bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival in ANCA-Associated Vasculitides in a Peruvian Center
Authors: Pimentel-Quiroz Victor R. , Sánchez-Torres Alfredo , Acevedo-Vásquez Eduardo , Gamboa-Cárdenas Rocío V. , Reátegui-Sokolova Cristina , Medina-Chinchón Mariela , Zevallos Francisco , Noriega-Zapata Erika , Alfaro-Lozano José , Cucho-Venegas Jorge M. , Sánchez-Schwartz César , Rodríguez-Bellido Zoila , Perich-Campos Risto , Pastor-Asurza César A. , Alarcón Graciela S. , Ugarte-Gil Manuel F.
Published: August 2020

Aim

The aim of this study was to identify demographic and clinical risk factors for mortality in patients with antineutrophil cytoplasmic antibodies–associated vasculitides (AAVs) in a Peruvian tertiary referral hospital.

Methods

Medical records of patients with AAV according to classification criteria or diagnosed by an experienced rheumatologist, covering the period between January 1990 and December 2018, were reviewed. Granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited vasculitis were included. Potential predictors of mortality were demographic factors, clinical manifestations, antineutrophil cytoplasmic antibodies status, diagnosis, disease categorization, the 2009 Five Factor Score (FFS), and treatment. Cox regression models were used to determine the risk factors for mortality. Univariable and multivariable analyses using a backward selection method were performed.

Results

One hundred ninety-six patients were included; female-to-male ratio was 2:1. The median (interquartile range) age at diagnosis and follow-up were 60.0 (51.0–68.0) and 4.8 (1.3–11.6) years, respectively. One hundred forty-eight patients (75.5%) had microscopic polyangiitis, 37 (18.9%) granulomatosis with polyangiitis, 5 (2.6%) eosinophilic granulomatosis with polyangiitis, and 6 (3.0%) renal-limited vasculitis. Overall survival rates at 1, 5, and 10 years were 83.4%, 68.2%, and 51.7%, respectively. Ocular involvement was protective (hazards ratio [HR], 0.36; 95% confidence interval [CI], 0.17–0.74; p = 0.006), whereas renal (HR, 2.09; 95% CI, 1.33–3.28; p = 0.001) and lung involvement (HR, 2.07; 95% CI, 1.31–3.28; p = 0.002) and the 2009 FFSs were predictive of mortality (2009 FFS = 1: HR, 2.46; 95% CI, 1.50–4.04; p < 0.001; 2009 FFS = 2: HR, 3.07; 95% CI, 1.54–6.10; p = 0.001; 2009 FFS = 3: HR, 13.29; 95% CI, 3.69–47.88; p < 0.001).

Conclusions

Ocular involvement was protective, whereas 2009 FFS ≥ 1 and renal and lung involvement were predictive factors of mortality in Peruvian AAV patients.
Ex Vivo Resection and Autotransplantation for Conventionally Unresectable Tumors – An 11-year Single Center Experience
Authors: Kato Tomoaki , Hwang Regina , Liou Peter , Weiner Joshua , Griesemer Adam , Samstein Benjamin , Halazun Karim , Mathur Abhishek , Schwartz Gary , Cherqui Daniel , Emond Jean
Published: August 2020

Background and Aims:

Ex vivo surgery may provide a chance at R0 resection for conventionally unresectable tumors. However, long-term outcomes have not been well documented. In this study, we analyze our 11-year outcomes to define its role.

Study Design:

We retrospectively analyzed 46 consecutive patients who underwent ex vivo surgery at our institution 2008–2019.

Results:

The types of tumors were: carcinoma (n = 20), sarcoma (n = 20) and benign to low grade tumor (n = 6). The type of ex vivo surgery was chosen based on tumor location and vascular involvement. The most commonly performed procedure was ex vivo hepatectomy (n = 18), followed by ex vivo resection and intestinal autotransplantation (n = 12), ex vivo Whipple procedure and liver autotransplantation (n = 8) and multivisceral ex vivo procedure (n = 7). Twenty-three patients (50%) are currently alive with median follow-up of 4.0-years (11 months–11.8 years). The overall survival was 70%/59%/52%, at 1-/3-/5-years, respectively. Patient survival for benign to low grade tumors, sarcoma, and carcinoma was 100%/100%/100%, 65%/60%/50%, and 65%/45%/40%, at 1-/3-/5-years, respectively. Ninety-one percent patients had R0 resection, and 57% had no recurrence to date with median follow-up of 3.1-years. Two patients (4.3%) died within 30 days due to sepsis and gastroduodenal artety (GDA) stump blowout. Two additional patients died between 30 and 90 days due to sepsis. Perioperative mortality in the last 23 consecutive cases was limited to 1 patient who died of sepsis between 30 and 90 days.

Conclusions:

For a selected group of patients with conventionally unresectable tumors, ex vivo surgery can offer effective surgical removal with a reasonably low perioperative mortality at experienced centers.
3D Versus 4K Display System – Influence of “State-of-the-art”-Display Technique on Surgical Performance (IDOSP-study) in Minimally Invasive Surgery
Authors: Wahba Roger , Datta Rabi , Bußhoff Jana , Bruns Thomas , Hedergott Andrea , Gietzelt Caroline , Dieplinger Georg , Fuchs Hans , Morgenstern Bernd , Möller Desdemona , Hellmich Martin , Bruns Christiane J. , Stippel Dirk L.
Published: August 2020

Objective:

To evaluate if “state-of-the-art” 3D- versus 4K-display techniques could influence surgical performance.

