bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduction of collinear inhibition in observers with central vision loss using anodal transcranial direct current stimulation: A case series
Authors: Raveendran Rajkumar Nallour , Chow Amy , Tsang Katelyn , Chakraborty Arijit , Thompson Benjamin 
Published: November 2020

AbstractPeople with central vision loss (CVL) due to macular degeneration are forced to rely on their residual peripheral vision and often develop a preferred retinal locus (PRL), a region of intact peripheral retina that is used for fixation. At the PRL, visual processing is impaired due to crowding (cluttering of visual objects). The problem of crowding still persists when images are magnified to account for the lower resolution of peripheral vision. We assessed whether anodal transcranial direct stimulation (a-tDCS), a neuro-modulation technique that alters cortical inhibition, would reduce collinear inhibition (an early component of crowding) when applied to the visual cortex in patients with CVL. Our results showed that applying a-tDCS to the visual cortex for 20mins reduced crowding in three patients with CVL and that the effect was sustained for up to 30mins. Sham stimulation delivered in a separate session had no effect. These initial observations mandate further research into the use of a-tDCS to enhance cortical processing of residual retinal input in patients with CVL.
Structure, interdomain dynamics and pH-dependent autoactivation of pro-rhodesain, the main lysosomal cysteine protease from African trypanosomes
Authors: Johé Patrick , Jaenicke Elmar , Neuweiler Hannes , Schirmeister Tanja , Kersten Christian , Hellmich Ute A. 
Published: November 2020

AbstractRhodesain is the lysosomal cathepsin L-like cysteine protease ofT. brucei rhodesiense, the causative agent of Human African Trypanosomiasis. The enzyme is essential for the proliferation and pathogenicity of the parasite as well as its ability to overcome the blood-brain barrier of the host. Lysosomal cathepsins are expressed as zymogens with an inactivating pro-domain that is cleaved under acidic conditions. A structure of the uncleaved maturation intermediate from a trypanosomal cathepsin L-like protease is currently not available. We thus established the heterologous expression ofT. brucei rhodesiensepro-rhodesain inE. coliand determined its crystal structure. The trypanosomal pro-domain differs from non-parasitic pro-cathepsins by a unique, extended α-helix that blocks the active site and whose interactions resemble that of the antiprotozoal inhibitor K11777. Interdomain dynamics between pro- and core protease domain as observed by photoinduced electron transfer fluorescence correlation spectroscopy increase at low pH, where pro-rhodesain also undergoes autocleavage. Using the crystal structure, molecular dynamics simulations and mutagenesis, we identify a conserved interdomain salt bridge that prevents premature intramolecular cleavage at higher pH values and may thus present a control switch for the observed pH-sensitivity of pro-enzyme cleavage in (trypanosomal) CathL-like proteases.
The Brain Activation-based Sexual Image Classifier (BASIC): A sensitive and specific fMRI activity pattern for sexual image perception
Authors: van ’t Hof Sophie R. , Van Oudenhove Lukas , Klein Sanja , Reddan Marianne C. , Kragel Philip A. , Stark Rudolf , Wager Tor D. 
Published: November 2020

AbstractSexual stimuli processing is a key element in the repertoire of human affective and motivational states. Previous neuroimaging studies of sexual stimulus processing have revealed a complicated mosaic of activated regions, leaving unresolved questions about their sensitivity and specificity to sexual stimuli per se, generalizability across individuals, and potential utility as neuromarkers for sexual stimulus processing. In this study, data on sexual, negative, non-sexual positive, and neutral images from Wehrum et al. (2013) (N = 100) were re-analyzed with multivariate Support Vector Machine models to create the Brain Activation-based Sexual Image Classifier (BASIC) model. This model was tested for sensitivity, specificity, and generalizability in cross-validation (N = 100) and an independent test cohort (N = 18; Kragel et al. 2019). The BASIC model showed highly accurate performance (94-100%) in classifying sexual versus neutral or nonsexual affective images in both datasets. Virtual lesions and test of individual large-scale networks (e.g., ‘visual’ or ‘attention’ networks) show that these individual networks are neither necessary nor sufficient to capture sexual stimulus processing. These findings suggest that brain responses to sexual stimuli constitute a category of mental event that is distinct from general affect and involves multiple brain networks. It is, however, largely conserved across individuals, permitting the development of neuromarkers for sexual processing in individual persons. Future studies could assess performance of BASIC to a broader array of affective/motivational stimuli and link brain responses with physiological and subjective measures of sexual arousal.
Evaluating the reproducibility of single-cell gene regulatory network inference algorithms
Authors: Kang Yoonjee , Thieffry Denis , Cantini Laura 
Published: November 2020

