bluuebunny/crossref_metadata_2025_split huggingface dataset:
Establishment of a Prognostic Prediction and Drug Selection Model for Patients with Clear Cell Renal Cell Carcinoma by Multi-Omics Data Analysis
Authors: Jiang Aimin , Bao Yewei , Wang Anbang , Gan Xinxin , Wang Jie , Bao Yi , Wu Zhenjie , Liu Bing , Lu Juan , Wang Linhui 
Published: August 2021

AbstractRationalePatients with clear cell renal cell cancer (ccRCC) may have completely different treatment choices and prognoses due to the wide range of heterogeneity of the disease. However, there is a lack of effective models for risk stratification, treatment decision making and prognostic prediction of renal cancer patients. The aim of the present study was to establish a model to stratify ccRCC patients in terms of prognostic prediction and drug selection based on multi-omics data analysis.MethodsThis study was based on the multi-omics data (including mRNA, lncRNA, miRNA, methylation and WES) of 258 ccRCC patients from TCGA database. Firstly, we screened the feature values that had impact on the prognosis and obtained two subtypes. Then, we used 10 algorithms to achieve multi-omics clustering, and conducted pseudo-timing analysis to further validate the robustness of our clustering method, based on which the two subtypes of ccRCC patients were further subtyped. Meanwhile, the immune infiltration was compared between the two subtypes, and drug sensitivity and potential drugs were analyzed. Furthermore, to analyze the heterogeneity of patients at the multi-omics level, biological functions between two subtypes were compared. Finally, Boruta and PCA methods were used for dimensionality reduction and cluster analysis to construct a renal cancer risk model based on mRNA expression.ResultsA prognosis predicting model of ccRCC was established by dividing patients into high- and low-risk groups. It was found that overall survival (OS) and progression-free interval (PFI) were significantly different between the two groups (p<0.01). The area under the OS time dependent ROC curve for 1, 3, 5 and 10 years in the training set was 0.75, 0.72, 0.71 and 0.68 respectively.ConclusionThe model could precisely predict the prognosis of ccRCC patients and may have implications for drug selection for ccRCC patients.
Identification and Targeting Putative G-Quadruplex Sequences in Candida glabrata: A Route to Virulence and Pathogenesis Control?
Authors: Yadav Ankush 
Published: August 2021

AbstractAn increase in the number of Candida species that are resistant to antifungal medication and increases worldwide. Even individuals that are never exposed to antibiotics showing resistance to antifungal drugs. The increase in resistant candida species strains requires a search for novel targets for new antifungal agents. Preventing infection caused by candida species is a tremendous challenge in medicine. Although availability and use of antifungal drugs, disseminated candidiasis leads to a high mortality rate of about 40-60%, poor diagnosis, and improper disease management. Interest in G-quadruplexes as a therapeutic target has been increased in recent years, following the implication of this non-canonical G-quadruplex secondary structure in pathological diseases. However, G-quadruplex has been reported in many pathogens contributing to virulence and pathogenesis, including bacterial pathogens such as Staphylcoccus aureus and Enterococcus spp. Etc, viruses such as SARS-CoV2, HIV, HPV etc., and Fungi such as Candida species, Aspergillus fumigatus, etc. The present aim of the study is to identify and targeting G-Quadruplex forming sequences present in the Candida glabrata. PQSFinder (R Package) identified more than 5000 putative G-quadruplex forming sequences. Out of these, we have used PQS present in the SDH1 gene of Candida glabrata. It may be a key target to ameliorate the C.glabrata infection because it encodes a protein that plays a vital role in energy production in C.glabrata cells shown in the figure. The structure was built based on the already current structure that is telomeric G4 AGGG (TTAGGG)3 {PDB ID-4G0F} for identifying its stabilization by Gold carbine derivatives. Molecular docking and ADMET analysis show that Compound A has the highest binding affinity and has the best ADMET properties among the two compounds. The present study represents PQS in the SDH1 gene could be a novel antifungal target.
Printed Texts Tracking and Following for a Finger-Wearable Electro-Braille System Through Opto-electrotactile Feedback
Authors: Rahimi Mehdi , Shen Yantao , Liu Zhiming , Jiang Fang 
Published: August 2021

