a general strategy for tuning the functional output of protein complexes. The flagellar motor is a prime example of a macromolecular machine in which the functional regulation of assembly can be rigorously studied.
Identification and characterization of a G-quadruplex structure in the pre-core promoter region of hepatitis B virus
Authors: Meier-Stephenson Vanessa , Badmalia Maulik D , Mrozowich Tyler , Lau Keith CK , Schultz Sarah K , Gemmill Darren L , Osiowy Carla , van Marle Guido , Coffin Carla S , Patel Trushar R
Published: January 2021

Worldwide, ∼250 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of cirrhosis and hepatocellular carcinoma. The HBV persists as covalently closed circular DNA (cccDNA), which acts as the template for all HBV mRNA transcripts. Nucleos(t)ide analogs do not directly target the HBV cccDNA and cannot eradicate the HBV. We have discovered a unique structural motif, a G-quadruplex in HBV’s pre-core promoter region that is conserved amongst nearly all genotypes, and is central to critical steps in the viral life-cycle including the production of pre-genomic RNA, core and polymerase proteins, and encapsidation. Thus, an increased understanding of the HBV pre-core may lead to the development of novel anti-HBV cccDNA targets. We utilized biophysical methods to characterize the presence of the G-quadruplex, employed assays using a known quadruplex- binding protein (DHX36) to pull-down HBV cccDNA, and compared HBV infection in HepG2 cells transfected with wild-type and mutant HBV plasmids. This study provides insights into the presence of a G-quadruplex in the HBV pre-core promoter region essential for HBV replication. The evaluation of this critical host-protein interaction site in the HBV cccDNA may ultimately facilitate the development of novel anti-HBV therapeutics against the resilient cccDNA template.
Plants export 2-monopalmitin and supply both fatty acyl and glyceryl moieties to arbuscular mycorrhizal fungi
Authors: Luginbuehl Leonie H , van Erp Harrie , Cheeld Henry , Mysore Kirankumar S , Wen Jiangqi , Oldroyd Giles ED , Eastmond Peter J
Published: January 2021

Arbuscular mycorrhizal fungi (AMF) rely on their host plants to provide them with fatty acids (FA), but the precise form(s) in which they are supplied is still unclear. Here we show that ectopic expression of the transcription factor REQUIRED FOR ARBUSCULAR MYCORRHIZATION 1 (RAM1) can drive secretion of 2-monoacylglycerols (2MGs) fromMedicago truncatularoots and that their main FA moiety is palmitic acid, although myristic acid and stearic acid were also detected. RAM1-dependent 2MG secretion requires the acyl-acyl carrier protein thioesterase FATM, the glycerol-3-phosphate (G3P) acyltransferase RAM2 and the ATP binding cassette transporter STR. Furthermore,14C glycerol labelling experiments using mycorrhizalM. truncatularoots that are deficient in glycerol kinase, FAD-dependent G3P dehydrogenase and the G3P acyltransferase RAM2 suggest that most of the glyceryl moieties inRhizophagus irregularisstorage lipids are provided by their host plant through the 2MG pathway. Taken together, our data support the hypothesis that the plant exports 2MGs across the peri-arbuscular membrane in mycorrhizal roots and that the AMF receive and utilise both the FA and glyceryl moieties to make their storage lipids.
Single particle combinatorial multiplexed liposome fusion mediated by DNA
Authors: Malle Mette Galsgaard , Löffler Philipp M. G. , Bohr Søren S.-R. , Sletfjerding Magnus Berg , Risgaard Nikolaj Alexander , Jensen Simon Bo , Zhang Min , Hedegaard Per , Vogel Stefan , Hatzakis Nikos S.
Published: January 2021