AbstractNetworks are powerful tools to represent and investigate biological systems. The development of algorithms inferring regulatory interactions from functional genomics data has been an active area of research. With the advent of single-cell RNA-seq data (scRNA-seq), numerous methods specifically designed to take advantage of single-cell datasets have been proposed. However, published benchmarks on single-cell network inference are mostly based on simulated data. Once applied to real data, these benchmarks take into account only a small set of genes and only compare the inferred networks with an imposed ground-truth.Here, we benchmark four single-cell network inference methods based on their reproducibility, i.e. their ability to infer similar networks when applied to two independent datasets for the same biological condition. We tested each of these methods on real data from three biological conditions: human retina, T-cells in colorectal cancer, and human hematopoiesis.GENIE3 results to be the most reproducible algorithm, independently from the single-cell sequencing platform, the cell type annotation system, the number of cells constituting the dataset, or the thresholding applied to the links of the inferred networks. In order to ensure the reproducibility and ease extensions of this benchmark study, we implemented all the analyses in scNET, a Jupyter notebook available athttps://github.com/ComputationalSystemsBiology/scNET.
Dihydroceramide desaturase promotes the formation of intraluminal vesicles and inhibits autophagy to increase exosome production
Authors: Wu Chen-Yi , Jhang Jhih-Gang , Lin Wan-Syuan , Lin Chih-Wei , Chu Li-An , Chiang Ann-Shyn , Ho Han-Chen , Chan Chih-Chiang , Huang Shu-Yi 
Published: November 2020

SummaryExosomes are important for cell-cell communication. Deficiencies in the human dihydroceramide desaturase gene,DEGS1, increase the dihydroceramide-to-ceramide ratio and causes hypomyelinating leukodystrophy. However, the disease mechanism remains unknown. Here, we developed anin vivoassay with spatially controlled expression of exosome markers inDrosophilaeye imaginal discs and showed that the level and activity of the DEGS1 ortholog,ifc, correlated with exosome production. Knocking outifcdecreased the density of the exosome precursor intraluminal vesicles (ILVs) in the multivesicular endosomes and reduced the number of exosomes released. Whileifcoverexpression and autophagy inhibition both enhanced exosome production, combining the two had no additive effect. Moreover, DEGS1 activity was sufficient to drive ILV formationin vitro. Together, DEGS1/Ifc controls the dihydroceramide-to-ceramide ration and enhances exosome secretion by promoting ILV formation and preventing the autophagic degradation of MVEs.These findings provide a potential cause for the neuropathy associated with DEGS1-deficient mutations.Graphical AbstractHighlightsAnin vivosystem was developed for observing exosome production inDrosophila.Dihydroceramide desaturase (DEGS1/Ifc) promotes exosome production by two means.Ifc drives membrane invagination to promote the formation of intraluminal vesicles.Ifc inhibits autophagic degradation of MVEs and increases exosome release.eTOC BlurbThe level and activity of dihydroceramide desaturase (human DEGS1 and Drosophila Ifc) correlate with exosome production. Wu et al. show that DEGS1 drives the formation of intraluminal vesiclesin vivoandin vitro. Overexpressing Ifc inhibits autophagy and reduces the degradation of multivesicular endosomes, thus increases exosome release.
ECM remodeling and spatial cell cycle coordination determine tissue growth kinetics
Authors: Ainslie Anna P. , Davis John Robert , Williamson John J. , Ferreira Ana , Torres-Sánchez Alejandro , Hoppe Andreas , Mangione Federica , Smith Matthew B. , Martin-Blanco Enrique , Salbreux Guillaume , Tapon Nicolas 
Published: November 2020

