bluuebunny/crossref_metadata_2025 huggingface dataset:
A Health Economic Evaluation of the World Health Organization Surgical Safety Checklist
Authors: Healey Andy , Søfteland Eirik , Harthug Stig , Haaverstad Rune , Mahesparan Rupavathana , Hjallen Bjørg Merete , Eide Geir Egil , Sevdalis Nick , Haugen Arvid Steinar
Published: October 2020

Objectives:

To evaluate cost-effectiveness of the WHO Surgical Safety Checklist.

Background:

The clinical effectiveness of surgical checklists is largely understood. Few studies to-date have evaluated the cost-effectiveness of checklist use.

Methods:

An economic evaluation was carried out using data from the only available randomized controlled trial of the checklist. Analyses were based on 3702 procedures. Costs considered included checklist implementation costs and length and cost of hospital stay, costs of warming blanket use, blood transfusions and antibiotics used in the operating room, and the cost of clinical time in the operating room – all calculated for each procedure and its associated admission. Nonparametric bootstrapping was used to simulate an empirical distribution of the mean effect of the checklist on total admission costs and the probability of observing a complication-free admission and to quantify sampling uncertainty around mean cost estimates.

Results:

The overall cost of checklist implementation was calculated to be $900 per 100 admissions. Implementation of the WHO checklist resulted in an additional 5.9 complication-free admissions per 100 admissions and an average of 110 bed-days saved per 100 admissions. Accounting for all costs included in the analysis, for every 100 admissions, use of the WHO checklist was estimated to save $55,899.

Conclusions:

Implementation of the WHO checklist was a cost-effective strategy for improving surgical safety.
Distribution of Residual Disease and Recurrence Patterns in Pathological Responders After Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma
Authors: Matsuda Satoru , Kawakubo Hirofumi , Okamura Akihiko , Takahashi Keita , Toihata Tasuku , Takemura Ryo , Mayanagi Shuhei , Hirata Kenro , Irino Tomoyuki , Hamamoto Yasuo , Takeuchi Hiroya , FACS  , Watanabe Masayuki , Kitagawa Yuko
Published: October 2020

Objective:

This study aimed to elucidate the residual disease distribution and recurrence patterns in patients with ESCC responding to NAC.

Summary Background Data:

To appropriately plan a prospective trial for the organ preservation approach which includes additional chemoradiotherapy in patients who responded to NAC, the distribution of residual disease needs to be elucidated. Given that the residual tumor is located in the regional field, chemoradiotherapy can be safely added to eliminate the residual disease.

Methods:

Overall, 483 patients with resectable ESCC who received NAC followed by transthoracic esophagectomy at 2 high-volume centers were reviewed. The recurrence-free survival, overall survival (OS), and residual and recurrent tumor patterns were compared among the pathological responses.

Results:

Compared with nonpathological responders, pathological responders exhibited significantly longer recurrence-free survival [hazard ratio of Grade 1b/2/3 compared with Grade 0; 0.25 (P < 0.001)/0.17 (P < 0.001)/0.16 (P = 0.003)] and OS [hazard ratio of Grade 1b/2/3 compared with Grade 0; 0.26 (P < 0.001)/0.12 (P < 0.001)/0.11 (P = 0.003)]. In terms of the distribution of recurrence, the percentages of solitary recurrence in the regional field out of all recurrence was significantly higher in patients with Grade 1b (60%)/2 (67%)/3 (67%) whereas less than 25% in Grade 0 or 1a.

Conclusions:

It was found that postoperative recurrence in responders occurred in the regional field mostly as a solitary lesion without the distant failure, indicating that the residual tumor cells can be eliminated by additional chemoradiotherapy.
Using Direct-to-Consumer Genetic Testing Results to Accelerate Alzheimer Disease Clinical Trial Recruitment
Authors: Ryan Mary M. , Cox Chelsea G. , Witbracht Megan , Hoang Dan , Gillen Daniel L. , Grill Joshua D.
Published: October 2020

Introduction:

The apolipoprotein E (APOE) gene is the strongest known genetic risk factor for sporadic Alzheimer disease (AD). APOE can be used as an enrichment strategy or inclusion criterion for AD prevention trials. Personal genomics companies market direct-to-consumer (DTC) genetic tests, including APOE. We assessed DTC APOE testing usage among enrollees of the University of California Irvine Consent-to-Contact Registry, an online recruitment registry, and attitudes toward using this information in clinical trial recruitment.

Methods:

We emailed links to an electronic survey to registry enrollees age 50 years or older. We assessed participants’ use of DTC services, willingness to learn APOE status, and willingness to share genetic information. Logistic regression models assessed relationships between DTC testing usage and demographic characteristics, and with willingness to share results to assist trial recruitment.

Results:

Among 1312 responders (57% response rate), few (7%) had used DTC testing for APOE. Non-Hispanic Asian enrollees were 93% less likely to have used DTC testing, compared with non-Hispanic Whites [95% confidence interval: (0.01, 0.67)]. Willingness to share APOE information for study recruitment was >90% for both users and nonusers.

