bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Vitamin-D receptor (VDR) by a small molecule antagonist MeTC7 inhibits PD-L1 but controls THMYCN neuroblastoma growth PD-L1 independently
Authors: Singh Rakesh K. , Kim KyuKwang , Rowswell-Turner Rachael B. , Hansen Jeanne N. , Khazan Negar , Jones Aaron , Sivagnanalingam Umayal , Teramoto Yuki , Goto Takuro , Jian Ye , Battaglia Nicholas , Conley Thomas , Hovanesian Virginia , Yano Naohiro , Pandita Ravina , Arnold Leggy A. , Hopson Russel , Ojha Debasmita , Sharon Ashoke , Ashton John , Miyamoto Hiroshi , Schor Nina F. , Milano Michael T. , Linehan David C. , Gerber Scott A. , Moore Richard G. 
Published: August 2020

AbstractVitamin-D receptor (VDR) mRNA is enriched in malignant lung, ovarian and pancreatic tissues and showed poor prognoses. Calcitriol and stable or CRISPR-directed VDR upregulation increased PD-L1mRNA and protein expression in cancer cells in-vitro. A ChIP assay showed the binding of VDR with VDREPD-L1. Stattic, a STAT3 phosphorylation inhibitor blocked calcitriol or VDR overexpression induced PD-L1 upregulation. MeTC7, a VDR antagonist developed by us, reduced PD-L1 expression on macrophages, ovarian, lung, breast, and pancreatic cancer cells in-vitro. In radiotherapy inducible PD-L1 model of orthotopic MC38 murine colon cancer, MeTC7 decreased PD-L1 surface expression, suppressed inflammatory monocytes (IMs) population and increased intra-tumoral CD69+PD1+CD8+T-cells. Intriguingly, MeTC7 reduced TH-MYCN transgenic neuroblastoma tumor growth without affecting PD-L1 and tumor immune milieu. In summary, Vitamin-D/VDR drives PD-L1 expression on cancer cells via STAT-3. Inhibiting VDR exhibited anti-checkpoint effects in orthotopic colon tumors, whereas PDL1-independent and anti-VDR/MYCN effects controlled growth of transgenic neuroblastoma and xenografted tumors.SummaryVitamin-D/VDR induces PD-L1 expression on cancer cells via STAT-3; and targeting VDR by a novel small molecule antagonist MeTC7 exhibits both anti-PD-L1 and anti-VDR/MYCN effects in tumor models.
From the Andes to the desert: First overview of the bacterial community in the Rimac river, the main source of water for Lima, Peru
Authors: Romero Pedro E. , Calla-Quispe Erika , Castillo-Vilcahuaman Camila , Yokoo Mateo , Fuentes-Rivera Hammerly Lino , Ramirez Jorge L. , Ibáñez Alfredo J. , Wong Paolo 
Published: August 2020

AbstractBackgroundThe Rimac river is the main source of water for Lima, Peru’s capital megacity. The river is constantly affected by different types of contamination including mine tailings in the Andes and urban sewage in the metropolitan area. We aim to produce the first characterization of bacterial communities in the Rimac river using a 16S rRNA amplicon sequencing approach which would be useful to identify bacterial diversity and potential understudied pathogens.ResultsWe report a higher diversity in bacterial communities from the Upper and, especially, Middle Rimac compared to the Lower Rimac (Metropolitan zone). Samples were generally grouped according to their geographical location. Bacterial classes Alphaproteobacteria, Bacteroidia, Campylobacteria, Fusobacteriia, and Gammaproteobacteria were the most frequent along the river.Arcobacter cryaerophilus(Campylobacteria) was the most frequent species in the Lower Rimac whileFlavobacterium succinicans(Bacteroidia) andHypnocyclicus(Fusobacteriia) were the most predominant in the Upper Rimac. Predicted metabolic functions in the microbiota include bacterial motility, quorum sensing and xenobiotics metabolism. Additional metabolomic analyses showed the presence natural flavonoids and antibiotics in the Upper Rimac, and herbicides in the Lower Rimac.ConclusionsThe dominance in the Metropolitan area ofArcobacter cryaerophilus, an emergent pathogen associated with fecal contamination and antibiotic multiresistance, but that is not usually reported in traditional microbiological quality assessments, highlights the necessity to apply next-generation sequencing tools to improve pathogen surveillance. We believe that our study will encourage the integration of omics sciences in Peru and its application on current environmental and public health issues.
Statelets: High dimensional predominant shapes in dynamic functional network connectivity
Authors: Rahaman Md Abdur , Damaraju Eswar , Saha Debbrata Kumar , Plis Sergey M. , Calhoun Vince D. 
Published: August 2020