SummaryDuring development, multicellular organisms undergo stereotypical patterns of tissue growth to yield organs of highly reproducible sizes and shapes. How this process is orchestrated remains unclear. Analysis of the temporal dynamics of tissue growth in theDrosophilaabdomen reveals that cell cycle times are spatially correlated and that growth termination occurs through the rapid emergence of a population of arrested cells rather than a gradual slowing down of cell cycle time. Reduction in apical tension associated with tissue crowding has been proposed as a developmental growth termination mechanism. Surprisingly, we find that growth arrest in the abdomen occurs while apical tension increases, showing that in this tissue a reduction in tension does not underlie the mechanism of growth arrest. However, remodeling of the extracellular matrix is necessary for tissue expansion. Thus, changes in the tissue microenvironment, and a rapid exit from proliferation, control the formation of the adultDrosophilaabdomen.
Docosahexaenoic acid alone and in combination with carboplatin significantly reduces tumor cell growth in preclinical models of ovarian cancer
Authors: Bilyk Olena , Hamedi Bahareh , Dutta Indrani , Newell Marnie , Bukhari Amirali B. , Gamper Armin M. , McVea Rojine C. , Liu Jiahui , Schueler Julia , Siegers Gabrielle M. , Field Catherine J. , Postovit Lynne-Marie 
Published: November 2020

ABSTRACTDespite recent advances in diagnosis and treatment, ovarian cancer (OC) is the most lethal gynecological malignancy and improving the efficacy of chemotherapy is of great interest. This study increases our understanding of how dietary intervention with docosahexaenoic acid (DHA)-a supplement proven safe for human consumption – enhances the anti-cancer effects of conventional chemotherapy. Our results demonstrated synergistic cell killing by DHA and carboplatin in OC cell lines. Furthermore, DHA supplementation alone and in combination with carboplatin significantly reduced OC growth in a high-grade serous OC patient-derived xenograft mouse model. Carboplatin administered intraperitoneally significantly reduced tumor growth in DHA-fed mice compared to mice on the control diet. Intravenous carboplatin administration in combination with DHA reduced tumor growth similarly to carboplatin or DHA monotherapies. The DHA-induced reduction in tumor growth in this model was associated with increased tumor necrosis and improved survival. As such, our findings provide a strong rationale to move to clinical trials that will determine whether DHA supplementation enhances the efficacy and tolerance of cytotoxic chemotherapy in patients with OC.
A novel membrane protein Hoka regulates septate junction organization and stem cell homeostasis in theDrosophilagut
Authors: Izumi Yasushi , Furuse Kyoko , Furuse Mikio 
Published: November 2020

AbstractSmooth septate junctions (sSJs) regulate the paracellular transport in the intestinal and renal system in arthropods. InDrosophila, the organization and physiological function of sSJs are regulated by at least three sSJ-specific membrane proteins: Ssk, Mesh, and Tsp2A. Here, we report a novel sSJ membrane protein Hoka, which has a single membrane-spanning segment with a short extracellular region having 13-amino acids, and a cytoplasmic region with three repeats of the Tyr-Thr-Pro-Ala motif. The larval midgut inhoka-mutants shows a defect in sSJ structure. Hoka forms a complex with Ssk, Mesh, and Tsp2A and is required for the correct localization of these proteins to sSJs. Knockdown ofhokain the adult midgut leads to intestinal barrier dysfunction, stem cell overproliferation, and epithelial tumors. Inhoka-knockdown midguts, aPKC is up-regulated in the cytoplasm and the apical membrane of epithelial cells. The depletion ofaPKCandykiinhoka-knockdown midguts results in reduced stem cell overproliferation. These findings indicate that Hoka cooperates with the sSJ-proteins Ssk, Mesh, and Tsp2A to organize sSJs, and is required for maintaining intestinal stem cell homeostasis through the regulation of aPKC and Yki activities in theDrosophilamidgut.Summary statementDepletion ofhoka, a gene encoding a novel septate junction protein, from theDrosophilamidgut results in the disruption of septate junctions, intestinal barrier dysfunction, stem cell overproliferation, and epithelial tumors.
Biochemical and structural studies of target lectin SapL1 from the emerging opportunistic microfungusScedosporium apiospermum
Authors: Martínez-Alarcón Dania , Balloy Viviane , Bouchara Jean-Philippe , Pieters Roland J. , Varrot Annabelle 
Published: November 2020

