bluuebunny/crossref_metadata_2025 huggingface dataset:
A bioelectric neural interface towards intuitive prosthetic control for amputees
Authors: Nguyen Anh Tuan , Xu Jian , Jiang Ming , Luu Diu Khue , Wu Tong , Tam Wing-kin , Zhao Wenfeng , Drealan Markus W. , Overstreet Cynthia K. , Zhao Qi , Cheng Jonathan , Keefer Edward W. , Yang Zhi
Published: September 2020

Objective

While prosthetic hands with independently actuated digits have become commercially available, state-of-the-art human-machine interfaces (HMI) only permit control over a limited set of grasp patterns, which does not enable amputees to experience sufficient improvement in their daily activities to make an active prosthesis useful.

Approach

Here we present a technology platform combining fully-integrated bioelectronics, implantable intrafascicular microelectrodes and deep learning-based artificial intelligence (AI) to facilitate this missing bridge by tapping into the intricate motor control signals of peripheral nerves. The bioelectric neural interface includes an ultra-low-noise neural recording system to sense electroneurography (ENG) signals from microelectrode arrays implanted in the residual nerves, and AI models employing the recurrent neural network (RNN) architecture to decode the subject’s motor intention.

Main results

A pilot human study has been carried out on a transradial amputee. We demonstrate that the information channel established by the proposed neural interface is sufficient to provide high accuracy control of a prosthetic hand up to 15 degrees of freedom (DOF). The interface is intuitive as it directly maps complex prosthesis movements to the patient’s true intention.

Significance

Our study layouts the foundation towards not only a robust and dexterous control strategy for modern neuroprostheses at a near-natural level approaching that of the able hand, but also an intuitive conduit for connecting human minds and machines through the peripheral neural pathways.

Clinical trial

DExterous Hand Control Through Fascicular Targeting (DEFT). Identifier:NCT02994160.
Prey-Driven Behavioral Habitat Use in a Low-Energy Ambush Predator
Authors: Tutterow Annalee M. , Hoffman Andrew S. , Buffington John L. , Truelock Zachary T. , Peterman William E.
Published: September 2020

Food acquisition is an important modulator of animal behavior and habitat selection that can affect fitness. Optimal foraging theory predicts that predators should select habitat patches to maximize their foraging success and net energy gain, which predators can achieve by targeting spaces with high prey availability. However, it is debated whether prey availability drives fine-scale habitat selection for predators.

We assessed whether an ambush predator, the timber rattlesnake (Crotalus horridus), exhibits optimal foraging site selection based on the spatial distribution and availability of prey.

We evaluated the spatial concordance of radio-telemetered timber rattlesnake foraging locations and passive infrared game camera trap detections of potential small mammal prey (Peromyscusspp.,Tamias striatus,andSciurusspp.) in a mixed-use forest in southeastern Ohio from 2016–2019. We replicated a characteristic timber rattlesnake ambush position by focusing cameras over logs and modeled small mammal encounters across the landscape in relation to remotely-sensed forest and landscape structural features. To determine whether snakes selectively forage in areas with higher prey availability, we projected the estimated prey spatial relationships across the landscape and modeled their overlap of occurrence with observed timber rattlesnake foraging locations.

We broadly predicted that prey availability was greatest in mature deciduous forests, butT.striatusandSciurusspp. exhibited greater spatial heterogeneity compared toPeromyscusspp. We also combined predicted species encounter rates to encompass a body size gradient in potential prey. The spatial distribution of cumulative small mammal encounters (i.e. overall prey availability), rather than the distribution of any one species, was highly predictive of snake foraging.

Timber rattlesnakes appear to select foraging locations where the probability of encountering prey is greatest. Our study provides evidence for fine-scale optimal foraging in a low-energy, ambush predator and offers new insights into drivers of snake foraging and habitat selection.
An accurate aging clock developed from the largest dataset of microbial and human gene expression reveals molecular mechanisms of aging
Authors: Gopu Vishakh , Cai Ying , Krishnan Subha , Rajagopal Sathyapriya , Camacho Francine R. , Toma Ryan , Torres Pedro J. , Vuyisich Momchilo , Perlina Ally , Banavar Guruduth , Tily Hal
Published: September 2020

Accurate measurement of the biological markers of the aging process could provide an “aging clock” measuring predicted longevity and allow for the quantification of the effects of specific lifestyle choices on healthy aging. Using modern machine learning techniques, we demonstrate that chronological age can be predicted accurately from (a) the expression level of human genes in capillary blood, and (b) the expression level of microbial genes in stool samples. The latter uses the largest existing metatranscriptomic dataset, stool samples from 90,303 individuals, and is the highest-performing gut microbiome-based aging model reported to date. Our analysis suggests associations between biological age and lifestyle/health factors, e.g., people on a paleo diet or with IBS tend to be biologically older, and people on a vegetarian diet tend to be biologically younger. We delineate the key pathways of systems-level biological decline based on the age-specific features of our model; targeting these mechanisms can aid in development of new anti-aging therapeutic strategies.
GREEN-DB: A framework for the annotation and prioritization of non-coding regulatory variants from whole-genome sequencing data
Authors: Giacopuzzi E , Popitsch N , Taylor JC
Published: September 2020