AbstractDynamic functional network connectivity (dFNC) analysis is a widely used approach for capturing brain activation patterns, connectivity states, and network organization. However, a typical sliding window plus clustering (SWC) approaches for analyzing dFNC continuously models the system through a fixed set of connectivity patterns or states. It assumes these patterns are span throughout the brain, but in practice, they are more spatially constrained and temporally short-lived. Thus, SWC is not designed to capture transient dynamic changes nor heterogeneity across subjects/time. Here, we adapt time series motifs to model the temporal dynamics of functional connectivity. We propose a state-space data mining approach that combines a probabilistic pattern summarization framework called ‘Statelets’ — a subset of high dimensional state-shape prototypes capturing the dynamics. We handle scale differences using the earth mover distance and utilize kernel density estimation to build a probability density profile for local motifs. We apply the framework to study dFNC collected from patients with schizophrenia (SZ) and healthy control (HC). Results demonstrate SZ subjects exhibit reduced modularity in their brain network organization relative to HC. These statelets in the HC group show more recurrence across the dFNC time-course compared to the SZ. An analysis of the consistency of the connections across time reveals significant differences within visual, sensorimotor, and default mode regions where HC subjects show higher consistency than SZ. The introduced statelet-approach also enables the handling of dynamic information in cross-modal applications to study healthy and disordered brains and multi-modal fusion within a single dataset.
THE YKI-CACTUS (IKBα)-JNK AXIS PROMOTES TUMOR GROWTH AND PROGRESSION IN DROSOPHILA
Authors: Snigdha Kirti , Singh Amit , Kango-Singh Madhuri 
Published: August 2020

AbstractPresence of inflammatory factors in the tumor microenvironment is well known yet their specific role in tumorigenesis is elusive. The core inflammatory pathways are conserved inDrosophila, including the Toll-Like Receptor (TLR) and the Tumor Necrosis Factor (TNF) pathway. We usedDrosophilatumor models to study the role of inflammatory factors in tumorigenesis. Specifically, we co-activated oncogenic forms ofRasV12or its major effector Yorkie (Yki3SA) in polarity deficient cells mutant for tumor suppressor genescribble(scrib) marked by GFP undernubGAL4or in somatic clones. This system recapitulates the clonal origins of cancer, and shows neoplastic growth, invasion and lethality. We investigated if TLR and TNF pathway affect growth ofYki3SAscribRNAiorRasV12scribRNAitumors through activation of tumor promoting Jun N-terminal Kinase (JNK) pathway and its target Matrix Metalloprotease1 (MMP1). We report, TLR component, Cactus (Cact) is highly upregulated inYki3SAscribRNAiorRasV12scribRNAitumors.DrosophilaCactus (mammalian IKBα) acts as an inhibitor of NFKB signaling that plays key roles in inflammatory and immune response. Here we show an alternative role for Cactus, and by extension cytokine mediated signaling, in tumorigenesis. Downregulating Cact affects both tumor progression and invasion. Interestingly, downregulating TNF receptors in tumor cells did not affect their invasiveness despite reducing JNK activity. Genetic analysis suggested that Cact and JNK are key regulators of tumor progression. Overall, we show that Yki plays a critical role in tumorigenesis by controlling Cact, which in turn, mediates tumor promoting JNK oncogenic signaling in tumor cells.
Entraining stepping movements of Parkinson’s patients to alternating subthalamic nucleus deep brain stimulation
Authors: Fischer Petra , He Shenghong , de Roquemaurel Alexis , Akram Harith , Foltynie Thomas , Limousin Patricia , Zrinzo Ludvic , Cagnan Hayriye , Brown Peter , Tan Huiling 
Published: August 2020