Conclusions:

Matching participants to trials on the basis of DTC APOE information may be an effective way to streamline AD prevention trial recruitment.
JAK out of the Box; The Rationale behind Janus Kinase Inhibitors in the COVID-19 setting, and their potential in obese and diabetic populations
Authors: Menshawey Rahma , Menshawey Esraa , Alserr Ayman H.K. , Abdelmassih Antoine Fakhry
Published: October 2020

The adaptive use of Janus kinase (JAK)-inhibitors has been suggested by rheumatology experts in the management of COVID-19. We recount the rationale behind their use in this setting, and the current evidence for and against their use in this review. JAK-inhibitors role in COVID-19 infection appears to be multifaceted, including preventing viral endocytosis and dampening the effect of excessive chemokines. This drug class may be able to achieve these effects at already preapproved dosages. Concerns arise regarding reactivation of latent viral infections and the feasibility of their use in those with severe disease. Most interestingly, JAK-Inhibitors may also have an additional advantage for diabetic and obese populations, where the dysregulation of JAK-signal transducer and activator of transcription pathway may be responsible for their increased risk of poor outcomes. Targeting this pathway may provide a therapeutic advantage for these patient groups.
Quantum computing using continuous-time evolution
Authors: Kendon Viv
Published: October 2020

Computational methods are the most effective tools we have besides scientific experiments to explore the properties of complex biological systems. Progress is slowing because digital silicon computers have reached their limits in terms of speed. Other types of computation using radically different architectures, including neuromorphic and quantum, promise breakthroughs in both speed and efficiency. Quantum computing exploits the coherence and superposition properties of quantum systems to explore many possible computational paths in parallel. This provides a fundamentally more efficient route to solving some types of computational problems, including several of relevance to biological simulations. In particular, optimization problems, both convex and non-convex, feature in many biological models, including protein folding and molecular dynamics. Early quantum computers will be small, reminiscent of the early days of digital silicon computing. Understanding how to exploit the first generation of quantum hardware is crucial for making progress in both biological simulation and the development of the next generations of quantum computers. This review outlines the current state-of-the-art and future prospects for quantum computing, and provides some indications of how and where to apply it to speed up bottlenecks in biological simulation.
Educating and engaging new communities of practice with high performance computing through the integration of teaching and research
Authors: Townsend-Nicholson Andrea
Published: October 2020

The identification of strategies by which to increase the representation of women and increase diversity in STEM fields (science, technology, engineering and mathematics), including medicine, has been a pressing matter for global agencies including the European Commission, UNESCO and numerous international scientific societies. In my role as UCL training lead for CompBioMed, a European Commission Horizon 2020-funded Centre of Excellence in Computational Biomedicine (compbiomed.eu), and as Head of Teaching for Molecular Biosciences at UCL from 2010 to 2019, I have integrated research and teaching to lead the development of high-performance computing (HPC)-based education targeting medical students and undergraduate students studying biosciences in a way that is explicitly integrated into the existing university curriculum as a credit-bearing module. One version of the credit-bearing module has been specifically designed for medical students in their pre-clinical years of study and one of the unique features of the course is the integration of clinical and computational aspects, with students obtaining and processing clinical samples and then interrogating the results computationally using code that was ported to HPC at CompBioMed's HPC Facility core partners (EPCC (UK), SURFsara (The Netherlands) and the Barcelona Supercomputing Centre (Spain)). Another version of the credit-bearing module has, over the course of this project, evolved into a replacement for the third year research project course for undergraduate biochemistry, biotechnology and molecular biology students, providing students with the opportunity to design and complete an entire specialist research project from the formulation of experimental hypotheses to the investigation of these hypotheses in a way that involves the integration of experimental and HPC-based computational methodologies. Since 2017–2018, these UCL modules have been successfully delivered to over 350 students—a cohort with a demographic of greater than 50% female. CompBioMed's experience with these two university modules has enabled us to distil our methodology into an educational template that can be delivered at other universities in Europe and worldwide. This educational approach to training enables new communities of practice to effectively engage with HPC and reveals a means by which to improve the underrepresentation of women in supercomputing.
Lewinella aurantiaca sp. nov., a carotenoid pigment-producing bacterium isolated from surface seawater
Authors: Kim Inhyup , Chhetri Geeta , Kim Jiyoun , Kang Minchung , Seo Taegun
Published: October 2020

A Gram-stain-negative, aerobic, rod-shaped, carotenoid-pigmented, motile-by-gliding bacterium, which was designated as SSH13T, was isolated from a surface seawater sample collected from Sehwa Beach in the Republic of Korea. Strain SSH13T was oxidase-negative, catalase-positive and grew at 2–37 °C (optimum, 30 °C), in the presence of 0.5–6% NaCl and within a pH range of pH 6–10 (optimum, pH 8). The novel isolate required NaCl for growth and grew optimally with approximately 2 % NaCl. Chemotaxonomic and morphological characteristics were consistent with members of the genus

Lewinella

. Furthermore, phylogenetic analysis based on 16S rRNA gene sequencing revealed that strain SSH13T was most closely related to the type strains of the genus

Lewinella

. Strain SSH13T had highest 16S rRNA gene sequence similarities to

Lewinella persica

DSM 23188T (95.3 %) and

Lewinella agarilytica

KCTC 12774T (95.0 %). The major fatty acids of SSH13T were summed feature 3 (C16 : 1
 ω7c and/or C16 : 1
 ω6c) and iso-C15 : 0. Strain SSH13T contained phosphatidylethanolamine as a major polar lipid. Menaquinone-7 was the predominant respiratory quinone. The average nucleotide identity values between strain SSH13T and