Background:

High quality minimally invasive surgery is challenging. Therefore excellent vision is crucial. 3D display technique (3D) and 2D-4K technique (4K) are designed to facilitate surgical performance, either due to spatial resolution (3D) or due to very high resolution (4K).

Methods:

In randomized cross-over trial the surgical performance of medical students (MS), non-board certified surgeons (NBC), and board certified surgeons (BC) was compared using 3D versus 4K display technique at a minimally invasive training Parkour.

Results:

One hundred twenty-eight participants were included (February 2018 through October 2019, 49 MS, 39 NBC, 40 BC). The overall Parkour time (s) 3D versus 4K was 712.5 s ± 17.5 s versus 999.5 s ± 25.1 s (P < 0.001) for all levels of experience. It was (3D vs 4K) for MS (30 tasks) 555.4 s ± 28.9 s versus 858.7 s ± 41.6 s, (P < 0.0001), for NBC (42 tasks) 935.9 s ± 31.5 s versus 1274.1 s ± 45.1 s (P =< 0.001) and for BC (42 task) 646.3 s ± 30.9 s versus 865.7 s ± 43.7 s (P < 0.001). The overall number of mistakes was (3D vs 4K) 10.0 ± 0.5 versus 13.3 ± 0.7 (P < 0.001), for MS 8.9 ± 0.9 versus 13.1 ± 1.1 (P < 0.001), for NBC 12.45 ± 1.0 versus 16.7 ± 1.2 (P < 0.001) and for BC 8.8 ± 1.0 versus 10.0 ± 1.2 (P = 0.18). MS, BC, and NBC showed shorter performance time in 100% of the task with 3D (significantly in 6/7 tasks). For number of mistakes the effect was less pronounced for more experienced surgeons. The National Aeronautics and Space Administration-task load index was lower with 3D.

Conclusion:

3D laparoscopic display technique optimizes surgical performance compared to the 4K technique. Surgeons benefit from the improved visualization regardless of their individual surgical expertise.
Self-organized cytoskeletal alignment duringDrosophilamesoderm invagination
Authors: Martin Adam C.
Published: August 2020

During tissue morphogenesis, mechanical forces are propagated across tissues, resulting in tissue shape changes. These forces in turn can influence cell behaviour, leading to a feedback process that can be described as self-organizing. Here, I discuss cytoskeletal self-organization and point to evidence that suggests its role in directing force during morphogenesis. DuringDrosophilamesoderm invagination, the shape of the region of cells that initiates constriction creates a mechanical pattern that in turn aligns the cytoskeleton with the axis of greatest resistance to contraction. The wild-type direction of the force controls the shape and orientation of the invaginating mesoderm. Given the ability of the actomyosin cytoskeleton to self-organize, these types of feedback mechanisms are likely to play important roles in a range of different morphogenetic events.

This article is part of the discussion meeting issue ‘Contemporary morphogenesis'.
Cell intercalation in a simple epithelium
Authors: Rauzi Matteo
Published: August 2020

Cell intercalation is a key topological transformation driving tissue morphogenesis, homeostasis and diseases such as cancer cell invasion. In recent years, much work has been undertaken to better elucidate the fundamental mechanisms controlling intercalation. Cells often use protrusions to propel themselves in between cell neighbours, resulting in topology changes. Nevertheless, in simple epithelial tissues, formed by a single layer of densely packed prism-shaped cells, topology change takes place in an astonishing fashion: cells exchange neighbours medio-laterally by conserving their apical–basal architecture and by maintaining an intact epithelial layer. Medio-lateral cell intercalation in simple epithelia is thus an exemplary case of both robustness and plasticity. Interestingly, in simple epithelia, cells use a combinatory set of mechanisms to ensure a topological transformation at the apical and basal sides.

This article is part of the discussion meeting issue ‘Contemporary morphogenesis’.
Arf6 determines tissue architecture by stabilizing intercellular adhesion
Authors: Greig Joshua , Bulgakova Natalia A.
Published: August 2020

Correct cell shape is indispensable for tissue architecture, with cell shape being determined by cortical actin and surface adhesion. The role of adhesion in remodelling tissue is to counteract the deformation of cells by force, resulting from actomyosin contractility, and to maintain tissue integrity. The dynamics of this adhesion are critical to the processes of cell shape formation and maintenance. Here, we show that the trafficking molecule Arf6 has a direct impact on cell elongation, by acting to stabilize E-cadherin-based adhesion complexes at the cell surface, in addition to its canonical role in endocytosis. We demonstrate that these functions of Arf6 are dependent on the molecule Flotillin1, which recruits Arf6 to the plasma membrane. Our data suggest that Arf6 and Flotillin1 operate in a pathway distinct from clathrin-mediated endocytosis. Altogether, we demonstrate that Arf6- and Flotillin1-dependent regulation of the dynamics of cell adhesion contribute to moulding tissuein vivo.