AbstractScedosporium apiospermumis an emerging opportunistic fungal pathogen responsible for life-threatening infections in humans. Host-pathogen interactions often implicate lectins that have become therapeutic targets for the development of carbohydrate mimics for antiadhesive therapy. Here, we present the first report on the identification and characterization of a lectin fromS. apiospermumnamed SapL1. SapL1 was found using bioinformatics as a homolog to the conidial surface lectin FleA fromAspergillus fumigatusknown to play a role in the adhesion to host glycoconjugates present in human lung epithelium. In our strategy to obtain recombinant SapL1, we discovered the importance of osmolytes to achieve its expression in soluble form in bacteria. Analysis of glycan arrays indicates specificity for fucosylated oligosaccharides as expected. Submicromolar affinity was measured for fucose using isothermal titration calorimetry. We solved SapL1 crystal structure in complex with α-methyl-L-fucoside and analyzed its structural basis for fucose binding. We finally demonstrated that SapL1 binds to bronchial epithelial cells in a fucose-dependent manner. The information gathered here will contribute to the design and development of glycodrugs targeting SapL1.
The endosomal TbTpr86/TbUsp7/SkpZ (TUS) complex controls surface protein abundance in trypanosomes
Authors: Yamada Kayo , Yaqub Farzana K. , Zoltner Martin , Field Mark C. 
Published: November 2020

AbstractIn trypanosomes the orthologs of human USP7 and VDU1 control abundance of a cohort of surface proteins, including invariant surface glycoproteins (ISGs) by functioning as deubiquitinases (DUBs) Silencing TbUsp7 partially inhibits endocytosis and invariant surface glycoprotein turnover. As a component of cullin E3 ubiquitin ligases, S-phase kinase-associated protein 1 (Skp1) has crucial roles in cell cycle progression, transcriptional regulation, signal transduction and other processes in animals and fungi. Unexpectedly, trypanosomes possess multiple Skp1 paralogs, including a divergent paralog designated SkpZ. SkpZ is implicated in suramin-sensitivity and endocytosis and decreases in abundance following TbUsp7 knockdown and physically interacts with TbUsp7 and TbTpr86. The latter is a tetratricopeptide-repeat protein also implicated in suramin sensitivity and located close to the flagellar pocket/endosomes, consistent with a role in endocytosis. Further, silencing SkpZ reduced abundance of TbUsp7 and TbTpr86 and manytrans-membrane domain surface proteins. Our data indicate that TbTpr86, TbUsp7 andSkpZ form the ‘TUS’ complex that regulates abundance of a significant cohort of trypanosome surface proteins.
CD127 imprints functional heterogeneity to diversify monocyte responses in human inflammatory diseases
Authors: Zhang Bin , Zhang Yuan , Xiong Lei , Li Yuzhe , Zhang Yunliang , Zhao Jiuliang , Jiang Hui , Li Can , Liu Yunqi , Liu Xindong , Liu Haofei , Ping Yi-Fang , Zhang Qiangfeng Cliff , Zhang Zheng , Bian Xiu-Wu , Zhao Yan , Hu Xiaoyu 
Published: November 2020

AbstractStudies on human monocytes historically focused on characterization of bulk responses, whereas functional heterogeneity is largely unknown. Here, we identified an inducible population of CD127-expressing human monocytes under inflammatory conditions and named the subset M127. M127 is nearly absent in healthy individuals yet abundantly present in patients with infectious and inflammatory conditions such as COVID-19 and rheumatoid arthritis. Multiple genomic and functional approaches revealed unique gene signatures of M127 and unified anti-inflammatory properties imposed by the CD127-STAT5 axis. M127 expansion correlated with mild COVID-19 disease outcomes. Thereby, we phenotypically and molecularly characterized a human monocyte subset marked by CD127 that retained anti-inflammatory properties within the pro-inflammatory environments, uncovering remarkable functional diversity among monocytes and signifying M127 as a potential therapeutic target for human inflammatory disorders.
Bispecific tau antibodies with additional binding to C1q or alpha-synuclein
Authors: Quint Wim Hendricus , Matečko-Burmann Irena , Schilcher Irene , Löffler Tina , Schöll Michael , Burmann Björn Marcus , Vogels Thomas 
Published: November 2020