L. persica

T-3T and

L. agarilytica

SST-19T were 72.9 and 72.6 %, respectively. The DNA G+C content of the genomic DNA was 52.8 mol%. The present study aimed to determine the multiple-antibiotic resistance of the novel bacterium. Based on phylogenetic and phenotypic analyses, strain SSH13T is considered to represent a novel species of the genus

Lewinella

, for which the name Lewinella aurantiaca sp. nov. (type strain SSH13T=KACC 21167T=NBRC 113866T) is proposed.
Stay-at-home policy: is it a case of exception fallacy? An internet-based ecological study
Authors: Savaris Ricardo F. , Pumi Guilherme , Dalzochio Jovani , Kunst Rafael
Published: October 2020

Background

Countries with strict lockdown had a spike on the number of deaths. A recent mathematical model has suggested that staying at home did not play a dominant role in reducing COVID-19 transmission. Comparison between number of deaths and social mobility is difficult due to the non-stationary nature of the COVID-19 data.

Objective

To propose a novel approach to assess the association between staying at home values and the reduction/increase in the number of deaths due to COVID-19 in several regions around the world.

Methods

In this ecological study, data fromwww.google.com/covid19/mobility/, ourworldindata.org and covid.saude.gov.br were combined. Countries with >100 deaths and with a Healthcare Access and Quality Index of ≥67 were included. Data were preprocessed and analyzed using the difference between number of deaths/million between 2 regions and the difference between the percentage of staying at home. Analysis was performed using linear regression and residual analysis

Results

After preprocessing the data, 87 regions around the world were included, yielding 3,741 pairwise comparisons for linear regression analysis. Only 63 (1.6%) comparisons were significant.

Discussion

With our results, we were not able to explain if COVID-19 mortality is reduced by staying as home in ∼98% of the comparisons after epidemiological weeks 9 to 34.
Sustainable Production of the Biofueln-Butanol byRhodopseudomonas palustrisTIE-1
Authors: Bai W. , Ranaivoarisoa T. O. , Singh R. , Rengasamy K. , Bose A.
Published: October 2020

Anthropogenic carbon dioxide (CO2) release in the atmosphere from fossil fuel combustion has inspired scientists to study CO2to fuel conversion. Oxygenic phototrophs such as cyanobacteria have been used to produce biofuels using CO2. However, oxygen generation during oxygenic photosynthesis affects biofuel production efficiency. To producen-butanol (biofuel) from CO2, here we introduced ann-butanol biosynthesis pathway into an anoxygenic (non-oxygen evolving) photoautotroph,Rhodopseudomonas palustrisTIE-1 (TIE-1). Using different carbon, nitrogen, and electron sources, we achievedn-butanol production in wild-type TIE-1 and mutants lacking electron-consuming (nitrogen-fixing) or acetyl-CoA-consuming (polyhydroxybutyrate and glycogen synthesis) pathways. The mutant lacking the nitrogen-fixing pathway produced highestn-butanol. Coupled with novel hybrid bioelectrochemical platforms, this mutant producedn-butanol using CO2, solar panel-generated electricity, and light, with high electrical energy conversion efficiency. Overall, this approach showcases TIE-1 as an attractive microbial chassis for carbon-neutraln-butanol bioproduction using sustainable, renewable, and abundant resources.
Comparison between instrumental variable and mediation-based methods for reconstructing causal gene networks in yeast
Authors: Ludl Adriaan-Alexander , Michoel Tom
Published: October 2020

Causal gene networks model the flow of information within a cell. Reconstructing causal networks from omics data is challenging because correlation does not imply causation. When genomics and transcriptomics data from a segregating population are combined, genomic variants can be used to orient the direction of causality between gene expression traits. Instrumental variable methods use a local expression quantitative trait locus (eQTL) as a randomized instrument for a gene’s expression level, and assign target genes based on distal eQTL associations. Mediation-based methods additionally require that distal eQTL associations are mediated by the source gene. A detailed comparison between these methods has not yet been conducted, due to the lack of a standardized implementation of different methods, the limited sample size of most multi-omics datasets, and the absence of ground-truth networks for most organisms. Here we used Findr, a software package providing uniform implementations of instrumental variable, mediation, and coexpression-based methods, a recent dataset of 1,012 segregants from a cross between two budding yeast strains, and the YEASTRACT database of known transcriptional interactions to compare causal gene network inference methods. We found that causal inference methods result in a significant overlap with the ground-truth, whereas coexpression did not perform better than random. A subsampling analysis revealed that the performance of mediation saturates at large sample sizes, due to a loss of sensitivity when residual correlations become significant. Instrumental variable methods on the other hand contain false positive predictions, due to genomic linkage between eQTL instruments. Instrumental variable and mediation-based methods also have complementary roles for identifying causal genes underlying transcriptional hotspots. Instrumental variable methods correctly predictedSTB5targets for a hotspot centred on the transcription factorSTB5, whereas mediation failed due to Stb5p auto-regulating its own expression. Mediation suggests a new candidate gene,DNM1, for a hotspot on Chr XII, whereas instrumental variable methods could not distinguish between multiple genes located within the hotspot. In conclusion, causal inference from genomics and transcriptomics data is a powerful approach for reconstructing causal gene networks, which could be further improved by the development of methods to control for residual correlations in mediation analyses and genomic linkage and pleiotropic effects from transcriptional hotspots in instrumental variable analyses.
Auxin guides germ cell specification inArabidopsisanthers
Authors: Zheng Yafeng , Wang Donghui , Ye Sida , Chen Wenqian , Li Guilan , Xu Zhihong , Bai Shunong , Zhao Feng
Published: October 2020