This article is part of the discussion meeting issue ‘Contemporary morphogenesis’.
Microbially-mediated pretreatment of aerated oil and gas produced water by addition of phosphorous or activated sludge
Authors: Honeyman Alexander S. , Nicholas Emily R. , Cath Tzahi Y. , Spear John R.
Published: August 2020

Produced Water (PW) from oil and gas (O&G) producing wells is a unique source of water in water-stressed regions. Microbiota within O&G formations have been well-studied on site/in-situ, but few applied works have considered their role in the treatment of PW in engineered water treatment systems. Herein, we operated a simple aeration/mixing bench-scale bioreactor fed with produced water under three conditions: 1) PW alone (control; hereafter referred to as ‘baseline’), 2) phosphorous dosed daily as KH2PO4, and 3) activated sludge (AS) dosed daily from a sequence batch membrane bioreactor (SB-MBR). Aerated and mixed PW alone (baseline) was able to attenuate PW chemistry with removal of soluble chemical oxygen demand (sCOD) and ammonia by 27.6% and 17.8%, respectively. Further KH2PO4and AS additions improved water treatment efficiency markedly; in the KH2PO4addition reactor, sCOD and ammonia were reduced by 50.0% and 61.5%, respectively, and in the AS addition reactor by 52.5% and 59.2%, respectively. Microbial consortia determined via 16S rRNA gene amplicons differ in composition between raw PW and all reactors; order Kiloniellales was most common in raw PW while orders Rhodobacterales, Pseudomonadales, and Caulobacterales were most abundant amongst AS, KH2PO4, and baseline conditions, respectively. Several different microbial consortia are capable of treating raw PW which suggests that functional redundancy amongst microbiota in engineered treatment systems may be underappreciated. With simple addition of phosphorous and/or activated sludge to PW as part of a treatment strategy, a higher quality water can then be subjected to conventional treatment and/or local reuse.

Importance

Multiple microbiological communities are capable of treating O&G PW in a simple, applied, engineered setting. The broad possibility of PW treatment by multiple different microbial consortia elucidates the potential for easy, effective, water reuse processes in the hydraulically-stressed arid west as well as any region generating PW from O&G operations.
Quarantine and testing strategies in contact tracing for SARS-CoV-2
Authors: Quilty Billy J , Clifford Samuel , Flasche Stefan , Kucharski Adam J ,   CMMID COVID-19 Working Group, Edmunds W John
Published: August 2020

Previous work has indicated that contact tracing and isolation of index case and quarantine of potential secondary cases can, in concert with physical distancing measures, be an effective strategy for reducing transmission of SARS-CoV-2 (1). Currently, contacts traced manually through the NHS Test and Trace scheme in the UK are asked to self-isolate for 14 days from the day they were exposed to the index case, which represents the upper bound for the incubation period (2). However, following previous work on screening strategies for air travellers (3,4) it may be possible that this quarantine period could be reduced if combined with PCR testing. Adapting the simulation model for contact tracing, we find that quarantine periods of at least 10 days combined with a PCR test on day 9 may largely emulate the results from a 14-day quarantine period in terms of the averted transmission potential from secondary cases (72% (95%UI: 3%, 100%) vs 75% (4%, 100%), respectively). These results assume the delays from testing index cases’ and tracing their contacts are minimised (no longer than 4.5 days on average). If secondary cases are traced and quarantined 1 day earlier on average, shorter quarantine periods of 8 days with a test on day 7 (76% (7%, 100%)) approach parity with the 14 day quarantine period with a 1 day longer delay to the index cases’ test. However, the risk of false-negative PCR tests early in a traced case’s infectious period likely prevents the use of testing to reduce quarantine periods further than this, and testing immediately upon tracing, with release if negative, will avert just 17% of transmission potential on average. In conclusion, the use of PCR testing is an effective strategy for reducing quarantine periods for secondary cases, while still reducing transmission of SARS-CoV-2, especially if delays in the test and trace system can be reduced, and may improve quarantine compliance rates.
Impact of population density on the Covid-19 infected and mortality rates in India
Authors: Bhadra Arunava , Mukherjee Arindam , Sarkar Kabita
Published: August 2020

The Covid-19 is a highly contagious disease which becomes a serious global health concern. The residents living in areas with high population density, such as big or metropolitan cities have a higher probability to come into close contact with others and consequently any contagious disease is expected to spread rapidly in dense areas. However, recently after analyzing Covid-19 cases in the US researchers at the Johns Hopkins Bloomberg School of Public Health, London school of economics and IZA – Institute of Labor Economics conclude that the spread of Covid-19 is not linked with population density. Here we investigate the influence of population density on Covid-19 spread and related mortality in the context of India. After a detailed correlation and regression analysis of infection and mortality rates due to Covid-19 at the district level we find moderate association between Covid-19 spread and population density.
The effect of BMI and physical activity levels on the duration of symptomatic days with Covid-19 infection
Authors: Alataibi Abdulazeem S , Boukelia Boukhemis
Published: August 2020

Regular exercise is known to boost immunity, increase immune response to fight infection, as well as speeding up recovery times and healing processes. This study seeks to assess if exercising regularly pre-SARS-CoV-2 (COVID-19) and/or BMI status has an effect on recovery time.

A total of 215 people infected with COVD-19 from the Kingdom of Saudi Arabia took part in this study (age 36±16 years, mass 72±15 kg, stature 166±11 cm). Only 10 patients were physically active and fulfil WHO physical activity requirement (Age 30±7 years, Mass 77±9 kg, Stature 176±1 cm).

There was a significant difference in recovery time between active and inactive patients (P = 0.00) with active patients’ recovery 2.7 times faster than inactive patients. Active patients showed a lower BMI level (p = 0.043).