Non-coding variants have emerged as important contributors to the pathogenesis of human diseases, not only as common susceptibility alleles but also as rare high-impact variants. Despite recent advances in the study of regulatory elements and the availability of specialized data collections, the systematic annotation of non-coding variants from genome sequencing remains challenging. Here, we propose a new framework for the prioritization of non-coding regulatory variants that integrates information about regulatory regions with prediction scores and HPO-based prioritization. Firstly, we created a comprehensive collection of annotations for regulatory regions including a curated database of 2.4 million regulatory elements (GREEN-DB) annotated with controlled gene(s), tissue(s) and associated phenotype(s) where available. Secondly, we calculated a variation constraint metric and showed that constrained regulatory regions associate with disease-associated genes and essential genes from mouse knock-out screens. Thirdly, we compared 19 non-coding impact prediction scores providing suggestions for variant prioritization. Finally, we developed a VCF annotation tool (GREEN-VARAN) that can integrate all these elements to annotate variants for their potential regulatory impact. In our evaluation, we show that GREEN-DB can capture previously published disease-associated non-coding variants as well as identify additional candidate disease genes in WGS trio analyses.
Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperoneHsc70-5/mortalininDrosophila
Authors: Zhu Jun-yi , Hannan Shabab B. , Dräger Nina M. , Vereshchagina Natalia , Krahl Ann-Christin , Fu Yulong , Elliott Christopher J.H. , Han Zhe , Jahn Thomas R. , Rasse Tobias M.
Published: September 2020

We investigate in larval and adultDrosophilamodels whether loss of the mitochondrial chaperoneHsc70-5/mortalinis sufficient to cause pathological alterations commonly observed in Parkinson disease. At affected larval neuromuscular junctions, no effects on terminal size, bouton size or number, synapse size, or number were observed, suggesting that we study an early stage of pathogenesis. At this stage, we noted a loss of synaptic vesicle proteins and active zone components, delayed synapse maturation, reduced evoked and spontaneous excitatory junctional potentials, increased synaptic fatigue, and cytoskeleton rearrangements. The adult model displays ATP depletion, altered body posture, and susceptibility to heat-induced paralysis. Adult phenotypes could be suppressed by knockdown ofDJ-1b, LRRK, p50, p150, Atg1, Atg101, Atg5, Atg7, andAtg12. The knockdown of components of the autophagy machinery or overexpression of humanmortalinbroadly rescued larval and adult phenotypes, while disease-associatedHSPA9variants did not. Overexpression ofPink1or promotion of autophagy exacerbated defects.
Utilization of Epigenome-wide DNA Methylation for Longitudinal Comparison of White Blood Cell Proportions Across Preeclamptic and Normotensive Pregnancy by Self-Reported Race
Authors: Ray Mitali , Heinsberg Lacey W. , Conley Yvette P. , Roberts James M. , Jeyabalan Arun , Hubel Carl A. , Weeks Daniel E. , Schmella Mandy J.
Published: September 2020

Objective

We utilized epigenome-wide DNA methylation data to estimate/compare white blood cell (WBC) proportions in plasma across preeclamptic (case) and uncomplicated, normotensive (control) pregnancy.

Methods

We previously collected methylation data using Infinium® MethylationEPIC Beadchips during the three trimesters in 28 cases and 28 controls (21 Black, 7 White participants/group). We employed Houseman’s regression calibration method to estimate and compare neutrophil, monocyte, B cell, NK cell, CD4+ T and CD8+ T cell proportions across pregnancy and between cases and controls.

Results

We observed changes in WBC proportions across pregnancy within cases and controls that varied by cell type and race. Neutrophils represented the largest WBC mean proportion in all three trimesters for cases (Mean±SD: 67.2±9.6% – 74.4±12%) and controls (64.2±11% – 74.0±7.9%). Mean B cell proportions were significantly lower in cases than controls in Trimester 1 (5.25±0.02% versus 6.30±0.02%, p=0.02). The remaining mean cell proportions did not significantly differ in the overall sample. Stratified analyses revealed race-specific differences. In White participants (n=14): (1) neutrophil proportions were significantly higher in cases in Trimester 1 (p=0.04), but significantly lower in Trimester 2 (p=0.02), (2) B cell proportions were significantly lower in cases in Trimester 1 (p=0.001). No significant differences were detected among Black participants (n=42).

Conclusions

Although chronic inflammation characterizes preeclampsia, few studies have investigated WBCs across pregnancy. We report differences between cases and controls across pregnancy. Our findings in a small sample demonstrate the need for additional studies investigating the relationship between race and WBCs in pregnancy, which could provide insight into preeclampsia pathophysiology.
Digital Speech Analysis in Progressive Supranuclear Palsy and Corticobasal Syndromes
Authors: Parjane Natalia , Cho Sunghye , Ash Sharon , Shellikeri Sanjana , Liberman Mark , Shaw Leslie M. , Irwin David J. , Grossman Murray , Nevler Naomi
Published: September 2020

Background

Progressive supranuclear palsy and corticobasal syndromes (PSPS-CBS) as well as nonfluent/agrammatic primary progressive aphasia (naPPA) are often due to misfolded 4-repeat Tau, but the diversity of the associated speech disorders beyond Apraxia of Speech (AoS) is poorly understood.

Objective

Investigate the full range of acoustic and lexical properties of speech to test the hypothesis that PSPS-CBS show a subset of speech impairments found in naPPA.

Methods

Acoustic and lexical measures, extracted from natural, digitized semi-structured speech samples using novel, automated methods, were compared in PSPS-CBS (n=87), naPPA (n=25) and healthy controls (HC, n=41). We also explored speech in a group of PSPS-CBS patients with concomitant naPPA (PSPS-CBS+naPPA, n=8). We related these measures to grammatical performance and speech fluency, core features of naPPA, and to cerebrospinal fluid (CSF) phosphorylated tau (pTau) in patients with available biofluid.