AbstractPatients with advanced Parkinson’s can be treated by deep brain stimulation of the subthalamic nucleus (STN). This affords a unique opportunity to record from this nucleus and stimulate it in a controlled manner. Previous work has shown that activity in the STN is modulated in a rhythmic pattern when Parkinson’s patients perform stepping movements, raising the question whether the STN is involved in the dynamic control of stepping. To answer this question, we tested whether an alternating stimulation pattern resembling the stepping-related modulation of activity in the STN could entrain patients’ stepping movements as evidence of the STN’s involvement in stepping control. Group analyses of ten Parkinson’s patients (one female) showed that alternating stimulation significantly entrained stepping rhythms. We found a remarkably consistent alignment between the stepping and stimulation cycle when the stimulation speed was close to the stepping speed in the five patients that demonstrated significant individual entrainment to the stimulation cycle. Our study provides evidence that the STN is causally involved in dynamic control of step timing, and motivates further exploration of this biomimetic stimulation pattern as a basis for the development of specific deep brain stimulation strategies to ameliorate gait impairments.
Enhancing SNR and generating contrast for cryo-EM images with convolutional neural networks
Authors: Palovcak Eugene , Asarnow Daniel , Campbell Melody G. , Yu Zanlin , Cheng Yifan 
Published: August 2020

AbstractIn cryogenic electron microscopy (cryo-EM) of radiation-sensitive biological samples, both the signal-to-noise ratio (SNR) and the contrast of images are critically important in the image processing pipeline. Classic methods improve low-frequency image contrast experimentally, by imaging with high defocus, or computationally, by applying various types of low-pass filter. These contrast improvements typically come at the expense of high-frequency SNR, which is suppressed by high-defocus imaging and removed by low pass filtration. Here, we demonstrate that a convolutional neural network (CNN) denoising algorithm can be used to significantly enhance SNR and generate contrast in cryo-EM images. We provide a quantitative evaluation of bias introduced by the denoising procedure and its influences on image processing and three-dimensional reconstructions. Our study suggests that besides enhancing the visual contrast of cryo-EM images, the enhanced SNR of denoised images may facilitate better outcomes in the other parts of the image processing pipeline, such as classification and 3D alignment. Overall, our results provide a ground of using denoising CNNs in the cryo-EM image processing pipeline.
Structure of an atypical homodimeric actin capping protein from the malaria parasite
Authors: Bendes Ábris Ádám , Kursula Petri , Kursula Inari 
Published: August 2020

AbstractActin capping proteins (CPs) are essential regulators of actin dynamics in all eukaryotes. Their structure and function have been extensively characterized in higher eukaryotes but their role and mechanism of action in apicomplexan parasites remain enigmatic. Here, we present a crystal structure of a unique homodimeric CP from the rodent malaria parasitePlasmodium berghei. In addition, we compare homo- and heterodimeric arrangements ofP. bergheiCPs (PbCPs) in solution. We complement our findings by describing the regulatory effects ofPbCPs on heterologous skeletal muscle α-actin as well as parasite actin. Comprehensive kinetic and steadystate measurements show atypical regulation of actin dynamics;PbCPs facilitate rapid turnover of parasite actin I without affecting the apparent critical concentration. Possibly to rescue actin filament capping in life cycle stages where the CP β-subunit is downregulated, homo- and heterodimericPbCPs show redundant effectsin vitro. However, our data suggest that homodimers may in addition influence actin kinetics by recruiting lateral actin dimers. This unusual function could arise from the absence of a β-subunit, as the asymmetricPbCP homodimer lacks the structural elements essential for canonical barbed end interactions, suggesting a novel CP binding mode. These findings facilitate further studies aimed at elucidating the precise actin filament capping mechanism inPlasmodiumand the eligibility ofPbCPs as drug targets against malaria.Significance statementMalaria parasites of the genusPlasmodiumdisplay a unique form of gliding motility, which depends on an unconventional actomyosin motor. Actin capping proteins (CPs) play a major role in regulating parasite motility. Here, we describe a uniquePlasmodium bergheiCP (PbCP) system, behaving contradictory to canonical heterodimeric CPs, more suited to regulate the fast dynamics of the parasite actin system. We present the crystal structure of a distinctive homodimeric form ofPbCP and extensive biochemical data, describing the atypical behavior of eachPbCP form. ThePbCP homodimer displays capping even in the absence of canonical conserved structural elements, suggesting a novel actin-CP interaction mode. These distinct structural properties could provide opportunities for drug design against malaria.
The adaptor protein NumbL is involved in the control of glucolipotoxicity-induced pancreatic beta cell apoptosis
Authors: Basavarajappa Halesha D. , Irimia Jose M. , Fueger Patrick T. 
Published: August 2020