Germ cells (GCs) transmit genetic information from one generation to the next. Unlike animal GCs, plant GCs are induced post-embryonically, forming locally from somatic cells. This induction is coordinated with organogenesis and might be guided by positional cues. In angiosperms, male GCs initiate from the internal layers at the four corners of the anther primordia and are gradually enclosed by parietal cell (PC) layers, leading to a concentric GC-PC pattern.1,2However, the underlying mechanism of GC initiation and GC-PC pattern formation is unclear. Auxin affects pattern formation3and anther development.4–11However, whether GC formation involves auxin remains unknown. We report that the auxin distribution in pre-meiotic anthers parallels GC initiation, forming a centripetal gradient between the outer primordial cells and the inner GCs. The auxin biosynthesis genesTRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS 1(TAA1) andTRYPTOPHAN AMINOTRANSFERASE RELATED 2(TAR2)5,12are responsible for this patterning and essential for GC specification.SPOROCYTELESS/NOZZLE(SPL/NZZ, a determinant for GC specification)13–15mediates the effect of auxin on GC specification, modulates auxin homeostasis, and maintains centripetal auxin patterning. Our results reveal that auxin is a key factor guiding GC specification inArabidopsisanthers.
Reducing SAR in 7T brain fMRI by circumventing fat suppression while removing the lipid signal through a parallel acquisition approach
Authors: Seginer Amir , Furman-Haran Edna , Goldberg Ilan , Schmidt Rita
Published: October 2020

Ultra-high-field functional magnetic resonance imaging (fMRI) offers the way to new insights while increasing the spatial and temporal resolution. However, a crucial concern in 7T human MRI is the increase in power deposition, supervised through the specific absorption rate (SAR). The SAR limitation can restrict the brain coverage or the minimal repetition time of fMRI experiments. fMRI is based on the well-known gradient-echo echo-planar imaging (GRE-EPI) sequence, which offers ultrafast acquisition. Commonly, the GRE-EPI sequence comprises two pulses: fat suppression and excitation. This work provides the means for a significant reduction in the SAR by circumventing the fat-suppression pulse. Without this fat-suppression, however, lipid signal can result in artifacts due to the chemical shift between the lipid and water signals. Our approach exploits a reconstruction similar to the simultaneous-multi-slice (SMS) method to separate the lipid and water images, thus avoiding undesired lipid artifacts in brain images. The lipid-water separation is based on the known spatial shift of the lipid signal, which can be detected by the multi-channel coils sensitivity profiles. Our study shows robust human imaging, offering greater flexibility to reduce the SAR, shorten the repetition time or increase the volume coverage with substantial benefit for brain functional studies.
Tau pathology spreads between anatomically-connected regions of the brain and is modulated by a LRRK2 mutation
Authors: Henderson Michael X. , Cornblath Eli J. , Li Howard L. , Changolkar Lakshmi , Zhang Bin , Brown Hannah J. , Gathagan Ronald J. , Olufemi Modupe F. , Bassett Danielle S. , Trojanowski John Q. , Lee Virginia M.Y.
Published: October 2020

Tau pathology is a diagnostic feature of Alzheimer’s disease (AD) but is also a prominent feature of Parkinson’s disease (PD), including genetic forms of PD with mutations in leucine-rich repeat kinase 2 (LRRK2). In both diseases, tau pathology is progressive and correlates with cognitive decline. Neuropathological staging studies in humans and mouse models have suggested that tau spreads through the brain, but it is unclear how neuroanatomical connections, spatial proximity, and regional vulnerability contribute to pathology spread. Further, it is unknown how mutations in theLRRK2gene may modulate susceptibility to tau pathology’s initiation or spread. In this study, we used seed-based models of tauopathy to capture spatiotemporal patterns of pathology in mice. Following the injection of AD brain-derived tau into the brains of non-transgenic mice, tau pathology spreads progressively through the brain in a spatiotemporal pattern that is well-explained by anatomical connectivity. We validated and compared network models based on diffusion along anatomical connections to predict tau spread, estimate regional vulnerability to tau pathology, and investigate gene expression patterns related to regional vulnerability. We further investigated tau pathology spread in mice harboring a mutation in LRRK2 and found that while tau pathology spread is still constrained by anatomical connectivity, it spreads preferentially in a retrograde direction to regions that are otherwise resilient in wildtype mice. This study provides a quantitative demonstration that tau pathology spreads along anatomical connections, explores the kinetics of this spread, and provides a platform for investigating the effect of genetic risk factors and treatments on the progression of tauopathies.
Cross-modal orienting of exogenous attention results in visual-cortical facilitation, not suppression
Authors: Keefe Jonathan M. , Pokta Emilia , Störmer Viola S.
Published: October 2020