Results

Both naPPA and PSPS-CBS speech had shorter speech segments, longer pauses, higher pause rate, reduced fundamental frequency (f0) range, and slower speech rate compared to HC. naPPA speech was distinct from PSPS-CBS with shorter speech segments, more frequent pauses, slower speech rate, and reduced verb production. In both groups, acoustic duration measures generally correlated with speech fluency and grammatical performance. PSPS-CBS+naPPA resembled naPPA in most speech measures and had the narrowest f0 range. CSF pTau levels correlated with f0 range and verb production in PSPS-CBS and naPPA.

Conclusion

The speech pattern of PSPS-CBS overlaps that of naPPA apart from AoS, and may be related to CSF pTau.
Bronchus-associated macrophages efficiently capture and present soluble inhaled antigens and are capable of local Th2 cell activation
Authors: Tang Xin-Zi , Kreuk Lieselotte S. M. , Cho Cynthia , Metzger Ross J. , Allen Christopher D. C.
Published: September 2020

In allergic asthma, allergen inhalation leads to local Th2 cell activation and peribronchial inflammation. However, the mechanisms for local antigen capture and presentation remain unclear. By two-photon microscopy, we established that soluble antigens in the bronchial airway lumen were efficiently captured and presented by a population of CD11c+interstitial macrophages with high CX3CR1-GFP and MHC class II expression. We refer to these cells as Bronchus-Associated Macrophages (BAMs) based on their localization underneath the bronchial epithelium. BAMs were enriched in collagen-rich regions near some airway branchpoints, where inhaled antigens are likely to deposit. BAMs engaged in extended interactions with effector Th2 cells and promoted Th2 cytokine production. BAMs were also often in contact with dendritic cells (DCs). After exposure to inflammatory stimuli, DCs migrated to draining lymph nodes, whereas BAMs remained lung resident. We propose that BAMs act as local antigen presenting cells in the lung and also transfer antigen to DCs.
The CD28-transmembrane domain mediates chimeric antigen receptor heterodimerization with CD28
Authors: Muller Yannick D. , Nguyen Duy P. , Ferreira Leonardo M.R. , Ho Patrick , Raffin Caroline , Valencia Roxxana Beltran , Congrave-Wilson Zion , Roth Theodore , Eyquem Justin , Van Gool Frederic , Marson Alexander , Wells James A. , Bluestone Jeffrey A. , Tang Qizhi
Published: September 2020

Anti-CD19 chimeric antigen receptor (CD19-CAR)-engineered T cells are approved therapeutics for malignancies. The impact of the hinge (HD) and transmembrane (TMD) domains between the extracellular antigen-targeting and the intracellular signaling modalities of CARs has not been systemically studied. Here, a series of CD19-CARs differing only by their HD (CD8/CD28/IgG4) and TMD (CD8/CD28) was generated. CARs containing a CD28-TMD, but not a CD8-TMD, formed heterodimers with the endogenous CD28 in human T cells, as shown by co-immunoprecipitation and CAR-dependent proliferation to anti-CD28 stimulation. This dimerization depended on polar amino-acids in the CD28-TMD. CD28-CAR heterodimerization was more efficient in CARs containing a CD8-HD or CD28-HD as compared to an IgG4-HD. CD28-CAR heterodimers did not respond to CD80 and CD86 stimulation but led to a significant reduction of CD28 cell-surface expression. These data unveil a new property of the CD28-TMD and suggest that TMDs can modulate CAR T-cell activities by engaging endogenous partners.

Abstract Figure
“The anti-angiogenic compound axitinib demonstrates low toxicity and anti-tumoral effects against medulloblastoma”
Authors: Pagnuzzi-Boncompagni Marina , Picco Vincent , Vial Valérie , Planas-Bielsa Victor , Vandenberghe Ashaina , Grépin Renaud , Durivault Jérôme , Montemagno Christopher , Martial Sonia , Doyen Jérôme , Gavard Julie , Pagès Gilles
Published: September 2020

Evolution of medulloblastoma (MB) treatments has increased the 5-year overall survival of to more than 70%. However, an increasing number of survivors face severe long-term adverse effects and associated morbidity due to multimodal treatments particularly harsh for the younger patients. Chemotherapeutic compounds inducing less adverse effects are key to improving the care of MB patients. The preclinical relevance of last generation anti-angiogenic compounds deserves to be fully assessed. Among these, axitinib showed the highest selectivity index for MB cells, efficiently reduced the growth rate of experimental tumors and led to less toxicity towards normal cells than did a reference treatment. In vivo, axitinib did not lead to acute toxicity in very young rats and was able to cross the blood brain barrier. Analysis of public databases shows that high expression of axitinib targets are of poor prognosis. Altogether, our results suggest that axitinib is a compelling candidate for MB treatment.
Consistent ultra-long DNA sequencing with automated slow pipetting
Authors: Prall Trent M. , Neumann Emma K. , Karl Julie A. , Shortreed Cecilia G. , Baker David A. , Bussan Hailey E. , Wiseman Roger W. , O’Connor David H.
Published: September 2020

Background

Oxford Nanopore Technologies instruments can sequence reads of great length. Long reads improve sequence assemblies by unambiguously spanning repetitive elements of the genome. Sequencing reads of significant length requires the preservation of long DNA template molecules through library preparation by pipetting reagents as slowly as possible to minimize shearing. This process is time-consuming and inconsistent at preserving read length as even small changes in volumetric flow rate can result in template shearing.

Results

We have designed SNAILS (Slow Nucleic Acid Instrument for Long Sequences), a 3D-printable instrument that automates slow pipetting of reagents used in long read library preparation for Oxford Nanopore sequencing. Across six sequencing libraries, SNAILS preserved more reads exceeding one hundred kilobases in length and increased its libraries’ average read length over manual slow pipetting.