AbstractAvoiding loss of functional beta cell mass is critical for preventing or treating diabetes. Currently, the molecular mechanisms underlying beta cell death are partially understood, and there is a need to identify new targets for developing novel therapeutics to treat diabetes. Previously, our group established that Mig6, an inhibitor of EGF signaling, mediates beta cell death under diabetogenic conditions. The objective of this study was to clarify the mechanisms linking diabetogenic stimuli to beta cell death by investigating Mig6-interacting proteins. Using co-immunoprecipitation and mass spectrometry, we evaluated the binding partners of Mig6 under both normal glucose (NG) and glucolipotoxic (GLT) conditions in beta cells. We identified that Mig6 interacts dynamically with NumbL; whereas Mig6 associates with NumbL under NG, this interaction is disrupted under GLT conditions. Further, we demonstrate that siRNA-mediated suppression of NumbL expression in beta cells prevented apoptosis under GLT conditions by blocking activation of NF-κB signaling. Using co-immunoprecipitation experiments we observed that NumbL’s interactions with TRAF6, a key component of NFκB signaling, are increased under GLT conditions. The interactions among Mig6, NumbL, and TRAF6 are dynamic and context-dependent. We propose a model wherein these interactions activate pro-apoptotic NF-κB signaling while blocking pro-survival EGF signaling under diabetogenic conditions, leading to beta cell apoptosis. These findings indicate that NumbL should be further investigated as a candidate anti-diabetic therapeutic target.
Identification of microbial markers across populations in early detection of colorectal cancer
Authors: Wu Yuanqi , Jiao Na , Zhu Ruixin , Zhang Yida , Wu Dingfeng , Wang An-Jun , Fang Sa , Tao Liwen , Li Yichen , Cheng Sijing , He Xiaosheng , Lan Ping , Tian Chuan , Liu Ning-Ning , Zhu Lixin 
Published: August 2020

AbstractSeveral studies have investigated the association between microbial and colorectal cancer (CRC). However, the replicable markers for early stage adenoma diagnosis across multiple populations remain elusive. Here, a meta-analysis of six studies, comprising a total of 1057 fecal samples, was performed to identify candidate markers. By adjusting the potential confounders, 11 and 26 markers (P<0.05) were identified and separately applied into constructing Random Forest classifier models to discriminate adenoma from control, and adenoma from CRC, achieving robust diagnostic accuracy with AUC = 0.80 and 0.89, respectively. Moreover, these markers demonstrated high diagnostic accuracy in independent validation cohorts. Pooled functional analysis and targeted qRT-PCR based genetic profiles reveal that the altered microbiome triggers different pathways of ADP-heptose and menaquinone biosynthesis (P<0.05) in adenoma vs. control and adenoma vs. CRC sequences respectively. The combined analysis of heterogeneous studies confirm adenoma-specific but universal markers across multi-populations, which improves early diagnosis and prompt treatment of CRC.
Deuteration improves small-molecule fluorophores
Authors: Grimm Jonathan B. , Xie Liangqi , Casler Jason C. , Patel Ronak , Tkachuk Ariana N. , Choi Heejun , Lippincott-Schwartz Jennifer , Brown Timothy A. , Glick Benjamin S. , Liu Zhe , Lavis Luke D. 
Published: August 2020

ABSTRACTFluorescence microscopy relies on dyes that absorb short-wavelength photons and emit longer-wavelength light. In addition to this fluorescence process, dyes can undergo other photochemical reactions that result in spectral shifts and irreversible photobleaching. Increases in brightness, ‘chromostability’, and photostability of fluorescent dyes are therefore crucial for advancing the frontier of bioimaging. Here, we describe a general approach to improve small-molecule fluorophores using deuteration. Incorporating deuterium into the alkylamino substituents of rhodamines and other dyes improves fluorescence quantum yield, inhibits photochemically induced spectral shifts, and slows irreparable photobleaching. These compounds are easily synthesized and show improved performance in cellular imaging experiments.
RevisitingCryptococcusextracellular vesicles properties and their use as vaccine platforms
Authors: Rizzo Juliana , Wong Sarah Sze Wah , Gazi Anastasia D. , Moyrand Frédérique , Chaze Thibault , Commere Pierre-Henri , Novault Sophie , Matondo Mariette , Pehau-Arnaudet Gerard , Reis Flavia C. G. , Vos Matthijn , Alves Lysangela R , May Robin C. , Nimrichter Leonardo , Rodrigues Marcio L. , Aimanianda Vishukumar , Janbon Guilhem 
Published: August 2020