AbstractBackgroundAlzheimer’s disease (AD) and other tauopathies are neurodegenerative disorders characterized by cellular accumulation of aggregated tau protein. Tau pathology within these disorders is accompanied by chronic neuroinflammation, such as activation of the classical complement pathway by complement initiation factor C1q. Additionally, about half of the AD cases present with inclusions composed of aggregated alpha-synuclein called Lewy bodies. Lewy bodies in disorders such as Parkinson’s disease and Lewy body dementia also frequently occur together with tau pathology. Immunotherapy is currently the most promising treatment strategy for tauopathies. However, the presence of multiple pathological processes within tauopathies makes it desirable to simultaneously target more than one disease pathway.MethodsHerein, we have developed three bispecific antibodies based on published antibody binding region sequences. One bispecific antibody binds to tau plus alpha-synuclein and two bispecific antibodies bind to tau plus C1q.ResultsThe affinity of the bispecific antibodies to their targets compared to their monospecific counterparts ranged from nearly identical to one order of magnitude lower. All bispecific antibodies retained binding to aggregated protein in patient-derived brain sections. The bispecific antibodies also retained their ability to inhibit aggregation of recombinant tau, regardless of whether the tau binding sites were in IgG or scFv format. Mono- and bispecific antibodies inhibited cellular seeding induced by AD-derived pathological tau with similar efficacy. Finally, both Tau-C1q bispecific antibodies completely inhibited the classical complement pathway.ConclusionBispecific antibodies that bind to multiple pathological targets may therefore present a promising approach to treat tauopathies and other neurodegenerative disorders.
Neural representation of words within phrases: Temporal evolution of color-adjectives and object-nouns during simple composition
Authors: Honari-Jahromi Maryam , Chouinard Brea , Blanco-Elorrieta Esti , Pylkkänen Liina , Fyshe Alona 
Published: November 2020

ABSTRACTIn language, stored representations of lexical items combine into an infinitude of complex expressions. While the neuroscience of composition has begun to mature, we do not yet understand how the stored representations evolve and morph during composition. New decoding techniques allow us to crack open this very hard question: we can train a model to recognize a representation in one context or time-point and assess its accuracy in another. We combined the decoding approach with magnetoencephalography recorded during a picture naming task to investigate the temporal evolution of noun and adjective representations during speech planning. We tracked word representations as they combined into simple two-word phrases, using single words and two-word lists as non-combinatory controls. We found that nouns were generally more decodable than adjectives, suggesting that noun representations were stronger and/or more consistent across trials than those of adjectives. When training and testing across contexts and times, the representations of isolated nouns were recoverable when those nouns were embedded in phrases, but not so if they were embedded in lists. Adjective representations did not show a similar consistency across isolated and phrasal contexts. Noun representations in phrases also sustained over time in a way that was not observed for any other pairing of word class and context. These findings offer a new window into the temporal evolution and context sensitivity of word representations during composition, revealing a clear asymmetry between adjectives and nouns. The impact of phrasal contexts on the decodability of nouns may be due to the nouns’ status as head of phrase—an intriguing hypothesis for future research.
Bi-level positive airway pressure (biPAP) for non-invasive respiratory support of foals
Authors: Raidal Sharanne L , Burgmeestre Lexi , Catanchin Chee Sum Melanie , Quinn Chris T 
Published: November 2020

AbstractRespiratory insufficiency and pulmonary health are important considerations in equine neonatal care, as the majority of foals are bred for athletic function. The administration of supplementary oxygen is readily implemented in equine practice settings, but this does not address respiratory insufficiency due to inadequate ventilation and is no longer considered optimal care for hypoxia in some settings. Non-invasive ventilatory strategies including continuous or bi-level positive airway pressure are effective in human and veterinary studies, and may offer improved respiratory support in equine clinical practice. The current study was conducted in two parts to investigate the use of a commercial bilevel positive airway pressure (biPAP) ventilator, designed for home care of people with obstructive respiratory conditions, for respiratory support of foals. In Part 1 a prospective observational study was conducted to evaluate the effect of sequential application of supplementary oxygen and then biPAP for respiratory support of five foals ≤ 4 days of age hospitalised with respiratory in sufficiency (Group 1) and four healthy, sedated foals < 28 days of age (Group 2). In Part 2, biPAP and supplementary oxygen were administered to six healthy foals with pharmacologically induced respiratory insufficiency in a two sequence, two phase, cross-over study (Group 3). Non-invasive ventilation by biPAP improved gas exchange and mechanics of breathing (increased tidal volume, decreased respiratory rate and increased peak inspiratory flow) in foals, but modest hypercapnia was observed in healthy, sedated foals (Groups 2 and 3). Clinical cases (Group 1) appeared less likely to develop hypercapnia in response to treatment, however the response in individual foals was variable, and close monitoring is necessary. Clinical observations, pulse oximetry and CO2monitoring of expired gases were of limited benefit in identification of foals responding inappropriately to biPAP, and improved methods to assess and monitor respiratory function are required in foals.