Combinatorial high throughput methodologies are central for both screening and discovery in synthetic biochemistry and biomedical sciences. They are, however, often reliant on large scale analyses and thus limited by long running time and excessive materials cost. We herein presentSinglePARticleCombinatorial multiplexedLiposome fusion mediated byDNA (SPARCLD), for the parallelized, multi-step and non-deterministic fusion of individual zeptoliter nanocontainers. We observed directly the efficient (>93%), and leakage free stochastic fusion sequences for arrays of surface tetheredtargetliposomes with six freely diffusing populations ofcargoliposomes, each functionalized with individual lipidated ssDNA (LiNA) and fluorescent barcoded by distinct ratio of chromophores. The stochastic fusion results in distinct permutation of fusion sequences for each autonomous nanocontainer. Real-time TIRF imaging allowed the direct observation of >16000 fusions and 566 distinct fusion sequences accurately classified using machine learning. The high-density arrays of surface tethered target nanocontainers ∼42,000 containers per mm2offers entire combinatorial multiplex screens using only picograms of material.
Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein
Authors: Suryadevara Naveenchandra , Shrihari Swathi , Gilchuk Pavlo , VanBlargan Laura A. , Binshtein Elad , Zost Seth J. , Nargi Rachel S. , Sutton Rachel E. , Winkler Emma S. , Chen Elaine C. , Fouch Mallorie E. , Davidson Edgar , Doranz Benjamin J. , Carnahan Robert H. , Thackray Larissa B. , Diamond Michael S. , Crowe James E.
Published: January 2021

Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.
Self-organization and information transfer in Antarctic krill swarms
Authors: Burns Alicia L. , Schaerf Timothy M. , Lizier Joseph T. , Kawaguchi So , Cox Martin , King Rob , Krause Jens , Ward Ashley J.W.
Published: January 2021

Antarctic krill swarms are one of the largest known animal aggregations. However, despite being the keystone species of the Southern Ocean, little is known about how swarms are formed and maintained, and we lack a detailed understanding of the local interactions between individuals that provide the basis for these swarms. Here we analyzed the trajectories of captive, wild-caught krill in 3D to determine individual level interaction rules and quantify patterns of information flow. Our results suggest krill operate a novel form of collective organization, with measures of information flow and individual movement adjustments expressed most strongly in the vertical dimension, a finding not seen in other swarming species. In addition, local directional alignment with near neighbors, and strong regulation of both direction and speed relative to the positions of groupmates suggest social factors are vital to the formation and maintenance of swarms. This research represents a first step in understanding the fundamentally important swarming behavior of krill.
An integrated comparative physiology and molecular approach pinpoints mediators of breath-hold capacity in dolphins
Authors: Blawas Ashley M. , Ware Kathryn E. , Schmaltz Emma , Zheng Larry , Spruance Jake , Allen Austin S. , West Nicole , Devos Nicolas , Corcoran David L. , Nowacek Douglas P. , Eward William C. , Fahlman Andreas , Somarelli Jason A.
Published: January 2021

Ischemic events, such as ischemic heart disease and ischemic stroke, are the number one cause of death globally. Ischemia prevents blood, carrying essential nutrients and oxygen, from reaching tissues and organ systems, leading to cell and tissue death, and eventual organ failure. While humans are relatively intolerant to these ischemic events, other species, such as marine mammals, have evolved remarkable tolerance to chronic ischemia/reperfusion during diving. Here we capitalized on the unique adaptations of bottlenose dolphins (Tursiops truncatus) as a comparative model of ischemic stress and hypoxia tolerance to identify molecular features associated with breath-holding. Using RNA-Seq we observed time-dependent upregulation of the arachidonate 5-lipoxygenase (ALOX5) gene during breath-holding. Consistent with the RNA-Seq data, we also observed increased ALOX5 enzymatic activity in the serum of dolphins undergoing breath holds. ALOX5 has previously been shown to be activated during hypoxia in rodent models, and its metabolites, leukotrienes, induce vasoconstriction. The upregulation of ALOX5 occurred within the estimated aerobic dive limit of the species, suggesting that ALOX5 enzymatic activity may promote tolerance to ischemic stress through sustained vasoconstriction in dolphins during diving. These observations pinpoint a potential molecular mechanism by which dolphins, and perhaps other marine mammals, have adapted to the prolonged breath-holds associated with diving.
Colonial Servicemen and their British ‘War Brides’: First World War Marriages in the British Empire
Authors: Maguire Anna
Published: January 2021