Attention may be oriented exogenously (i.e., involuntarily) to the location of salient stimuli, resulting in improved perception. However, it is unknown whether exogenous attention improves perception by facilitating processing of attended information, suppressing processing of unattended information, or both. To test this question, we measured behavioral performance and cue-elicited neural changes in the electroencephalogram as participants (N = 19) performed a task in which a spatially non-predictive auditory cue preceded a visual target. Critically, this cue was either presented at a peripheral target location or from the center of the screen, allowing us to isolate spatially specific attentional activity. We find that both behavior and attention-mediated changes in visual-cortical activity are enhanced at the location of a cue prior to the onset of a target, but that behavior and neural activity at an unattended target location are equivalent to that following a central cue that does not direct attention (i.e., baseline). These results suggest that exogenous attention operates solely via facilitation of information at an attended location.
Modelling selection response in plant breeding programs using crop models as mechanistic gene-to-phenotype (CGM-G2P) multi-trait link functions
Authors: Cooper M , Powell O , Voss-Fels KP , Messina CD , Gho C , Podlich DW , Technow F , Chapman SC , Beveridge CA , Ortiz-Barientos D , Hammer GL
Published: October 2020

Plant breeding programs are designed and operated over multiple cycles to systematically change the genetic makeup of plants to achieve improved trait performance for a Target Population of Environments (TPE). Within each cycle, selection applied to the standing genetic variation within a structured reference population of genotypes (RPG) is the primary mechanism by which breeding programs make the desired genetic changes. Selection operates to change the frequencies of the alleles of the genes controlling trait variation within the RPG. The structure of the RPG and the TPE has important implications for the design of optimal breeding strategies. The breeder’s equation, together with the quantitative genetic theory behind the equation, informs many of the principles for design of breeding programs. The breeder’s equation can take many forms depending on the details of the breeding strategy. Through the genetic changes achieved by selection, the cultivated varieties of crops (cultivars) are improved for use in agriculture. From a breeding perspective, selection for specific trait combinations requires a quantitative link between the effects of the alleles of the genes impacted by selection and the trait phenotypes of plants and their breeding value. This gene-to-phenotype link function provides the G2P map for one to many traits. For complex traits controlled by many genes, the infinitesimal model for trait genetic variation is the dominant G2P model of quantitative genetics. Here we consider motivations and potential benefits of using the hierarchical structure of crop models as CGM-G2P trait link functions in combination with the infinitesimal model for the design and optimisation of selection in breeding programs.
FastMLST: A multi-core tool for multilocus sequence typing of draft genome assemblies
Authors: Guerrero-Araya Enzo , Muñoz Marina , Rodríguez César , Paredes-Sabja Daniel
Published: October 2020

Multilocus Sequence Typing (MLST) is a precise microbial typing approach at the intra-species level for epidemiological and evolutionary purposes. It operates by assigning a sequence type (ST) identifier to each specimen, based on a combination of allelic sequences obtained for multiple housekeeping genes included in a defined scheme. The use of MLST has multiplied due to the availability of large numbers of genomic sequences and epidemiological data in public repositories. However, data processing speed has become problematic due to datasets’ massive size. Here, we present FastMLST, a tool that is designed to perform PubMLST searches using BLASTn and a divide-and-conquer approach. Compared with mlst, CGE/MLST, MLSTar, and PubMLST, FastMLST takes advantage of current multi-core computers to simultaneously type thousands of genome assemblies in minutes, reducing processing times by at least 4-fold and with more than 99.95% consistency.

Availability and Implementation

The source code, installation instructions and documentation are available athttps://github.com/EnzoAndree/FastMLST
Dynamic visualisation of million-tip trees: the OneZoom project
Authors: Wong Yan , Rosindell James
Published: October 2020

The complete tree of life is now available, but methods to visualise it are still needed to meet needs in research, teaching and science communication. Dynamic visualisation of million-tip trees requires many challenges in data synthesis, data handling and computer graphics to be overcome.

Our approach is to automate data processing, synthesise data from a wide range of available sources, then to feed these data to a client-side visualisation engine in parts. We develop a way to store the whole tree topology locally in a highly compressed form, then dynamically populate metadata such as text and images as the user explores.

The result is a seamless and smooth way to explore the complete tree of life, including images and metadata, even on relatively old mobile devices.

The underlying methods developed have applications that transcend tree of life visualisation. For the whole complete tree, we describe automated ID mappings between well known resources without resorting to taxonomic name resolution, automated methods to collate sets of public domain representative images for higher taxa, and an index to measure public interest of individual species.

The visualisation layout and the client user interface are both abstracted components of the codebase enabling other zoomable tree layouts to be swapped in, and supporting multiple applications including exhibition kiosks and digital art.

After ten years of work, our tree of life explorer is now broadly complete, it has attracted nearly 1.5 million online users, and is backed by a novel long-term sustainability plan. We conclude our description of the OneZoom project by suggesting the next challenges that need to be solved in this field: extinct species and guided tours around the tree.
3D test sample for the calibration and quality control of super-resolution and confocal microscopes
Authors: van der Wee Ernest B. , Fokkema Jantina , Kennedy Chris L. , del Pozo Marc , de Winter D.A. Matthijs , Speets Peter N.A. , Gerritsen Hans C. , van Blaaderen Alfons
Published: October 2020