Anthropometric measurement characteristics and the fitness level could be used in decision making scenarios for the estimation of the risk of complications in patients with COVID-19.

Novelty:

Covid-19 physical active patients shows faster recovery time.

Active patients recorded a BMI of over 25kg/m2, recovered faster than those inactive patients with similar BMI’s.
The Wooden Skull: An Innovation Through The Use Of Local Materials And Technology To Promote The Teaching And Learning Of Human Anatomy
Authors: Mugagga Kintu , Mwarisi Masilili G. , Dare Samuel S.
Published: August 2020

Skeleton models are important in facilitating student’s easy retention and recollection of information in the future. These may assist students carry out hands-on practice in order to acquire and practice new skills that are relevant to first aid.

The increasing number of medical institutions and medical students attracts the challenge of inadequate facilitation of the teaching and learning processes. This warrants a study and/or an exploration of an alternative solution such as wooden models in order to solve the problem of scarce and ethically restricted human teaching aids.

Wooden pieces (50cmlengthx 20cmdiameter) from aJacaranda mimosifoliatree were prepared for the carving process and wooden replicas of human skulls were made. Two experimental groups of randomly selected medical students (60: Active and 60: Control) were separately taught using wooden and natural skull models respectively. The two groups were assessed and evaluated using the natural skull models to compare their understanding of the Anatomy of the skull. Additionally, opinion statements were collected from participants in the active group during the oral examination.

Six (6) wooden skull models were produced and used for experimental study. Comparisons of academic scores (mean and median) between Active (students using the wooden skull) and control (students using natural skull) groups showed no statistical significant difference (P ≥ 0.05). Concerning the enhancement of learning skills; the wooden model was constructed in a way that would be able to enhance learning as it would be the natural skull.

The wooden skull model, with more improvement in structural formation, can adequately facilitate the teaching and learning of anatomy of the Human skull.

This project and the experimental study about utilization of the wooden skull model provides a good potential of using the wooden models to supplement the use of the natural human skull.
In a nutshell, a reciprocal transplant experiment reveals local adaptation and fitness trade-offs in response to urban evolution in an acorn-dwelling ant
Authors: Martin Ryan A. , Chick Lacy D. , Garvin Matthew L. , Diamond Sarah E.
Published: August 2020

Urban-driven evolution is widely evident, but whether these changes confer fitness benefits and thus represent cases of adaptive urban evolution is less clear. We performed a multi-year field reciprocal transplant experiment of acorn-dwelling ants across urban and rural environments. Fitness trade-offs via survival were consistent with local adaptation: we found a survival advantage of the ‘home’ treatments compared to the ‘away’ treatments. Seasonal bias in survival was consistent with evolutionary patterns of gains and losses in thermal tolerance traits across the urbanization gradient, such that rural ants in the urban environment were more vulnerable in the summer, putatively due to low heat tolerance and urban ants in the rural environment were more vulnerable in winter, putatively due to an evolved loss of cold tolerance. The results for fitness via fecundity were more complex. Fecundity differences were present in the rural environment, but not the urban environment, and could reflect mismatched cues for the seasonal production of reproductives. To broadly contextualize our results, we performed a multi-species meta-analysis of urban adaptive evolution studies and found general support for local adaptation. The rural adaptation signal was stronger than for urban adaptation, consistent with the relative differences in time for adaptation to occur.
Microbial activation converts neutrophils into anti-tumor effectors
Authors: Yam Andrew O. , Bailey Jacqueline , Lin Francis , Jakovija Arnolda , Counoupas Claudio , Triccas James A. , Gunzer Matthias , Bald Tobias , Grey Shane T. , Chtanova Tatyana
Published: August 2020

Neutrophils infiltrate most solid tumors and their presence is usually correlated with suppression of anti-tumor responses, metastasis and poor prognosis. Here we used microbial bioparticles administered into the tumor microenvironment to transform neutrophils into anti-tumor effectors. Microbially activated neutrophils acquired an effector phenotype associated with pathogen killing and lost vascular endothelial growth factor expression associated with tumor growth and metastasis. They became the dominant immune cell infiltrating the tumor and inhibited tumor growth. Using intravital two-photon microscopy microbially activated neutrophils could be seen forming close contacts with tumor cells resulting in tumor tissue remodeling and tumor cell death. Thus, microbial bioparticle treatment can endow neutrophils with anti-tumor properties, suggesting that neutrophil plasticity in cancer could be exploited for tumor killing. These data highlight a pathway for the rational development of neutrophil-based cancer therapy.
Contributions by N-terminal Domains to NMDA Receptor Currents
Authors: Amico-Ruvio Stacy A. , Paganelli Meaghan A. , Abbott Jamie A. , Myers Jason M. , Kasperek Eileen M , Iacobucci Gary I. , Popescu Gabriela K.
Published: August 2020