This article uses the phenomenon and failure of war marriages between British women and ‘colonial’ servicemen, mostly from the settler dominions, to explore the gendered, classed and racialised conditions of migration after the First World War. Positioning this migration of British war brides as part of the continued normalisation of settler occupation, the article demonstrates the patriarchal social expectations to which white women were subject. Fears of ‘khaki fever’ were extended to the protection of naïve ‘colonial’ soldiers from the manipulative sexuality of white, particularly working‐class, women and girls. At the same time, ‘respectable’ women were prepared for frontier life and protected from the indignities of bigamy and desertion. The emphasis on their role as ‘daughters of Empire’ meant ‘undesirable’ matches and marital failure, as reported by the press, had consequences for the closeness of the imperial family and the maintenance of white superiority. The mediation of mobility in cases of mixed‐race marriage indicate a more explicit, and sometimes violent, policing of the sexual independence of women and Black and indigenous men of colour. In doing so, the article makes an important contribution to understandings of the legacies of global mobilisation and colonial encounters during the First World War.
Conditional Income Disparity between Farm and Non‐farm Households in the European Union: A Longitudinal Analysis
Authors: Marino Maria , Rocchi Benedetto , Severini Simone
Published: January 2021

Government interventions in the agricultural sector have been historically justified by the existence of an income disparity between farmers and non‐farmers. However, recent studies have found that such disparity is disappearing over time, particularly in the United States. This work offers the first longitudinal systematic assessment on the average income disparity between farm and non‐farm units in the European Union, differentiating between old and new Member States. Using the EU‐SILC dataset, both broad (having some farm income) and narrow (living mainly on agriculture) farm households are compared with a general sample of non‐farm households and a more restricted sample of self‐employed non‐farm households. To control for household observable characteristics and time‐constant unobserved factors, we use a fixed effects regression. Results suggest that the farm/non‐farm income disparity has disappeared in the European Union unless we compare narrow farm households with all non‐farm households: in this case, the former are more likely to be better off than the latter. A limited income disparity is found only in the case of new Member States for broad farm households only. Results are used to draw policy implications regarding the role of CAP in supporting farm income.
Effectiveness of monitoring free carnitine levels for L‐carnitine supplementation in hemodialysis patients to maintain carnitine sufficiency and nutritional factors
Authors: Kumagai Etsuko , Hosohata Keiko , Furumachi Kazuhiro , Takai Shinji
Published: January 2021

We investigated the effectiveness of monitoring serum carnitine levels in hemodialysis patients receiving L‐carnitine supplementation. One‐hundred forty‐five hemodialysis patients were divided into three groups. Group 1 consisted of patients (n = 30) who had been receiving supplementation before this study and then discontinued at the beginning. The remaining patients were divided into Group 2 (n = 13) and Group 3 (n = 102) based on their baseline free carnitine (FC) level, <20 or ≥ 20 μmol/L. Group 2 was started on supplementation, and Groups 1 and 3 were observed without any intervention for the first 6 months. FC was measured every 6 months in all three groups up to 18 months. All patients in whom FC was less than 20 μmol/L at 6 and 12 months were prescribed supplementation. After the first 6 months, the mean ± SD of FC changed from 262.5 ± 87.5 μmol/L at baseline to 70.8 ± 33.6 μmol/L (P < 0.001) in Group 1, from 17.4 ± 1.9 to 193.9 ± 43.3 μmol/L (P < 0.001) in Group 2, and from 49.2 ± 24.6 to 44.2 ± 19.8 μmol/L (P < 0.05) in Group 3. The acyl/free carnitine changed from 0.62 to 0.59 in Group 1 (P = 0.287), from 0.76 to 0.66 in Group 2 (P = 0.054) and from 0.57 to 0.60 in Group 3 (P < 0.05). Of the 145 patients, 126 continued follow‐up for the full 18 months. FC remained in the normal range (36–74 μmol/L) within the 95% CI. FC was considered a strong predictor of carnitine deficiency after 6 months (AUC: 0.9146, cut‐off value: 33.8 μmol/L). FC monitoring is essential for appropriate carnitine supplementation in hemodialysis patients.
Addressing the Humanitarian and Environmental Consequences of Atmospheric Nuclear Weapon Tests: A Case Study of UK and US Test Programs at Kiritimati (Christmas) and Malden Islands, Republic of Kiribati
Authors: Alexis‐Martin Becky , Bolton Matthew Breay , Hawkins Dimity , Tisch Sydney , Mangioni Talei Luscia
Published: January 2021