Conclusions

SNAILS is a low-cost, easily deployable solution for improving sequencing projects that require reads of significant length. By automating the slow pipetting of library preparation reagents, SNAILS increases the consistency and throughput of long read Nanopore sequencing.
Who acquires infection from whom? Estimating herpesvirus transmission rates between wild rodent host groups
Authors: Erazo Diana , Pedersen Amy B. , Gallagher Kayleigh , Fenton Andy
Published: September 2020

To date, few studies of parasite epidemiology have investigated ‘who acquires infection from whom’ in wildlife populations. Nonetheless, identifying routes of disease transmission within a population, and determining the key groups of individuals that drive parasite transmission and maintenance, are fundamental to understanding disease dynamics. Gammaherpesviruses are a widespread group of DNA viruses that infect many vertebrate species, and murine gammaherpesviruses (i.e. MuHV-4) are a standard lab model for studying human herpesviruses, for which much about the pathology and immune response elicited to infection is well understood. However, despite this extensive research effort, primarily in the lab, the transmission route of murine gammaherpesviruses within their natural host populations is not well understood. Here, we aimed to understand wood mouse herpesvirus (WMHV) transmission, by fitting a series of population dynamic models to field data on wood mice naturally infected with WMHV and then estimating transmission parameters within and between demographic groups of the host population. Different models accounted for different combinations of host sex (male/female), age (subadult/adult) and transmission functions (density/frequency-dependent). We found that a density-dependent transmission model incorporating explicit sex groups fitted the data better than all other proposed models. Male-to-male transmission was the highest among all demographic groups, suggesting that male behaviour is a key factor driving WMHV transmission. Our models also suggest that transmission between sexes, although important, wasn’t symmetrical, with infected males playing a significant role in infecting naïve females but not vice versa. Overall this work shows the power of coupling population dynamic models with long-term field data to elucidate otherwise unobservable transmission processes in wild disease systems.
Primary sex determination in chickens depends on DMRT1 dosage, but gonadal sex does not determine secondary sexual characteristics in adult birds
Authors: Ioannidis Jason , Taylor Gunes , Zhao Debiao , Liu Long , Idoko-Akoh Alewo , Gong Daoqing , Lovell-Badge Robin , Guioli Silvana , McGrew Mike , Clinton Michael
Published: September 2020

In birds, males are the homogametic sex (ZZ) and females the heterogametic sex (ZW), and primary sex determination is thought to depend on a sex chromosome gene dosage mechanism. Previous studies have suggested that the most likely sex-determinant is the Z chromosome geneDMRT1(Doublesex and Mab-3 Related Transcription factor 1). To clarify this issue, we used a CRISPR-Cas9 based mono-allelic targeting approach and sterile surrogate hosts to generate birds with targeted mutations in theDMRT1gene. The resulting chromosomally male (ZZ) chicken with a single functional copy ofDMRT1developed ovaries in place of testes, demonstrating the avian sex determining mechanism is based on DMRT1 dosage. These ZZ ovaries expressed typical female markers and showed clear evidence of follicular development. However, these ZZ adult birds with an ovary in place of testes were indistinguishable in appearance to wild type adult males, supporting the concept of cell-autonomous sex identity (CASI) in birds. In experiments where oestrogen synthesis was blocked in control ZW embryos, the resulting gonads developed as testes. In contrast, if oestrogen synthesis was blocked in ZW embryos that lackedDMRT1, the gonads invariably adopted an ovarian fate. Our analysis shows that DMRT1 is the key sex determination switch in birds and that it is essential for testis development, but that production of oestrogen is also a key factor in primary sex determination in chickens, and that this production is linked to DMRT1 expression.
Semi-coordinated allelic-bursting shape dynamic random monoallelic expression in pre-gastrulation embryos
Authors: Naik C H , Hari K , Chandel D , Mandal S , Jolly M K , Gayen S
Published: September 2020

In recent years, allele-specific single-cell RNA-seq (scRNA-seq) analysis has demonstrated wide-spread dynamic random monoallelic expression of autosomal genes (aRME) in different cell types. However, the prevalence of dynamic aRME during pre-gastrulation development remains unknown. Here, we show that dynamic aRME is wide-spread in different lineages of pre-gastrulation embryos. Additionally, the origin of dynamic aRME remains poorly understood. Theoretically, it is believed that independent transcriptional bursting from each allele leads to the dynamic aRME. However, based on analysis of allele-specific burst kinetics of autosomal genes, we found that allelic burst is not perfectly independent, rather it happens in semi-coordinated fashion. Importantly, we show that semi-coordinated allelic bursting of the genes; particularly with low burst frequency, leads to frequent asynchronous allelic bursting, thereby shaping the landscape of dynamic aRME in pre-gastrulation embryos. Altogether, our study provides significant insight into the prevalence and origin of dynamic aRME and cell to cell expression heterogeneity during early mammalian development.
Zika virus NS3 protease and its cellular substrates
Authors: Dabrowska Agnieszka , Milewska Aleksandra , Ner-Kluza Joanna , Suder Piotr , Pyrc Krzysztof
Published: September 2020