To investigate the role of the N-terminal domains (NTDs) in NMDA receptor signaling we used kinetic analyses of one-channel currents and compared the reaction mechanism of recombinant wild-type GluN1/GluN2A and GluN1/GluN2B receptors with those observed for NDT-lacking receptors. We found that truncated receptors maintained the fundamental gating mechanism characteristic of NMDA receptors, which includes a multi-state activation sequence, desensitization steps, and mode transitions. This result establishes that none of the functionally-defined NMDA receptor activation events require the NTD. Notably, receptors that lacked the entire NTD layer retained isoform-specific kinetics. Together with previous reports, these results demonstrate that the entire gating machinery of NMDA receptors resides within a core domain that contains the ligand-binding and the channel-forming transmembrane domains, whereas the NTD and C-terminal layers serve modulatory functions, exclusively.
Longitudinal clonal tracking in humanized mice reveals sustained polyclonal repopulation of gene-modified human-HSPC despite vector integration bias
Authors: Suryawanshi Gajendra W. , Arokium Hubert , Kim Sanggu , Khamaikawin Wannisa , Lin Samantha , Shimizu Saki , Chupradit Koollawat , Lee YooJin , Xie Yiming , Guan Xin , Suryawanshi Vasantika , Presson Angela P. , An Dong-Sung , Chen Irvin S. Y.
Published: August 2020

Background

Current understanding of hematopoiesis is largely derived from mouse models that are physiologically distant from humans. Humanized mice provide the most physiologically relevant small animal model to study human diseases, most notably preclinical gene-therapy studies. However, the clonal repopulation dynamics of human hematopoietic stem and progenitor cells (HSPC) in these animal models is only partially understood. Using a new clonal tracking methodology designed for small sample volumes, we aim to reveal the underlying clonal dynamics of human cell repopulation in a mouse environment.

Methods

Humanized BLT (bone marrow-liver-thymus) mice were generated by transplanting lentiviral vector transduced human fetal liver HSPC (FL-HSPC) in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice implanted with a piece of human fetal thymus. We developed a methodology to track vector integration sites (VIS) in a mere 25µl of mouse blood for longitudinal and quantitative clonal analysis of human HSPC repopulation in mouse environment. We explored transcriptional and epigenetic features of human HSPC for possible VIS bias.

Results

897 HSPC clones were longitudinally tracked in BLT mice—providing a first-ever demonstration of clonal dynamics and competitive expansion of therapeutic and control vector-modified human cell populations simultaneously repopulating in the same humanized mice. The polyclonal repopulation stabilized at 19 weeks post-transplant and the contribution of the largest clone doubled within 4 weeks. Moreover, 550 (∼60%) clones persisted over 6 weeks and were highly shared between different organs. The normal clonal profiles confirmed the safety of our gene therapy vectors. Multi-omics analysis of human FL-HSPC revealed that 54% of vector integrations in repopulating clones occurred within ±1kb of H3K36me3-enriched regions.

Conclusions

Human repopulation in mice is polyclonal and stabilizes more rapidly than that previously observed in humans. VIS preference for H3K36me3 has no apparent negative effects on HSPC repopulation. Our study provides a methodology to longitudinally track clonal repopulation in small animal models extensively used for stem cell and gene-therapy research and with lentiviral vectors designed for clinical applications. Results of this study provide a framework for understanding the clonal behavior of human HPSC repopulating in a mouse environment, critical for translating results from humanized mice models to the human settings.
Deep Feature Extraction for Resting-State Functional MRI by Self-Supervised Learning and Application to Schizophrenia Diagnosis
Authors: Hashimoto Yuki , Ogata Yosuke , Honda Manabu , Yamashita Yuichi
Published: August 2020

In this study, we propose a novel deep-learning technique for functional MRI analysis. We introduced an “identity feature” by a self-supervised learning schema, in which a neural network is trained solely based on the MRI-scans; furthermore, training does not require any explicit labels. The proposed method demonstrated that each temporal slice of resting state functional MRI contains enough information to identify the subject. The network learned a feature space in which the features were clustered per subject for the test data as well as for the training data; this is unlike the features extracted by conventional methods including region of interests pooling signals and principle component analysis. In addition, using a simple linear classifier for the identity features, we demonstrated that the extracted features could contribute to schizophrenia diagnosis. The classification accuracy of our identity features was higher than that of the conventional functional connectivity. Our results suggested that our proposed training scheme of the neural network captured brain functioning related to the diagnosis of psychiatric disorders as well as the identity of the subject. Our results together highlight the validity of our proposed technique as a design for self-supervised learning.
Sub-Millimetre Resolution Laminar Fmri Using Arterial Spin Labelling in Humans at 7 T
Authors: Kashyap Sriranga , Ivanov Dimo , Havlicek Martin , Huber Laurentius , Poser Benedikt A. , Uludağ Kâmil
Published: August 2020

Laminar fMRI at ultra-high magnetic field strength is typically carried out using the Blood Oxygenation Level-Dependent (BOLD) contrast. Despite its unrivalled sensitivity to detecting activation, the BOLD contrast is limited in its spatial specificity due to signals stemming from intra-cortical ascending and pial veins. Alternatively, regional changes in perfusion (i.e., cerebral blood flow through tissue) are colocalised to neuronal activation, which can be non-invasively measured using arterial spin labelling (ASL) MRI. In addition, ASL provides a quantitative marker of neuronal activation in terms of perfusion signal, which is simultaneously acquired along with the BOLD signal. However, ASL for laminar imaging is challenging due to the lower SNR of the perfusion signal and higher RF power deposition i.e., specific absorption rate (SAR) of ASL sequences. In the present study, we present for the first time in humans, isotropic sub-millimetre spatial resolution functional perfusion images using Flow-sensitive Alternating Inversion Recovery (FAIR) ASL with a 3D-EPI readout at 7T. We show that robust statistical activation maps can be obtained with perfusion-weighting in a single session. We observed the characteristic BOLD amplitude increase towards the superficial laminae, and, in apparent discrepancy, the relative perfusion profile shows a decrease of the amplitude and the absolute perfusion profile a much smaller increase towards the cortical surface. Considering the draining vein effect on the BOLD signal using model-based spatial ‘convolution’, we show that the empirically measured perfusion and BOLD profiles are, in fact, consistent with each other. This study demonstrates that laminar perfusion fMRI in humans is feasible at 7T and that caution must be exercised when interpreting BOLD signal laminar profiles as direct representation of the cortical distribution of neuronal activity.
e-MutPath: Computational modelling reveals the functional landscape of genetic mutations rewiring interactome networks
Authors: Li Yongsheng , McGrail Daniel J. , Burgman Brandon , Yi S. Stephen , Sahni Nidhi
Published: August 2020