Between 1957 and 1962, the UK and USA conducted 33 atmospheric nuclear weapons test detonations at or close to Malden and Kiritimati (Christmas) Islands (total yield 31 megatons), formerly British colonial territories in the central Pacific region, now part of the Republic of Kiribati. Some 40,000 British, Fijian, New Zealand and US civilian and military personnel participated in the test program and 500 i‐Kiribati civilians lived on Kiritimati at the time. This article reviews humanitarian and environmental consequences of the UK and US nuclear weapons testing programs in Kiribati, as well as the policy measures that have addressed them. The authors contend that policy interventions to date have not adequately addressed the needs and rights of test survivors, nor ongoing environmental concerns. They argue that the victim assistance and environmental remediation obligations in the 2017 Treaty on the Prohibition of Nuclear Weapons offer an important new opportunity for addressing the consequences of nuclear detonations in Kiribati, by focusing policy attention and constituting a new field of development assistance.
Synchronous triple primary lung cancer with three different histological subtypes in the same lobe: A case report
Authors: Koyama Tsutomu , Shimizu Kimihiro , Uehara Takeshi , Matsuoka Shunichiro , Takeda Tetsu , Yamada Kyoko , Eguchi Takashi , Hamanaka Kazutoshi , Sano Kenji
Published: January 2021

Although the number of patients diagnosed with synchronous multiple primary lung cancer is growing because of increased screening and improved imaging technology, synchronous triple primary lung cancer with different histological tumor subtypes occurring in the same lobe of the lung is extremely rare. In this report, we encountered a 64‐year‐old male patient with three different types of nodule in the right lower lobe of the lung found on chest computed tomography (CT) scan. We believed that the patient had triple primary lung cancer, and subsequently performed a right lower lobectomy using video‐assisted thoracoscopic surgery (VATS). The pathological diagnosis was the same as the presurgical diagnosis, but all the nodules were different histological subtypes. To the best of our knowledge, this is the first case reported in the literature of synchronous triple primary lung cancer with three different histological subtypes in the same lobe of the lung.

Key points

Significant findings of the study

This is the first case of synchronous triple primary lung cancer with three different histological subtypes in each tumor in the same lobe of the lung.

What this study adds

We report the details of the case with immunohistochemical and gene mutation findings, and a literature review of synchronous primary lung cancer.
HSP90 inhibition overcomes EGFR amplification‐induced resistance to third‐generation EGFR‐TKIs
Authors: Watanabe Sho , Goto Yasushi , Yasuda Hiroyuki , Kohno Takashi , Motoi Noriko , Ohe Yuichiro , Nishikawa Hiroyoshi , Kobayashi Susumu S. , Kuwano Kazuyoshi , Togashi Yosuke
Published: January 2021

Background

Patients with non‐small cell lung cancer (NSCLC) harboring activating EGFR mutations are sensitive to epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) but inevitably develop resistance to the inhibitors mostly through acquisition of the secondary T790M mutation. Although third‐generation EGFR‐TKIs overcome this resistance by selectively inhibiting EGFR with EGFR‐TKI‐sensitizing and T790M mutations, acquired resistance to third‐generation EGFR‐TKIs invariably develops.

Methods

Next‐generation sequencing (NGS) and fluorescence in situ hybridization (FISH) analysis were performed in an EGFR T790M‐mutated NSCLC patient who had progressed after a third‐generation EGFR‐TKI, TAS‐121. EGFR‐mutated cell lines were subjected to a cell proliferation assay and western blotting analysis with EGFR‐TKIs and a heat shock protein 90 (HSP90) inhibitor.

Results

NGS and FISH analysis revealed EGFR amplification in the resistant cancer cells. While EGFR L858R/T90M‐mutated cell line was sensitive to osimertinib or TAS‐121 in vitro, EGFR‐overexpressing cell lines displayed resistance to these EGFR‐TKIs. Western blot analysis showed that EGFR phosphorylation and overexpression of EGFR in cell lines was not suppressed by third‐generation EGFR‐TKIs. In contrast, an HSP90 inhibitor reduced total and phosphorylated EGFR and inhibited the proliferation of resistant cell lines.