AbstractThis paper presents our recent development on a portable and refreshable text reading and sensory substitution system for the blind or visually impaired (BVI), called Finger-eye. The system mainly consists of an opto-text processing unit and a compact electro-tactile based display that can deliver text-related electrical signals to the fingertip skin through a wearable and Braille-dot patterned electrode array and thus delivers the electro-stimulation based Braille touch sensations to the fingertip. To achieve the goal of aiding BVI to read any text not written in Braille through this portable system, in this work, a Rapid Optical Character Recognition (R-OCR) method is firstly developed for real-time processing text information based on a Fisheye imaging device mounted at the finger-wearable electrotactile display. This allows real-time translation of printed text to electro-Braille along with natural movement of user’s fingertip as if reading any Braille display or book. More importantly, an electro-tactile neuro-stimulation feedback mechanism is proposed and incorporated with the R-OCR method, which facilitates a new opto-electrotactile feedback based text line tracking control approach that enables text line following by user fingertip during reading. Multiple experiments were designed and conducted to test the ability of blindfolded participants to read through and follow the text line based on the opto-electrotactile-feedback method. The experiments show that as the result of the opto-electrotactile-feedback, the users were able to maintain their fingertip within a 2mmdistance of the text while scanning a text line. This research is a significant step to aid the BVI users with a portable means to translate and follow to read any printed text to Braille, whether in the digital realm or physically, on any surface.
Hasty sensorimotor decisions rely on an overlap of broad and selective changes in motor activity
Authors: Derosiere Gerard , Thura David , Cisek Paul , Duque Julie 
Published: August 2021

SummaryHumans and other animals are able to adjust their speed-accuracy tradeoff (SAT) at will depending on the urge to act, favoring either cautious or hasty decision policies in different contexts. An emerging view is that SAT regulation relies on influences exerting broad changes on the motor system, tuning its activity up globally when hastiness is at premium. The present study aimed to test this hypothesis. Fifty subjects performed a task involving choices between left and right index fingers, in which incorrect choices led either to a high or to a low penalty in two contexts, inciting them to emphasize either cautious or hasty policies. We applied transcranial magnetic stimulation on multiple motor representations, eliciting motor evoked potentials (MEP) in nine finger and leg muscles. MEP amplitudes allowed us to probe activity changes in the corresponding finger and leg representations, while subjects were deliberating about which index to choose. Our data indicate that hastiness entails a broad amplification of motor activity, though this amplification was limited to the chosen side. On top of this effect, we identified a local suppression of motor activity, surrounding the chosen index representation. Hence, a decision policy favoring speed over accuracy appears to rely on overlapping processes producing a broad (but not global) amplification and a surround suppression of motor activity. The latter effect may help to increase the signal-to-noise ratio of the chosen representation, as supported by single-trial correlation analyses indicating a stronger differentiation of activity changes in finger representations in the hasty context.
Classification and genetic targeting of cell types in the primary taste and premotor center of the Drosophila brain
Authors: Sterne Gabriella R. , Otsuna Hideo , Dickson Barry J. , Scott Kristin 
Published: August 2021

AbstractNeural circuits carry out complex computations that allow animals to evaluate food, select mates, move toward attractive stimuli, and move away from threats. In insects, the subesophageal zone (SEZ) is a brain region that receives gustatory, pheromonal, and mechanosensory inputs and contributes to the control of diverse behaviors, including feeding, grooming, and locomotion. Despite its importance in sensorimotor transformations, the study of SEZ circuits has been hindered by limited knowledge of the underlying diversity of SEZ neurons. Here, we generate a collection of split-GAL4 lines that provides precise genetic targeting of 138 different SEZ cell types in D. melanogaster, comprising approximately one third of all SEZ neurons. We characterize the single cell anatomy of these neurons and find that they cluster by morphology into six supergroups that organize the SEZ into discrete anatomical domains. We find that the majority of local SEZ interneurons are not classically polarized, suggesting rich local processing, whereas SEZ projection neurons tend to be classically polarized, conveying information to a limited number of higher brain regions. This study provides insight into the anatomical organization of the SEZ and generates resources that will facilitate further study of SEZ neurons and their contributions to sensory processing and behavior.
Comparative untargeted metabolomic profiling of induced mitochondrial fusion in pancreatic cancer
Authors: Nguyen Nicholas D. , Yu Meifang , Reddy Vinit Y. , Acevedo-Diaz Ariana , Mesarick Enzo C. , Jaoude Joseph Abi , Yuan Min , Asara John M. , Taniguchi Cullen M. 
Published: August 2021