A multitude of samples is required to monitor and optimize the quality and reliability of quantitative measurements of (super-resolution) light microscopes. Here, we present a single sample to calibrate microscopes, align their laser beams and measure their point spread function (PSF) in 3D. The sample is composed of a refractive index matched colloidal crystal of silica beads with fluorescent and gold cores. The microscope can be calibrated in three dimensions using the periodicity of the crystal; the alignment of the laser beams can be checked using the reflection of the gold cores; and the PSF can be measured at multiple positions and depths using the fluorescent cores. It is demonstrated how this sample can be used to visualize and improve the quality of confocal and super-resolution images. The sample is adjustable to meet the requirements of different NA objectives and microscopy techniques and additionally can be used to evaluate refractive index mismatches as a function of depth quantitatively.
A structure-function substrate of memory for spatial configurations in medial and lateral temporal cortices
Authors: Tavakol Shahin , Li Qiongling , Royer Jessica , Vos de Wael Reinder , Larivière Sara , Lowe Alex , Paquola Casey , Jefferies Elizabeth , Hartley Tom , Bernasconi Andrea , Bernasconi Neda , Smallwood Jonathan , Bohbot Veronique , Caciagli Lorenzo , Bernhardt Boris
Published: October 2020

Abstract

Prior research has shown that structures of the mesiotemporal lobe, particularly the hippocampal-parahippocampal complex, are engaged in different forms of spatial cognition. Here, we developed a new paradigm, the Conformational Shift Spatial task (CSST), which examines the ability to encode and retrieve spatial relations between three unrelated items. This task is short, uses symbolic cues, and incorporates two difficulty levels and can be administered inside and outside the scanner. A cohort of 48 healthy young adults underwent the CSST, together with a set of validated behavioral measures and multimodal magnetic resonance imaging (MRI). Interindividual differences in CSST performance correlated with scores on an established spatial memory paradigm, but neither with episodic memory nor pattern separation performance, highlighting the specificity of the new measure. Analyzing high resolution structural MRI data, individuals with better spatial memory showed thicker medial as well as lateral temporal cortices. Functional relevance of these findings was supported by task-based functional MRI analysis in the same participants andad hocmeta-analysis. Exploratory resting-state functional MRI analyses centered on clusters of morphological effects revealed additional modulation of intrinsic network integration, particularly between lateral and medial temporal structures. Our work presents a novel spatial memory paradigm and supports an integrated structure-function substrate in the human temporal lobe. Task paradigms are programmed in python and made open access.
Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters
Authors: Piepenbrink Michael S. , Park Jun-Gyu , Oladunni Fatai S. , Deshpande Ashlesha , Basu Madhubanti , Sarkar Sanghita , Loos Andreas , Woo Jennifer , Lovalenti Phillip , Sloan Derek , Ye Chengjin , Chiem Kevin , Erdmann Nathaniel B. , Goepfert Paul A. , Truong Vu L. , Walter Mark R. , Martinez-Sobrido Luis , Kobie James J.
Published: October 2020

SARS-CoV-2 infection results in viral burden in the upper and lower respiratory tract, enabling transmission and often leading to substantial lung pathology. Delivering the antiviral treatment directly to the lungs has the potential to improve lung bioavailability and dosing efficiency. As the SARS-CoV-2 Receptor Binding Domain (RBD) of the Spike (S) is increasingly deemed to be a clinically validated target, RBD-specific B cells were isolated from patients following SARS-CoV-2 infection to derive a panel of fully human monoclonal antibodies (hmAbs) that potently neutralize SARS-CoV-2. The most potent hmAb, 1212C2 was derived from an IgM memory B cell, has high affinity for SARS-CoV-2 RBD which enables its direct inhibition of RBD binding to ACE2. The 1212C2 hmAb exhibits in vivo prophylactic and therapeutic activity against SARS-CoV-2 in hamsters when delivered intraperitoneally, achieving a meaningful reduction in upper and lower respiratory viral burden and lung pathology. Furthermore, liquid nebulized inhale treatment of SARS-CoV-2 infected hamsters with as low as 0.6 mg/kg of inhaled dose, corresponding to approximately 0.03 mg/kg of lung deposited dose, mediated a reduction in respiratory viral burden that is below the detection limit, and mitigated lung pathology. The therapeutic efficacy achieved at an exceedingly low-dose of inhaled 1212C2 supports the rationale for local lung delivery and achieving dose-sparing benefits as compared to the conventional parenteral route of administration. Taken together, these results warrant an accelerated clinical development of 1212C2 hmAb formulated and delivered via inhalation for the prevention and treatment of SARS-CoV-2 infection.
The claustrum-medial prefrontal cortex network controls attentional set-shifting
Authors: Fodoulian Leon , Gschwend Olivier , Huber Chieko , Mutel Sophie , Salazar Rodrigo F. , Leone Roberta , Renfer Jean-Rodolphe , Ekundayo Kazadi , Rodriguez Ivan , Carleton Alan
Published: October 2020