Conclusions

EGFR amplification confers resistance to third‐generation EGFR‐TKIs which can be overcome by HSP90 inhibition. The results provide a preclinical rationale for the use of HSP90 inhibitors to overcome EGFR amplification‐mediated resistance.
Economic Diplomacy and Economic Security under Abe
Authors: Armstrong Shiro
Published: January 2021

As Japan's longest serving Prime Minister, Shinzo Abe brought political stability to Japan and regional and global leadership on trade and economic diplomacy at a time of great uncertainty. Japan navigated a more assertive China and a USA in retreat from global leadership. Abe led the conclusion of the Trans‐Pacific Partnership agreement after US withdrawal and a more strategic approach to international economic diplomacy for Japan. Repair of the China relationship culminated in a state visit to Beijing in 2018 and agreement to cooperate on joint infrastructure investment projects. The trade and political dispute with South Korea and new economic security policies now erode Japan's openness and are a challenge going forward.
An expert consensus to standardise the assessment of histological disease activity in Crohn's disease clinical trials
Authors: Almradi Ahmed , Ma Christopher , D'Haens Geert R. , Sandborn William J. , Parker Claire E. , Guizzetti Leonardo , Borralho Nunes Paula , De Hertogh Gert , Feakins Roger M. , Khanna Reena , Lauwers Gregory Y. , Mookhoek Aart , Pai Reetesh K. , Peyrin‐Biroulet Laurent , Riddell Robert , Rosty Christophe , Schaeffer David F. , Valasek Mark A. , Singh Siddharth , Crowley Eileen , Feagan Brian G. , Jairath Vipul , Pai Rish K.
Published: January 2021

Background

Targeting histological remission or response in Crohn's disease (CD) is not recommended in clinical practice guidelines or as an outcome in clinical trials due to uncertainties regarding index validity and prognostic relevance.

Aims

To conduct a modified RAND/University of California Los Angeles appropriateness process with the goal of producing a framework to standardise histological assessment of CD activity in clinical trials.

Methods

A total of 115 statements generated from literature review and expert opinion were rated on a scale of 1‐9 by a panel of 11 histopathologists and 6 gastroenterologists. Statements were classified as inappropriate, uncertain or appropriate based upon the median panel rating and degree of disagreement.

Results

The panellists considered it important to measure histological activity in clinical trials to determine efficacy and that absence of neutrophilic inflammation is an appropriate histological target. They were uncertain whether the Global Histological Activity Score was an appropriate instrument for measuring histological activity. The Geboes Score and Robarts Histopathology Index were considered appropriate. Two biopsies from five segments should be biopsied, and the colon and the ileum should be analysed separately for all indices. Endoscopic mucosal appearance should guide biopsy procurement site with biopsies taken from the ulcer edge, or the most macroscopically inflamed area in the absence of ulcers.

Conclusion

We evaluated the appropriateness of items for assessing histological disease activity in CD clinical trials. These items will be used to develop a novel histological index.
Calpain–calpastatin system and cancer progression
Authors: Nian Hong , Ma Binyun
Published: January 2021

The calpain system is required by many important physiological processes, including the cell cycle, cytoskeleton remodelling, cellular proliferation, migration, cancer cell invasion, metastasis, survival, autophagy, apoptosis and signalling, as well as the pathogenesis of a wide range of disorders, in which it may function to promote tumorigenesis. Calpains are intracellular conserved calcium‐activated neutral cysteine proteinases that are involved in mediating cancer progression via catalysing and regulating the proteolysis of their specific substrates, which are important signalling molecules during cancer progression. μ‐calpain, m‐calpain, and their specific inhibitor calpastatin are the three molecules originally identified as comprising the calpain system and they contain several crucial domains, specific motifs, and functional sites. A large amount of data supports the roles of the calpain–calpastatin system in cancer progression via regulation of cellular adhesion, proliferation, invasion, metastasis, and cellular survival and death, as well as inflammation and angiogenesis during tumorigenesis, implying that the inhibition of calpain activity may be a potential anti‐cancer intervention strategy targeting cancer cell survival, invasion and chemotherapy resistance.