Abstract

Zika virus is a flavivirus discovered in 1947, but the association between Zika virus infection and brain disorders was not demonstrated until 2015 in Brazil. Infection mostly poses a threat to women during pregnancy, since it may cause microcephaly and other neurological dysfunctions in the developing fetus. However, infection is also associated with Guillain-Barré syndrome. The nonstructural NS3 protein is essential for virus replication because it helps to remodel the cellular microenvironment. Several reports show that this protease can process cellular substrates and thereby modify cellular pathways that are important for the virus. Herein, we explored some of the targets of NS3, but we could not confirm the biological relevance of its protease activity. Thus, although mass spectrometry is highly sensitive and useful in many instances, being also able to show directions, where cell/virus interaction occurs, we believe that biological validation of the observed results is essential.
Mechanism of selectivity reveals novel antifolate drug interactions
Authors: Kordus Shannon Lynn , Lamont Elise A. , Howe Michael D. , Bauman Allison A. , McCue William , Finzel Barry , Baughn Anthony D.
Published: September 2020

Antimicrobial agents that target a specific pathogen of interest is the gold standard in drug design.para-Aminosalicylic acid (PAS), remains a cornerstone therapy, in the treatment againstMycobacterium tuberculosis, owing to its high level of selectivity. Despite its high level of selectivity, PAS has been reassigned to treat drug-resistant strains ofM. tuberculosisbecause it causes severe gastrointestinal (GI) distress that results in poor patient compliance. We have previously shown PAS inhibits the folate biosynthetic pathway specifically inhibiting dihydrofolate reductase1,2. In this study, we sought to determine the mechanistic basis of PAS selectivity and determined that PAS can be utilized in folate biosynthesis by other bacterial pathogens. The utilization of PAS ultimately led to the antagonism of key antibiotics, specifically the sulfonamides, used to prophylactically treat individuals with HIV-AIDS3. In addition, we found many bacteria in the GI tract could also utilize PAS to make a hydroxy-folate species which resulted in GI toxicity. Using sulfonamides as a tool to prevent PAS associated toxicity in the GI tract, we discovered that the sulfonamides antagonized the antimycobacterial activity of PAS. These findings indicate a new need for understanding the mechanisms of selective therapies and more important, that HIV-AIDS/M. tuberculosisco-infected individuals should avoid co-treatment of PAS and sulfonamides.
Nanomechanical phenotypes in cMyBP-C mutants that cause hypertrophic cardiomyopathy
Authors: Suay-Corredera Carmen , Pricolo Maria Rosaria , Velázquez-Carreras Diana , Pimenta-Lopes Carolina , Sánchez-Ortiz David , Urrutia-Irazabal Iñigo , Vilches Silvia , Dominguez Fernando , Frisso Giulia , Monserrat Lorenzo , García-Pavía Pablo , Herrero-Galán Elías , Alegre-Cebollada Jorge
Published: September 2020

Hypertrophic cardiomyopathy (HCM) is a disease of the myocardium caused by mutations in sarcomeric proteins with mechanical roles, such as the molecular motor myosin. Around half of the HCM-causing genetic variants target contraction modulator cardiac myosin-binding protein C (cMyBP-C), although the underlying pathogenic mechanisms remain unclear since many of these mutations cause no alterations in protein structure and stability. As an alternative pathomechanism, here we have examined whether pathogenic mutations perturb the nanomechanics of cMyBP-C, which would compromise its modulatory mechanical tethers across sliding actomyosin filaments. Using single-molecule atomic force spectroscopy, we have quantified mechanical folding and unfolding transitions in cMyBP-C mutant domains. Our results show that domains containing mutation R495W are mechanically weaker than wild-type at forces below 40 pN, and that R502Q mutant domains fold faster than wild-type. None of these alterations are found in control, non-pathogenic variants, suggesting that nanomechanical phenotypes induced by pathogenic cMyBP-C mutations contribute to HCM development. We propose that mutation-induced nanomechanical alterations may be common in mechanical proteins involved in human pathologies.
Targeting G-quadruplex Forming Sequences with Cas9
Authors: Balci Hamza , Globyte Viktorija , Joo Chirlmin
Published: September 2020

Clustered Regularly Interspaced Palindromic Repeats (CRISPR) and CRISPR-associated (Cas) proteins, particularly Cas9, have provided unprecedented control on targeting and editing specific DNA sequences. If the target sequences are prone to folding into non-canonical secondary structures, such as G-quadruplex (GQ), the conformational states and activity of CRISPR-Cas9 complex would be influenced, but the impact has not been assessed. Using single molecule FRET, we investigated structural characteristics of the complex formed by CRISPR-Cas9 and target DNA, which contains a potentially GQ forming sequence (PQS) in either the target or the non-target strand (TS or NTS). We observed different conformational states and dynamics depending on the stability of the GQ and the position of PQS. When PQS was in NTS, we observed evidence for GQ formation for both weak and stable GQs. This is consistent with R-loop formation between TS and crRNA releasing NTS from Watson-Crick pairing and facilitating secondary structure formation in it. When PQS was in TS, R-loop formation was adequate to maintain a weak GQ in the unfolded state but not a GQ with moderate or high stability. The observed structural heterogeneity within the target dsDNA and the R-loop strongly depended on whether the PQS was in TS or NTS. We propose these variations in the complex structures to have functional implications for Cas9 activity.
Stage-Specific Long Non-coding RNAs inCryptosporidium parvumas Revealed by Stranded RNA-Seq
Authors: Li Yiran , Baptista Rodrigo P. , Sateriale Adam , Striepen Boris , Kissinger Jessica C.
Published: September 2020