In various mental disorders, dysfunction of the prefrontal cortex contributes to cognitive deficits. Here we studied how the claustrum (CLA), a nucleus sharing reciprocal connections with the cortex, may participate in these cognitive impairments. We show that specific ensembles of CLA and of medial prefrontal cortex (mPFC) neurons are activated during a task requiring cognitive control such as attentional set-shifting, i.e. the ability to shift attention towards newly relevant stimulus-reward associations while disengaging from irrelevant ones. CLA neurons exert a direct excitatory input on mPFC pyramidal cells, and chemogenetic inhibition of CLA neurons suppresses the formation of specific mPFC assemblies during attentional set-shifting. Furthermore, impairing the recruitment of specific CLA assemblies through opto/chemogenetic manipulations prevents attentional set-shifting. In conclusion, we propose that the CLA controls the reorganization of mPFC ensembles to enable attentional set-shifting, emphasizing a potential role of the CLA-mPFC network in attentional dysfunctions.
Connexin 43 confers chemoresistance through activating PI3K
Authors: Pridham Kevin J , Shah Farah , Sheng Kevin L , Guo Sujuan , Liu Min , Kanabur Pratik , Lamouille Samy , Lewis Gabrielle , Morales Marc , Jourdan Jane , Grek Christina L , Ghatnekar Gautam G , Varghese Robin , Kelly Deborah F , Gourdie Robert G , Sheng Zhi
Published: October 2020

Circumventing chemoresistance is crucial for effectively treating glioblastoma due to limited therapeutic options. The gap junction protein connexin 43 (Cx43) renders glioblastoma resistant to the frontline chemotherapy temozolomide; however, targeting Cx43 is difficult because mechanisms underlying Cx43-mediated chemoresistance remain elusive. Here we show that Cx43, but not other connexins, is highly expressed in glioblastoma and strongly correlates with poor patient prognosis and chemoresistance, making Cx43 the prime therapeutic target among all connexins. The intracellular carboxyl terminus of Cx43 binds to phosphatidylinositol 3-kinase (PI3K) catalytic subunit β (PIK3CB, also called PI3Kβ or p110β), thereby activating PI3K signaling independent of Cx43-channels and subsequently inducing temozolomide resistance. A combination of αCT1, a Cx43-targeting peptide inhibitor, and PIK3CB-selective inhibitors restores temozolomide sensitivityin vitroandin vivo. This study not only reveals novel mechanistic insights into chemoresistance in glioblastoma, but also demonstrates that targeting Cx43 and PIK3CB/p110β is an effective approach for overcoming chemoresistance.
Synthetic lethality between TP53 and ENDOD1
Authors: Tang Zizhi , Zeng Ming , Wang Xiaojun , Guo Chang , Yue Peng , Zhang Xiaohu , Lou Huiqiang , Chen Jun , Mu Dezhi , Kong Daochun , Carr Antony M. , Liu Cong
Published: October 2020

The atypical nuclease ENDOD1 functions with cGAS-STING in innate immunity. Here we identify a previously uncharacterized ENDOD1 function in DNA repair. ENDOD1 is enriched in the nucleus following H2O2treatment andENDOD1-/-cells show increased PARP chromatin-association. Loss of ENDOD1 function is synthetic lethal with homologous recombination defects, with affected cells accumulating DNA double strand breaks. Remarkably, we also uncover an additional synthetic lethality between ENDOD1 and p53. ENDOD1 depletion inTP53mutated tumour cells, or p53 depletion inENDOD1-/-cells, results in rapid single stranded DNA accumulation and cell death. BecauseTP53is mutated in ∼50% of tumours, ENDOD1 has potential as a wide-spectrum target for synthetic lethal treatments. To support this we demonstrate that systemic knockdown of mouseEndoD1is well tolerated and whole-animal siRNA against humanENDOD1restrainsTP53mutated tumour progression in xenograft models. These data identify ENDOD1 as a potential cancer-specific target for SL drug discovery.
Cell size homeostasis is maintained by a circuitry involving a CDK4-determined target size that programs the cell size-dependent activation of p38
Authors: Tan Ceryl , Ginzberg Miriam B. , Webster Rachel , Iyengar Seshu , Liu Shixuan , Concannon John , Wang Yuan , Auld Douglas S. , Jenkins Jeremy L. , Rost Hannes , Hilfinger Andreas , Derry W. Brent , Patel Nish , Kafri Ran
Published: October 2020

While molecules that promote the growth of animal cells have been identified, the following question remains: How are growth promoting pathways regulated to specify a characteristic size for each of the different cell types? In 1975, Hartwell and Nurse suggested that in eukaryotes, cell size is determined by size checkpoints – mechanisms that restrict cell cycle progression from cells that aresmallerthan theirtarget size. Curiously, such checkpoint mechanisms imply a conceptual distinction between a cell’sactualsize and cell’stargetsize. In the present study, we materialize this conceptual distinction by describing experimental assays that discriminately quantify a cell’s target size value. With these assays, we show that a cell’s size and target size are distinct phenotypes that are subject to different upstream regulators. While mTORC1 promotes growth in cell size, our data suggests that a cell’s target size value is regulated by other pathways including FGFR3, ROCK2, and CDK4. For example, while rapamycin (an mTORC1 inhibitor) decreases cell size, rapamycin does not change the target size that is required for the G1/S transition. The CDK4/Rb pathway has been previously proposed as a putative regulator of target size. Yet, in lacking experimental means that discriminate perturbations of cell growth from perturbations that reprogram target size, such claims on target size were not validated. To investigate the functions of CDK4 in target size determination, we used genetic and chemical means to ‘dial’ higher and lower levels of CDK4 activity. These measurements identified functions of CDK4 on target size that are distinct from other G1 CDKs. UsingC. elegans, we further demonstrate that these influences of CDK4 on size determination functionin vivo. Finally, we propose a model whereby mTORC1, p38, and CDK4 cooperate in a manner that is analogous to the function of a thermostat. While mTORC1 promotes cellular growth as prompted by p38, CDK4 is analogous to the thermostatdialthat sets the critical target size associated with cell size homeostasis.
Synergistic anticancer effect of plasma-activated infusion and salinomycin by targeting autophagy and mitochondrial morphology
Authors: Ando Takashi , Suzuki-Karasaki Manami , Suzuki-Karasaki Miki , Ichikawa Jiro , Ochiai Toyoko , Yoshida Yukihiro , Haro Hirotaka , Suzuki-Karasaki Yoshihiro
Published: October 2020