Understanding the functional impact of cancer somatic mutations represents a critical knowledge gap for implementing precision oncology. It has been increasingly appreciated that the ‘edgotype’ of a genomic mutation provides a fundamental link between genotype and phenotype. However, specific effects on biological signaling networks for the majority of mutations are largely unknown by experimental approaches. To resolve this challenge, we developed e-MutPath, a network-based computational method to identify candidate ‘edgetic’ mutations that perturb functional pathways. e-MutPath identifies informative paths that could be used to distinguish disease risk factors from neutral elements and to stratify disease subtypes with clinical relevance. The predicted targets are enriched in cancer vulnerability genes, known drug targets but depleted for proteins associated with side effects, demonstrating the power of network-based strategies to investigate the functional impact and perturbation profiles of genomic mutations. Together, e-MutPath represents a robust computational tool to systematically assign functions to genetic mutations, especially in the context of their specific pathway perturbation effect. The code for e-MutPath is available as a user-friendly R package at the GitHub website (https://github.com/lyshaerbin/eMutPath).
Audio-visual interactions in egocentric distance perception: Ventriloquism effect and aftereffect
Authors: Hládek Ľuboš , Seitz Aaron R , Kopčo Norbert
Published: August 2020

The processes of audio-visual integration and of visually-guided re-calibration of auditory distance perception are not well understood. Here, the ventriloquism effect (VE) and aftereffect (VAE) were used to study these processes in a real reverberant environment. Auditory and audio-visual (AV) stimuli were presented, in interleaved trials, over a range of distances from 0.7 to 2.04 m in front of the listener, whose task was to judge the distance of auditory stimuli or of the auditory components of AV stimuli. The relative location of the visual and auditory components of AV stimuli was fixed within a session such that the visual component was presented from distance 30% closer (V-closer) than the auditory component, 30% farther (V-farther), or aligned (V-aligned). The study examined the strength of VE and VAE as a function of the reference distance and of the direction of the visual component displacement, and the temporal profile of the build-up/break-down of these effects. All observed effects were approximately independent of target distance when expressed in logarithmic units. The VE strength, measured in the AV trials, was roughly constant for both directions of visual-component displacement such that, on average, the responses shifted in the direction of the visual component by 72% of the audio-visual disparity. The VAE strength, measured on the interleaved auditory-only trials, was stronger in the V-farther than the V-closer condition (44% vs. 31% of the audio-visual disparity, respectively). The VAE persisted to post-adaptation auditory-only blocks of trials, however it was weaker and the V-farther/V-closer asymmetry was reduced. The rates of build-up/break-down of the VAE were also asymmetrical, with slower adaptation in the V-closer condition. These results suggest that, on a logarithmic scale, the AV distance integration is symmetrical, independent of the direction of induced shift, while the visually-induced auditory distance re-callibration is asymmetrical, stronger and faster when evoked by more distant visual stimuli.
Tumor Immunity Microenvironment-based classifications of bladder cancer for enhancing cancer immunotherapy
Authors: Meng Jialin , Lu Xiaofan , Zhou Yujie , Zhang Meng , Zhou Jun , Hao Zongyao , Du Yinan , Yan Fangrong , Liang Chaozhao
Published: August 2020

Background

Bladder cancer is composed by a mass of heterogenetic characteristics, immunotherapy is a potential way to save the life of bladder cancer patients, but only benefit to about 20% patients.

Methods and materials

A total of 4003 bladder cancer patients from 19 cohorts was enrolled in this study, collecting the clinical information and mRNA expression profile. The unsupervised non-negative matrix factorization (NMF) and nearest template prediction (NTP) algorithm was used to divide the patients to immune activated, immune exhausted and non-immune class. Verified gene sets of signatures were used to illustrate the characteristic of immunophenotypes. Clinical and genetic features were compared in different immunophenotypes.

Results

We identified the immune class and non-immune classes in from TCGA-BLCA cohort. The 150 top different expression genes between these two classes was extracted as the input profile for the reappearing of the classification in the other 19 cohorts. As to the activated and exhausted subgroups, a stromal activation signature was conducted by NTP algorithm. Patients in the immune classes shown the highly enriched signatures of immunocytes, while the exhausted subgroup also shown an increased signature of TITR, WNT/TGF-β, TGF-β1 activated, and C-ECM signatures. Patients in the immune activated shown a lower CNA burden, better overall survival, and favorable response to anti-PD-1 therapy.