Cryptosporidiumis a protist parasite that has been identified as the second leading cause of moderate to severe diarrhea in children younger than two and a significant cause of mortality worldwide.Cryptosporidiumhas a complex, obligate, intracellular but extra cytoplasmic lifecycle in a single host. How genes are regulated in this parasite remains largely unknown. Long non-coding RNAs (lncRNAs) play critical regulatory roles, including gene expression across a broad range of organisms.CryptosporidiumlncRNAs have been reported to enter the host cell nucleus and affect the host response. However, no systematic study of lncRNAs inCryptosporidiumhas been conducted to identify additional lncRNAs. In this study, we analyzed aC. parvum in vitrostrand-specific RNA-seq developmental time series covering both asexual and sexual stages to identify lncRNAs associated with parasite development. In total, we identified 396 novel lncRNAs 86% of which are differentially expressed. Nearly 10% of annotated mRNAs have an antisense lncRNA. lncRNAs also appear to occur most often at the 3’ end of their corresponding sense mRNA. Putative lncRNA regulatory regions were identified and many appear to encode bidirectional promoters. A positive correlation trend between lncRNA and the upstream mRNA expression was observed. Evolutionary conservation and expression of lncRNA candidates was observed betweenC. parvum, C. hominisandC. baileyi. TenC. parvumprotein-encoding genes with antisense transcripts haveP. falciparumorthologs that also have antisense transcripts. ThreeC. parvumlncRNAs with exceptional properties (e.g., intron splicing) were experimentally validated using RT-PCR and RT-qPCR. We provide an initial characterization of theC. parvumnon-coding transcriptome to facilitate further investigations into the roles of lncRNAs in parasite development and host-pathogen interactions.
Predictive value of 18F‐fluorodeoxyglucose positron emission tomography/computed tomography for PD‐L1 expression in non‐small cell lung cancer: A systematic review and meta‐analysis
Authors: Seol Hee Yun , Kim Yun Seong , Kim Seong‐Jang
Published: September 2020

Background

The purpose of the current study was to investigate the predictive value of 18F‐fluorodeoxyglucose positron emission tomography/computed tomography (18F‐FDG PET/CT) for programmed death ligand 1 (PD‐L1) in non‐small cell lung cancer (NSCLC) patients through a systematic review and meta‐analysis.

Methods

The PubMed, Cochrane, and EMBASE database, from the earliest available date of indexing through 30 April 2020, were searched for studies evaluating the diagnostic performance of 18F‐FDG PET/CT for prediction of PD‐L1 expression in NSCLC patients.

Results

Across six studies (1739 patients), the pooled sensitivity for 18F‐FDG PET/CT was 0.72 (95% CI: 0.58–0.82) with heterogeneity (I2 = 90.9, P < 0.001) and a pooled specificity of 0.69 (95% CI: 0.64–0.74) with heterogeneity (I2 = 77.9, P < 0.001). Likelihood ratio (LR) syntheses gave an overall positive likelihood ratio (LR +) of 2.3 (95% CI: 1.8–2.9) and negative likelihood ratio (LR‐) of 0.41 (95% CI: 0.26–0.63). The pooled diagnostic odds ratio (DOR) was six (95% CI: 3–11). Hierarchical summary receiver operating characteristic (ROC) curve indicated that the area under the curve was 0.74 (95% CI: 0.70–0.78).

Conclusions

The current meta‐analysis showed a moderate sensitivity and specificity of 18F‐FDG PET/CT for the prediction of PD‐L1 expression in NSCLC patients. The DOR was low and the likelihood ratio scatter‐gram indicated that 18F‐FDG PET/CT might not be useful for the prediction of PD‐L1 expression in NSCLC patients and not for its exclusion.

Key points

Significant findings of the study

The current meta‐analysis showed a moderate sensitivity and specificity of 18F‐FDG PET/CT for the prediction of PD‐L1 expression in NSCLC patients. The DOR was low and the likelihood ratio scattergram indicated that 18F‐FDG PET/CT might not be useful for the prediction of PD‐L1 expression in NSCLC patients and not for its exclusion.

What this study adds

This study concluded that the role of 18F‐FDG PET/CT in predicting tumor expression of PD‐L1 should be further elucidated.
Electrocardiograhic characteristics in patients with coronavirus infection: A single‐center observational study
Authors: Li Yi , Liu Tong , Tse Gary , Wu Mingxiang , Jiang Jingjing , Liu Ming , Tao Liang
Published: September 2020

Background

A global outbreak of coronavirus disease (COVID‐19), caused by severe acute respiratory coronavirus 2 (SARS‐CoV‐2), has emerged since December 2019, in Wuhan, China. However, electrocardiograhic (ECG) manifestations of patients with COVID‐19 have not been fully described. We aim to investigate ECG characteristics in COVID‐19 patients and risk factors of intensive care unit (ICU) admission.

Methods

This retrospective observational study included the patients with COVID‐19 at the Wuhan Asia General hospital between February 10, and 26, 2020. Demographic, clinical, and ECG characteristics were collected, and comparisons were made between the ICU and non‐ICU admission groups. Logistic regression was used to identify risk factors of ICU admission.

Results

Among 135 included patients (median age: 64 years [interquartile range: 48–72]), ST‐T abnormalities (40%) were the most common ECG feature, followed by arrhythmias (38%). Cardiovascular disease (CVD) was presented in 48% of the patients. Six (4.4%) died during hospitalization, and 23 (17.0%) were admitted to the ICU. Compared with non‐ICU group, the ICU group showed higher heart rate (p = .019) and P‐wave duration (p = .039) and was more frequently associated with CVD (p < .001), ST‐T abnormalities (p = .007), arrhythmias (p = .003), QTc interval prolongation (p = .003), and pathological Q waves (p < .001). Twenty‐seven patients were re‐examined ECG during admission, and 17 of them presented new findings compared with their initial ECG presentations. ST‐T abnormalities (p = .040) and history of CVD (p = .0047) were associated with increased risk of ICU hospitalization.