AbstractMitochondria are dynamic organelles that constantly alter their shape through the recruitment of specialized proteins, like mitofusin-2 (Mfn2) and dynamin-related protein 1 (Drp1). Mfn2 induces the fusion of nearby mitochondria, while Drp1 mediates mitochondrial fission. We previously found that the genetic or pharmacological activation of mitochondrial fusion was tumor suppressive against pancreatic ductal adenocarcinoma (PDAC) in several model systems [1]. The mechanisms of how these different inducers of mitochondrial fusion reduce pancreatic cancer growth are still unknown. Here, we characterized and compared the metabolic reprogramming of these three independent methods of inducing mitochondrial fusion in KPC cells: overexpression of Mfn2, genetic editing of Drp1, or treatment with leflunomide. We identified significantly altered metabolites via robust, orthogonal statistical analyses and found that mitochondrial fusion consistently produces alterations in the metabolism of amino acids. Our unbiased methodology revealed that metabolic perturbations were similar across all these methods of inducing mitochondrial fusion, proposing a common pathway for metabolic targeting with other drugs.
Top-down feedback enables flexible coding strategies in olfactory cortex
Authors: Chen Zhen , Padmanabhan Krishnan 
Published: August 2021

SummaryIn chemical sensation, multiple models have been proposed to explain how odors are represented by patterns of neuronal activity in the olfactory cortex. One hypothesis is that the identity of combinations of active neurons within specific sniff-related time windows are critical for encoding information about odors. Another model is that patterns of neural activity evolve across time and it is this temporal structure that is essential for encoding odor information. Interestingly, we found that top-down feedback to the olfactory bulb dictates what information is transmitted to the olfactory cortex by switching between these two strategies. Using a detailed model of the early olfactory system, we demonstrate that feedback control of inhibitory granule cells in the main olfactory bulb influences the balance between excitatory and inhibitory synaptic currents in mitral cells, thereby restructuring the firing patterns of piriform cortical cells across time. This resulted in performance gains in both the accuracy and reaction time of odor discrimination tasks. These findings lead us to propose a new framework for early olfactory computation, one in which top-down feedback to the bulb flexibly controls the temporal structure of neural activity in olfactory cortex, allowing the early olfactory system to dynamically switch between two distinct models of coding.HighlightsCentrifugal feedback shapes the temporal structure of neuronal firing in piriform cortical cellsFeedback controls information to piriform cortex by restructuring the ratio of excitatory and inhibitory synaptic inputs in the bulbCentrifugal feedback restructures how identity and timing of glomerular activity is represented in temporal patterns of activity in piriform cortexTemporal information improves behavioral performance in accuracy and reaction time of odor discrimination
Recombinant NAGLU-IGF2 prevents physical and neurological disease and improves survival in Sanfilippo B syndrome
Authors: Le Steven Q. , Kan Shih-hsin , Roberts Marie S. , Dearborn Joshua T. , Wang Feng , Li Shan , Snella Elizabeth M. , Jens Jackie K. , Valentine Bethann N. , Nelvagal Hemanth R. , Sorensen Alexander , Chintalapati Keerthana , Ohlemiller Kevin , Vogler Carole , Cooper Jonathan D. , Chou Tsui-Fen , Ellinwood N. Matthew , Smith Jodi D. , Sands Mark S. , Dickson Patricia I. 
Published: August 2021