Conclusion

We defined and validated a novel classifier among the 4003 bladder cancer patients. Anti-PD-1 immunotherapy could benefit more for the patients belong to immune activated subgroup, while ICB therapy plus TGF-β inhibitor or EP300 inhibitor might be more effectiveness for patients in immune exhausted subgroup.
Generative lesion pattern decomposition of cognitive impairment after stroke
Authors: Bonkhoff Anna K. , Lim Jae-Sung , Bae Hee-Joon , Weaver Nick A. , Kuijf Hugo J. , Biesbroek J. Matthijs , Rost Natalia S. , Bzdok Danilo
Published: August 2020

Cognitive impairment is a frequent and disabling sequela of stroke. There is however incomplete understanding of how lesion topographies in the left and right cerebral hemisphere brain interact to cause distinct cognitive deficits. We integrated machine learning and Bayesian hierarchical modeling to enable hemisphere-aware analysis of 1080 subacute ischemic stroke patients with deep profiling ∼3 months after stroke. We show relevance of the left hemisphere in the prediction of language and memory assessments, while global cognitive impairments were equally well predicted by lesion topographies from both sides. Damage to the hippocampal and occipital regions on the left were particularly informative about lost naming and memory function. Global cognitive impairment was predominantly linked to lesioned tissue in supramarginal and angular gyrus, the postcentral gyrus as well as the lateral occipital and opercular cortices of the left hemisphere. Hence, our analysis strategy uncovered that lesion patterns with unique hemispheric distributions are characteristic of how cognitive capacity is lost due to ischemic brain tissue damage.
Modular metabolite assembly inC. elegansdepends on carboxylesterases and formation of lysosome-related organelles
Authors: Le Henry H. , Wrobel Chester J. J. , Cohen Sarah M. , Yu Jingfang , Park Heenam , Helf Maximilian J. , Curtis Brian J. , Kruempel Joseph C. , Rodrigues Pedro R. , Hu Patrick J. , Sternberg Paul W. , Schroeder Frank C.
Published: August 2020

Signaling molecules derived from attachment of diverse metabolic building blocks to ascarosides play a central role in the life history ofC. elegansand other nematodes; however, many aspects of their biogenesis remain unclear. Using comparative metabolomics, we show that a pathway mediating formation of intestinal lysosome-related organelles (LROs) is required for biosynthesis of most modular ascarosides as well as previously undescribed modular glucosides. Similar to modular ascarosides, the modular glucosides are derived from highly selective assembly of moieties from nucleoside, amino acid, neurotransmitter, and lipid metabolism, suggesting that modular glucosides, like the ascarosides, may serve signaling functions. We further show that carboxylesterases that localize to intestinal organelles are required for the assembly of both modular ascarosides and glucosides via ester and amide linkages. Further exploration of LRO function and carboxylesterase homologs inC. elegansand other animals may reveal additional new compound families and signaling paradigms.

Abstract Figure
Intra-exon motif correlations as a proxy measure for mean per-tile sequence quality data in RNA-Seq
Authors: Alnasir Jamie J. , Shanahan Hugh P.
Published: August 2020

Abstract

Given the wide variability in the quality of NGS data submitted to public repositories, it is essential to identify methods that can perform quality control on these datasets when additional quality control data, such as mean tile data, is missing. This is particularly important because such datasets are routinely deposited in public archives that now store data at an unprecedented scale. In this paper, we show that correlating counts of reads corresponding to pairs of motifs separated over specific distances on individual exons corresponds to mean tile data in the datasets we analysed, and can therefore be used when mean tile data is not available.

As test datasets we use theH. sapiensIVT (in-vitrotranscribed) dataset of Lahens et al., and aD. melanogasterdataset comprising wild and mutant types from Aerts et al.

Theintra-exonmotif correlations as a function of both GC content parameters are much higher in theIVT-PlasmidsmRNAselection freeRNA-Seq sample (control) than in the other RNA-Seq samples that did undergo mRNA selection: both ribosomal depletion (IVT-Only) and PolyA selection (IVT-polyA, wild-type, and mutant). There is considerable degradation of similar correlations in the mutant samples from theD. melanogasterdataset. This matches with the available mean tile data that has been gathered for these datasets. We observe that extremely low correlations are indicative of bias of technical origin, such as flowcell errors.
THE DYNAMICS OF HISTORICAL AND RECENT RANGE SHIFTS IN THE RUFFED GROUSE (Bonasa umbellus)
Authors: Perktaş Utku
Published: August 2020