Conclusions

COVID‐19 is frequently related to cardiovascular manifestations including ECG abnormalities and cardiovascular comorbidities. ST‐T abnormalities and CVD at admission were associated with increased odds of ICU admission.
Variants of genes encoding TNF receptors and ligands and proteins regulating TNF activation in familial multiple sclerosis
Authors: Torre‐Fuentes Laura , Matías‐Guiu Jordi A. , Pytel Vanesa , Montero‐Escribano Paloma , Maietta Paolo , Álvarez Sara , Gómez‐Pinedo Ulises , Matías‐Guiu Jorge
Published: September 2020

Introduction

Numerous genetic variants have been associated with susceptibility to multiple sclerosis (MS). Variants located in genes involved in specific pathways, such as those affecting TNF‐α, can contribute to the risk of MS. The purpose of this study was to determine whether variants of these genes are associated with greater risk of MS.

Methods

We used whole‐exome sequencing to study genes coding for TNF‐α receptors and ligands, and proteins promoting TNF‐α expression in 116 individuals from 19 families including at least two MS patients. We compared patients with MS, patients with other autoimmune diseases, and healthy individuals.

Results

Greater polymorphism was observed in several genes in families with familial MS compared to the general population; this may reflect greater susceptibility to autoimmune diseases. Pedigree analysis also revealed that LT‐α variants rs1041981 and rs2229094 and LT‐β variant rs4647197 were associated with MS and that LT‐β variant rs4647183 was associated with other autoimmune diseases. The association between autoimmune disease and TNFAIP2 variant rs1132339 is particularly noteworthy, as is the fact that TNFAIP6 variant rs1046668 appears to follow a recessive inheritance pattern.

Conclusions

Our findings support the idea that the risk of familial MS is associated with variants of signaling pathways, including those involving TNF‐α.
Comprehensive analysis of ubiquitin‐specific protease 1 reveals its importance in hepatocellular carcinoma
Authors: Zhao Yalei , Xue Chen , Xie Zhongyang , Ouyang Xiaoxi , Li Lanjuan
Published: September 2020

Objectives

In this study, we comprehensively analysed the role of ubiquitin‐specific protease 1(USP1) in hepatocellular carcinoma (HCC) using data from a set of public databases.

Materials and Methods

We analysed the mRNA expression of USP1 in HCC and subgroups of HCC using Oncomine and UALCAN. Survival analysis of USP1 in HCC was conducted with the Kaplan‐Meier Plotter database. The mutations of USP1 in HCC were analysed using cBioPortal and the Catalogue of Somatic Mutations in Cancer database. Differential genes correlated with USP1 and WD repeat domain 48 (WDR48) were obtained using LinkedOmics. USP1 was knocked down with small interfering RNA (siRNA) or pharmacologically inhibited by ML‐323 in MHCC97H or SK‐Hep‐1 cell lines for function analysis.

Results

High USP1 expression predicted unfavourable overall survival in HCC patients. USP1 showed positive correlations with the abundances of macrophages and neutrophils. We identified 98 differential genes that were positively correlated with both USP1 and WDR48. These genes were mainly involved in the cell cycle, aldosterone synthesis and secretion and oestrogen signalling pathways. Interactions between USP1 and WDR 48 were confirmed using co‐immunoprecipitation. USP1 knockdown or ML‐323 treatment reduced the expression of proliferating cell nuclear antigen (PCNA), cyclin D1 and cyclin E1.

Conclusions

Overall, USP1 is a promising target for HCC treatment with good prognostic value. USP1 and WDR48 function together in regulating cancer cell proliferation via the cell cycle.
Subclinical left ventricular dysfunction in Sjögren’s syndrome assessed by four‐dimensional speckle tracking echocardiography
Authors: Akaycan Jülide , Hidayet Şıho , Bayramoğlu Adil , Yolbaş Servet , Karaca Yücel , Yiğit Yakup , Ulutaş Zeynep
Published: September 2020

Objective

The aim of this study was to evaluate the left ventricular (LV) systolic strain by four‐dimensional speckle tracking echocardiography (4D‐STE) in order to provide the early detection of myocardial dysfunction in patients with Sjögren's syndrome (SS).

Methods

Forty consecutive patients with primary SS diagnosed at the rheumatology outpatient clinic and 35 age‐ and sex‐matched healthy volunteers were included in the study. 4DSTE was performed, and global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), and global area strain (GAS) were measured. 4DSTE results were compared with the healthy volunteers.

Results

No significant differences were observed between the GRS and GCS values of the two groups. A significant difference was observed in the GLS and GAS measurements between the two groups (P = .005 for GLS, P < .001 for GAS). Positive correlation was detected between disease duration and LV‐GLS and LV‐GAS.

Conclusion

We demonstrated subclinical systolic dysfunction in SS patients by 4DSTE, which is a sensitive marker of ventricular dysfunction. Deterioration of the LV became more evident as duration of the disease increased. Therefore, we believe that a cardiac evaluation will be of benefit to patients with long‐term SS.
Impact of body mass index on relapse in children with acute lymphoblastic leukemia treated according to Nordic treatment protocols
Authors: Egnell Christina , Ranta Susanna , Banerjee Joanna , Merker Andrea , Niinimäki Riitta , Lund Bendik , Mogensen Pernille Rudebeck , Jonsson Ólafur G. , Vaitkeviciene Goda , Lepik Kristi , Forslund Anders , Heyman Mats , Harila‐Saari Arja
Published: September 2020

Objectives

High body mass index (BMI) is associated with poorer survival in childhood acute lymphoblastic leukemia (ALL), but the actual impact on the risk of relapse still needs to be clarified. We evaluated the impact of BMI at diagnosis on the risk of relapse in children with ALL treated according to Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols.