AbstractRecombinant human alpha-N-acetylglucosaminidase-insulin-like growth factor-2 (rhNAGLU-IGF2) is an investigational enzyme replacement therapy for Sanfilippo B, a lysosomal storage disease. Because recombinant human NAGLU (rhNAGLU) is poorly mannose 6-phosphorylated, we generated a fusion protein of NAGLU with IGF2 to permit its binding to the cation-independent mannose 6-phosphate receptor. We previously administered rhNAGLU-IGF2 intracerebroventricularly to Sanfilippo B mice, and demonstrated therapeutic restoration of NAGLU, normalization of lysosomal storage, and improvement in markers of neurodegeneration and inflammation. Here, we studied repeated intracerebroventricular rhNAGLU-IGF2 delivery in both murine and canine Sanfilippo B to determine potential effects on their behavioral phenotypes and survival. Treated mice showed improvement in disease markers such as heparan sulfate glycosaminoglycans, beta-hexosaminidase, microglial activation, and lysosomal-associated membrane protein-1. Sanfilippo B mice treated with rhNAGLU-IGF2 displayed partial normalization of their stretch attend postures, a defined fear pose in mice (p<0.001). We found an improved rotarod performance in Sanfilippo B mice treated with rhNAGLU-IGF2 compared to vehicle-treated Sanfilippo B mice (p=0.002). We also found a 61% increase in survival in Sanfilippo B mice treated with rhNAGLU-IGF2 (mean 53w, median 48w) compared to vehicle-treated Sanfilippo B mice (mean 33w, median 37w; p<0.001). In canine Sanfilippo B, we found that rhNAGLU-IGF2 administered into cerebrospinal fluid normalized HS and beta-hexosaminidase activity in gray and white matter brain regions. Proteomic analysis of cerebral cortex showed restoration of protein expression levels in pathways relevant to cognitive, synaptic, and lysosomal functions. These data suggest that treatment with rhNAGLU-IGF2 may improve the phenotype of Sanfilippo B disease.
Exploration of novel αβ-protein folds throughde novodesign
Authors: Minami Shintaro , Kobayashi Naohiro , Sugiki Toshihiko , Nagashima Toshio , Fujiwara Toshimichi , Koga Rie , Chikenji George , Koga Nobuyasu 
Published: August 2021

AbstractMost naturally occurring protein folds have likely been discovered1–3. The question is whether natural evolution has exhaustively sampled almost all possible protein folds4, or whether a large fraction of the possible folds remains unexplored5–7. To address this question, we introduce a set of rules for β-sheet topology to predict novel folds, and carry out the systematic de novo protein design for the novel folds predicted by the rules. The rules predicted eight novel αβ-folds with a four-stranded β-sheet, including a knot-forming one. We designed proteins for all the predicted αβ-folds and found that all the designs are monomeric with high thermal stability and fold into the structures close to the design models, demonstrating the ability of the set of rules to predict novel αβ-folds. The rules also predicted about twelve thousand novel αβ-folds with five- to eight-stranded β-sheets; the number is far exceeding the number of αβ-folds observed so far. This result suggests that the enormous number of αβ-folds are possible but have not emerged or become extinct due to evolutionary bias. The predicted novel folds should open up the possibility of designing functional proteins of our interests.
Temporally Auto-Correlated Predator Attacks Structure Ecological Communities
Authors: Schreiber Sebastian J. 
Published: August 2021

AbstractFor species primarily regulated by a common predator, the P* rule of Holt and Lawton [1993] predicts that the prey species that supports the highest mean predator density (P*) excludes the other prey species. This prediction is re-examined in the presence of temporal fluctuations in the vital rates of the interacting species including predator attack rates. When the fluctuations in predator attack rates are temporally uncorrelated, the P* rule still holds even when the other vital rates are temporally auto-correlated. However, when temporal auto-correlations in attack rates are positive but not too strong, the prey species can coexist due to the emergence of a positive covariance between predator density and prey vulnerability. This coexistence mechanism is similar to the storage effect for species regulated by a common resource. Negative or strongly positive auto-correlations in attack rates generate a negative covariance between predator density and prey vulnerability and a stochastic priority effect can emerge: with non-zero probability either prey species is excluded. These results highlight how temporally auto-correlated species’ interaction rates impact the structure and dynamics of ecological communities.
Production and characterization of virus-free, CRISPR-CAR T cells capable of inducing solid tumor regression
Authors: Mueller Katherine P. , Piscopo Nicole J. , Forsberg Matthew H. , Saraspe Louise A. , Das Amritava , Russell Brittany , Smerchansky Madeline , Shi Lei , Shankar Keerthana , Ali Adeela , Lazzarotto Cicera R. , Tsai Shengdar Q. , Capitini Christian M. , Saha Krishanu 
Published: August 2021