Climate variability is the most important force affecting distributional range dynamics of common and widespread species with important impacts on biogeographic patterns. This study integrates phylogeography with distributional analyses to understand the demographic history and range dynamics of a widespread bird species, the Ruffed Grouse (Bonasa umbellus), under several climate change scenarios. For this, I used an ecological niche modelling approach, together with Bayesian based phylogeographic analysis and landscape genetics, to develop robust inferences regarding this species’ demographic history and range dynamics. The model’s predictions were mostly congruent with the present distribution of the Ruffed Grouse. However, under the Last Glacial Maximum bioclimatic conditions, the model predicted a substantially narrower distribution than the present. The predictions for the Last Glacial Maximum also showed three allopatric refugia in south-eastern and west-coast North America, and a cryptic refugium in Alaska. The prediction for the Last Interglacial showed two separate distributions to the west and east of the Rocky Mountains. In addition, the predictions for 2050 and 2070 indicated that the Ruffed Grouse will most likely show slight range shifts to the north and will become more widely distributed than in the past or present. At present, effective population connectivity throughout North America was weakly positively correlated with Fstvalues. That is, the species’ distribution range showed a weak isolation-by-resistance pattern. The extended Bayesian Skyline Plot analysis, which provided good resolution of the effective population size changes over the Ruffed Grouse’s history, was mostly congruent with ecological niche modelling predictions for this species. This study offers the first investigation of the late-Quaternary history of the Ruffed Grouse based on ecological niche modelling and Bayesian based demographic analysis. The species’ present genetic structure is significantly affected by past climate changes, particularly during the last 130 kybp. That is, this study offers valuable evidence of the ‘expansion–contraction’ model of North America’s Pleistocene biogeography.
Temporally-Divergent Regulatory Mechanisms Govern Neuronal Development and Diversification in the Neocortex
Authors: Yuan Wen , Ma Sai , Brown Juliana R. , Kim Kwanho , Murek Vanessa , Trastulla Lucia , Meissner Alexander , Lodato Simona , Shetty Ashwin , Levin Joshua Z. , Buenrostro Jason D. , Ziller Michael J. , Arlotta Paola
Published: August 2020

Mammalian neocortical neurons span one of the most diverse cell type spectra of any tissue. The regulatory strategies that neurons use during progressive development and maturation remain unclear. We present an integrated single-cell epigenomic and transcriptional analysis of individual classes of neurons from both mouse and marmoset neocortex, sampled during both early postmitotic stages of identity acquisition and later stages of neuronal plasticity and circuit integration. We find that in both species, the regulatory strategies controlling these early and late stages diverge: early postmitotic neurons use molecular regulatory programs with broader tissue distribution and greater evolutionary conservation, while programs active during later neuronal maturation implement more brain- and neuron-specific mechanisms showing greater evolutionary divergence. The data uncovers a temporally-regulated shift in regulatory choices, likely reflecting unique evolutionary constraints on distinct events of neuronal development in the neocortex.
Cell intercalation driven by SMAD3 underlies secondary neural tube formation
Authors: Gonzalez-Gobartt Elena , Blanco-Ameijeiras José , Usieto Susana , Allio Guillaume , Benazeraf Bertrand , Martí Elisa
Published: August 2020

Body axis elongation is a hallmark of the vertebrate embryo, involving the architectural remodelling of the tailbud. Although it is clear how bi-potential neuro-mesodermal progenitors (NMPs) contribute to embryo elongation, the dynamic events that lead tode novolumen formation and that culminate in the formation of a 3-Dimensional, secondary neural tube from NMPs, are poorly understood. Here, we used in vivo imaging of the chicken embryo to show that cell intercalation downstream of TGF-beta/SMAD3 signalling is required for secondary neural tube formation. Our analysis describes the initial events in embryo elongation including lineage restriction, the epithelial-to-mesenchymal transition of NMPs, and the initiation of lumen formation. Importantly, we show that the resolution of a single, centrally positioned continuous lumen, which occurs through the intercalation of central cells, requires SMAD3 activity. We anticipate that these findings will be relevant to understand caudal, skin-covered neural tube defects, amongst the most frequent birth defects detected in humans.

HIGHLIGHTS

.- Initiation of the lumen formation follows the acquisition of neural identity and epithelial polarization.

.- Programmed cell death is not required for lumen resolution.

.- Resolution of a single central lumen requires cell intercalation, driven by Smad3 activity

.- The outcome of central cell division preceding cell intercalation, varies along the cranio-caudal axis.
Macrophages provide a transient muscle stem cell niche via NAMPT secretion
Authors: Ratnayake Dhanushika , Nguyen Phong D. , Rossello Fernando J. , Wimmer Verena C. , Isiaku Abdulsalam I. , Galvis Laura A. , Wood Alasdair J. , Julier Ziad , Boudier Thomas , Oorschot Viola , Rogers Kelly L. , Martino Mikaël M. , Marcelle Christophe , Lieschke Graham J. , Bakkers Jeroen , Currie Peter D.
Published: August 2020

Skeletal muscle is paradigmatic of a regenerative tissue that repairs itself via the activation of a resident stem cell1. Termed the satellite cell, these normally quiescent cells are induced to proliferate by ill-defined wound-derived signals2. Identifying the source and nature of these pro-regenerative cues has been hampered by an inability to visualise the complex cellular interactions that occur within the wound environment. We therefore developed a zebrafish muscle injury model to systematically capture satellite cell interactions within the injury site, in real time, throughout the repair process. This analysis identified that a specific subset of macrophages ‘dwells’ within the injury, establishing a transient but obligate stem cell niche required for stem cell proliferation. Single cell profiling identified specific signals secreted from dwelling macrophages that include the cytokine, Nicotinamide phosphoribosyltransferase (NAMPT/Visfatin/PBEF). Here we show that NAMPT secretion from the macrophage niche is required for muscle regeneration, acting through the C-C motif chemokine receptor type 5 (CCR5) expressed on muscle stem cells. This analysis reveals that along with their well-described ability to modulate the pro-inflammatory and anti-inflammatory phases of wound repair, specific macrophage populations also provide a transient stem cell-activating niche, directly supplying pro-proliferative cues that govern the timing and rate of muscle stem cell-mediated repair processes.