AbstractWhereas extracellular vesicle (EV) research has become commonplace in different biomedical fields, this field of research is still in its infancy in mycology. Here we provide a robust set of data regarding the structural and compositional aspects of EVs isolated from the fungal pathogenic speciesCryptococcus neoformans, C. deneoformans and C. deuterogattii. Using cutting-edge methodological approaches including cryogenic electron microscopy and cryogenic electron tomography, proteomics, and flow cytometry, we revisited cryptococcal EV features and suggest a new EV structural model, in which the vesicular lipid bilayer is covered by mannoprotein-based fibrillar decoration, bearing the capsule polysaccharide as its outer layer. About 10% of the EV population is devoid of fibrillar decoration, adding another aspect to EV diversity. By analyzing EV protein cargo from the three species, we characterized the typicalCryptococcusEV proteome. It contains several membrane-bound protein families, including some Tsh proteins bearing a SUR7/PalI motif. The presence of known protective antigens on the surface ofCryptococcusEVs, resembling the morphology of encapsulated virus structures, suggested their potential as a vaccine. Indeed, mice immunized with EVs obtained from an acapsularC. neoformansmutant strain rendered a strong antibody response in mice and significantly prolonged their survival uponC. neoformansinfection.
Automated and unbiased classification of motor neuron phenotypes with single cell resolution in ALS tissue
Authors: Hagemann Cathleen , Tyzack Giulia E. , Taha Doaa M. , Devine Helen , Greensmith Linda , Newcombe Jia , Patani Rickie , Serio Andrea , Luisier Raphaëlle 
Published: August 2020

SUMMARYHistopathological analysis of tissue sections is an invaluable resource in neurodegeneration research. Importantly, cell-to-cell variation in both the presence and severity of a given phenotype is however a key limitation of this approach, reducing the signal to noise ratio and leaving unresolved the potential of single-cell scoring for a given disease attribute. Here, we developed an image processing pipeline for automated identification and profiling of motor neurons (MNs) in amyotrophic lateral sclerosis (ALS) pathological tissue sections. This approach enabled unbiased analysis of hundreds of cells, from which hundreds of features were readily extracted. Next by testing different machine learning methods, we automated the identification of phenotypically distinct MN subpopulations in VCP- and SOD1-mutant transgenic mice, revealing common aberrant phenotypes in cellular shape. Additionally we established scoring metrics to rank cells and tissue samples for both disease probability and severity. Finally, by adapting this methodology to human post-mortem tissue analysis, we validated our core finding that morphological descriptors strongly discriminate ALS from control healthy tissue at the single cell level. In summary, we show that combining automated image processing with machine learning methods substantially improves the speed and reliability of identifying phenotypically diverse MN populations. Determining disease presence, severity and unbiased phenotypes at single cell resolution might prove transformational in our understanding of ALS and neurodegenerative diseases more broadly.
LinCoM: a graph theoretic approach for the production of Linear place fields in Complex Mazes
Authors: Papasavvas Christoforos A. 
Published: August 2020

AbstractStudies on spatial coding and episodic memory typically involve recordings of hippocampal place cell activity while rodents navigate in mazes. Linear place fields serve as reduced representations of the activity of place cells, revealing their spatial preference along the tracks of the maze. Sometimes, the experimental designs include complex mazes with irregular geometries and one or more decision points. Unfortunately, in such complex mazes, the production of linear place fields becomes a non-trivial problem. Here, I present a MATLAB toolbox which implements a graph-theoretic approach for the efficient production of linear place fields in a variety of complex mazes.
Endosomal trafficking defects alter neural progenitor proliferation and cause microcephaly
Authors: Carpentieri Jacopo A. , Di Cicco Amandine , Andreau David , Del Maestro Laurence , Marjou Fatima El , Coquand Laure , Brault Jean-Baptiste , Bahi-Buisson Nadia , Baffet Alexandre D. 
Published: August 2020

AbstractPrimary microcephaly and megalencephaly are severe brain malformations defined by reduced and increased brain size, respectively. Whether these two pathologies arise from related alterations at the molecular level is unclear. Microcephaly has been largely associated with centrosomal defects, leading to cell death. Here, we investigated the consequences ofWDR81loss of function, which cause severe microcephaly in patients. We show that WDR81 regulates endosomal trafficking of EGFR, and that loss of function leads to reduced MAP kinase pathway activation. Mouse radial glial progenitor cells knocked-out forWDR81display reduced proliferation rates, leading to reduced brain size. These proliferation defects are rescuedin vivoby the expression of megalencephaly-causing mutated Cyclin D2. Our results identify the endosomal machinery as an important regulator of RG cell proliferation rates and brain growth. They demonstrate that microcephaly and megalencephaly can be due to opposite effects on the proliferation rate of radial glial progenitors.