AbstractBackgroundChimeric antigen receptor (CAR) T cells traditionally harbor viral vector-based sequences that encode the CAR transgene in the genome. These T cell products have yet to show consistent anti-tumor activity in patients with solid tumors. Further, viral vector manufacturing is resource intensive, suffers from batch-to-batch variability, and includes several animal components, adding regulatory and supply chain pressures.MethodsAnti-GD2 CAR T cells were generated using CRISPR/Cas9 within nine days using recombinant Cas9 protein and nucleic acids, without any viral vectors or animal components. The CAR was specifically targeted to the T Cell Receptor Alpha Constant gene (TRAC). T cell products were characterized at the level of the genome, transcriptome, proteome, and secretome using CHANGE-seq, scRNA-seq, spectral cytometry, and ELISA assays. Functionality was evaluated in vivo in an NSG xenograft neuroblastoma model.ResultsIn comparison to traditional retroviral CAR T cells, virus-free CRISPR CAR (VFC-CAR) T cells exhibit TRAC-targeted genomic integration of the CAR transgene, elevation of transcriptional and protein characteristics associated with a memory phenotype, and low tonic signaling prior to infusion arising in part from the the knockout of the TCR. Upon exposure to the GD2 target antigen, anti-GD2 VFC-CAR T cells exhibited specific cytotoxicity against GD2+ cells in vitro and induced solid tumor regression in vivo, with robust homing, persistence, and low exhaustion against a human neuroblastoma xenograft model.ConclusionsThis proof-of-principle study leveraging virus-free genome editing technology could enable flexible manufacturing of clinically relevant, high-quality CAR T cells to treat cancers, including solid tumors.
A high-accuracy and high-efficiency digital volume correlation method to characterize in-vivo optic nerve head biomechanics from optical coherence tomography
Authors: Zhong Fuqiang , Wei Junchao , Hua Yi , Wang Bo , Reynaud Juan , Fortune Brad , Sigal Ian A. 
Published: August 2021

AbstractIn-vivo optic nerve head (ONH) biomechanics characterization is emerging as a promising way to study eye physiology and pathology. We propose a high-accuracy and high-efficiency digital volume correlation (DVC) method for the purpose of characterizing the in-vivo ONH deformation from volumes acquired by optical coherence tomography (OCT). Using a combination of synthetic tests and analysis of OCTs from monkey ONHs subjected to acute and chronically elevated intraocular pressure, we demonstrate that our proposed methodology overcomes several challenges for conventional DVC methods. First, it accounts for large ONH rigid body motion in the OCT volumes which could otherwise lead to analysis failure; second, sub-voxel-accuracy displacement can be guaranteed despite high noise and low image contrast of some OCT volumes; third, computational efficiency is greatly improved, such that the memory consumption of our method is substantially lower than with conventional methods; fourth, we introduce a parameter measuring displacements confidence. Test of image noise effects showed that the proposed DVC method had displacement errors smaller than 0.028 voxels with speckle noise and smaller than 0.037 voxels with Gaussian noise; The absolute (relative) strain errors in the three directions were lower than 0.0018 (4%) with speckle noise and than 0.0045 (8%) with Gaussian noise. Compared with conventional DVC methods, the proposed DVC method had substantially improved overall displacement and strain errors under large body motions (lower by up to 70%), with 75% lower computation times, while saving about 30% memory. The study thus demonstrates the potential of the proposed technique to investigate ONH biomechanics.