Method

In a multicenter study, we collected data on BMI at diagnosis and outcome of 2558 children aged 2.0‐17.9 years diagnosed between 1992 and 2016. Patients were divided into four groups according to International Obesity Task Force (IOTF) childhood BMI cut‐offs: underweight, <17; healthy weight, 17‐25; overweight, 25‐30; and obese, ≥30 kg/m2.

Results

In Cox multivariate regression analyses, an increased risk of relapse was observed in children aged 10‐17.9 years with unhealthy BMI at diagnosis (underweight hazard ratio HR: 2.90 [95% confidence interval: 1.24‐6.78], P = .01; overweight, HR: 1.95 [1.11‐3.43], P = .02, and obese HR: 4.32 [95% 2.08‐8.97], P < .001), compared to children with healthy weight. BMI had no impact on relapse in children under 10 years of age.

Conclusion

High BMI, and especially obesity at diagnosis, is an independent adverse prognostic factor for relapse in older children with ALL.
Breaking down experience—Heidegger's methodological use of breakdown in Being and Time
Authors: Ward Katherine
Published: September 2020

Phenomenologists draw on descriptions of experience to uncover the conditions that enable experience. However, a second‐order or distanced view of experience can distort it. In his analysis of the ready‐to‐hand, Heidegger utilizes experiences of breakdown to avoid this problem, but he does not provide a detailed account of why this methodology is effective. I use Heidegger's analysis of interpretation to reconstruct a detailed account of the breakdown methodology and show why it avoids the problem of “observation distortion.” Although Heidegger is only explicit about his use of this methodology in the analysis of the ready‐to‐hand, I show that analyses of breakdown experiences are implicit throughout Being and Time and have an important role in two key moments of the analysis of Dasein: Being‐with (publicness) and Dasein's structural whole (care).
Attended vs unattended systolic blood pressure measurement: A randomized comparison in patients with cardiovascular disease
Authors: Keeley Ellen C. , Villanueva Matthew , Chen Yiqing E. , Gong Yan , Handberg Eileen M. , Smith Steven M. , Pepine Carl J. , Cooper‐DeHoff Rhonda M.
Published: September 2020

Recent clinical guidelines recommend lower blood pressure (BP) goals for most patients, and recent trends have favored use of automated unattended BP measurements in the office setting to minimize observer error and white‐coat effects. Patients attending a routinely scheduled CVD clinic visit were prospectively randomized to BP measured using an attended, followed by an unattended method, or vice versa, after a controlled rest period. All study BP measurements were obtained in triplicate using the automated Omron HEM‐907XL BP monitor, and averaged. The outcome was difference in SBP. Routinely measured clinic BP from the same visit was extracted from the medical record, and compared with attended and unattended BP. A total of 102 patients were randomized, and mean age was 63 years, 52% female and 75% Caucasian. Attended and unattended SBP was 125.4 ± 20.4 and 122.6 ± 21.0 mm Hg, mean ± SD, respectively. Routine clinic SBP was 130.6 ± 23.6 mm Hg. Attended SBP was 2.7 mm Hg higher than the unattended measurement (95% CI 1.3‐4.1; P = .0002). Routine clinic SBP was 5.2 mm Hg higher than attended SBP (95% CI 2.4‐8.0; P = .0003) and 8.0 mm Hg higher than unattended SBP (95% CI 5.4‐10.5; P < .0001). Attended measurement of BP is significantly higher than unattended measurement and the difference is physiologically meaningful, even in a CVD cohort with generally well‐controlled hypertension. Furthermore, routine clinic SBP substantially overestimates both attended and unattended automated SBP, with important implications for treatment decisions like dose and/or drug escalation.
The longitudinal association between externalizing behavior and frontoamygdalar resting‐state functional connectivity in late adolescence and young adulthood
Authors: Thijssen Sandra , Collins Paul F. , Weiss Hannah , Luciana Monica
Published: September 2020

Background

Externalizing behavior has been attributed, in part, to decreased frontolimbic control over amygdala activation. However, little is known about developmental trajectories of frontoamygdalar functional connectivity and its relation to externalizing behavior. The present study addresses this gap by examining longitudinal associations between adolescent and adult externalizing behavior and amygdala–anterior cingulate cortex (ACC) and amygdala–orbitofrontal cortex (OFC) resting‐state functional connectivity in a sample of 111 typically developing participants aged 11–23 at baseline.

Methods

Participants completed two‐to‐four data waves spaced approximately two years apart, resulting in a total of 309 data points. At each data wave, externalizing behavior was measured using the Externalizing Behavior Broadband Scale from the Achenbach Youth/Adult Self‐Report questionnaire. Resting‐state fMRI preprocessing was performed using FSL. Amygdala functional connectivity was examined using AFNI. The longitudinal association between externalizing behavior and amygdala–ACC/OFC functional connectivity was examined using linear mixed effect models in R.

Results

Externalizing behavior was associated with increased amygdala–ACC and amygdala–OFC resting‐state functional connectivity across adolescence and young adulthood. For amygdala–ACC connectivity, externalizing behavior at baseline primarily drove this association, whereas for amygdala–OFC functional connectivity, change in externalizing behavior relative to baseline drove the main effect of externalizing behavior on amygdala–OFC functional connectivity. No evidence was found for differential developmental trajectories of frontoamygdalar connectivity for different levels of externalizing behavior (i.e., age‐by‐externalizing behavior interaction effect).

Conclusions

Higher externalizing behavior is associated with increased resting‐state attunement between the amygdala and ACC/OFC, perhaps indicating a generally more vigilant state for neural networks important for emotional processing and control.