Non-thermal atmospheric plasma (NTAP)-activated liquids have emerged as new promising anticancer agents because they preferentially injure malignant cells. Here, we report plasma-activated infusion (PAI) as a novel NTAP-based anti-neoplastic agent. PAI was prepared by irradiating helium NTAP to form a clinically approved infusion fluid. PAI dose-dependently killed malignant melanoma and osteosarcoma cell lines showed much lower cytotoxic effects on dermal and lung fibroblasts. We found that PAI and salinomycin (Sal), an emerging anti-cancer stem cell agent, mutually operated as adjuvants. Combined administration of PAI and Sal was much more effective than single agent application in reducing the growth and lung metastasis of osteosarcoma allografts with minimal adverse effects. Mechanistically, PAI explicitly induced necroptosis and increased the phosphorylation of receptor-interacting protein 1/3 in a rapid and transient manner. PAI also suppressed the ambient autophagic flux by activating the mammalian target of rapamycin pathway. PAI increased the phosphorylation of Raptor, Rictor, and p70-S6 kinase, along with decreased LC3-I/II expression. In contrast, Sal promoted autophagy. Moreover, Sal exacerbated the mitochondrial network collapse caused by PAI, resulting in aberrant clustering of fragmented mitochondrial in a tumor-specific manner. Our findings suggest that combined administration of PAI and Sal is a promising approach for treating these apoptosis-resistant cancers.
Collective nuclear behavior shapes bilateral nuclear symmetry for subsequent left-right asymmetric morphogenesis inDrosophila
Authors: Shin Dongsun , Nakamura Mitsutoshi , Morishita Yoshitaka , Eiraku Mototsugu , Yamakawa Tomoko , Sasamura Takeshi , Akiyama Masakazu , Inaki Mikiko , Matsuno Kenji
Published: October 2020

Proper organ development often requires nuclei to move to a specific position within the cell. To determine how nuclear positioning affects left-right (LR) development in theDrosophilaanterior midgut (AMG), we developed a surface-modeling method to measure and describe nuclear behavior at stages 13-14, captured in three-dimensional time-lapse movies. We describe the distinctive positioning and a novelcollective nuclear behaviorby which nuclei align LR-symmetrically along the anterior-posterior axis in the visceral muscles that overlie the midgut and are responsible for this organ’s LR-asymmetric development. Wnt4 signaling is crucial for the collective behavior and proper positioning of the nuclei, as are myosin II and LINC complex, without which the nuclei failed to align LR-symmetrically. The LR-symmetric positioning of the nuclei is important for the subsequent LR-asymmetric development of the AMG. We propose that the bilaterally symmetrical positioning of these nuclei may be mechanically coupled with subsequent LR-asymmetric morphogenesis.
Identification of silkworm hemocyte subsets and analysis of their response to BmNPV infection based on single-cell RNA sequencing
Authors: Feng Min , Xia Junming , Fei Shigang , Wang Xiong , Zhou Yaohong , Wang Pengwei , Swevers Luc , Sun Jingchen
Published: October 2020

A wide range of hemocyte types exist in insects but a full definition of the different subclasses is not yet established. The current knowledge of the classification of silkworm hemocytes mainly comes from morphology rather than specific markers, so our understanding of the detailed classification, hemocyte lineage and functions of silkworm hemocytes is very incomplete.Bombyx morinucleopolyhedrovirus (BmNPV) is a representative member of the baculoviruses, which are a major pathogens that specifically infects silkworms and cause serious loss in sericulture industry. Here, we performed single-cell RNA sequencing (scRNA-seq) of silkworm hemocytes in BmNPV and mock-infected larvae to comprehensively identify silkworm hemocyte subsets and determined specific molecular and cellular characteristics in each hemocyte subset before and after viral infection. A total of 19 cell clusters and their potential marker genes were identified in silkworm hemocytes. Among these hemocyte clusters, clusters 0, 1, 2, 5 and 9 might be granulocytes (GR); clusters 14 and 17 were predicted as plasmatocytes (PL); cluster 18 was tentatively identified as spherulocytes (SP); and clusters 7 and 11 could possibly correspond to oenocytoids (OE). In addition, all of the hemocyte clusters were infected by BmNPV and some infected cells carried high viral-load in silkworm larvae at 3 day post infection (dpi). Interestingly, BmNPV infection can cause severe and diverse changes in gene expression in hemocytes. Cells belonging to the infection group mainly located at the early stage of the pseudotime trajectories. Furthermore, we found that BmNPV infection suppresses the immune response in the major hemocyte types. In summary, our scRNA-seq analysis revealed the diversity of silkworm hemocytes and provided a rich resource of gene expression profiles for a systems-level understanding of their functions in the uninfected condition and as a response to BmNPV.