bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative computational approach identifies drug targets in CD4+ T-cell-mediated immune disorders
Authors: Puniya Bhanwar Lal , Amin Rada , Lichter Bailee , Moore Robert , Ciurej Alex , Bennett Sydney J. , Shah Ab Rauf , Barberis Matteo , Helikar Tomáš 
Published: January 2021

AbstractCD4+ T cells provide adaptive immunity against pathogens and abnormal cells, and they are also associated with various immune-related diseases. CD4+ T cells’ metabolism is dysregulated in these pathologies and represents an opportunity for drug discovery and development. Genome-scale metabolic modeling offers an opportunity to accelerate drug discovery by providing high-quality information about possible target space in the context of a modeled disease. Here, we develop genome-scale models of naïve, Th1, Th2, and Th17 CD4+ T-cell subtypes to map metabolic perturbations in rheumatoid arthritis, multiple sclerosis, and primary biliary cholangitis. We subjected these models to in silico simulations for drug response analysis of existing FDA-approved drugs and compounds. Integration of disease-specific differentially expressed genes with altered reactions in response to metabolic perturbations identified 68 drug targets for the three autoimmune diseases. In vitro experimental validation, together with literature-based evidence, showed that modulation of fifty percent of identified drug targets suppressed CD4+ T cells, further increasing their potential impact as therapeutic interventions. Our approach can be generalized in the context of other diseases, and the metabolic models can be further used to dissect CD4+ T-cell metabolism.
High-dose methotrexate-based regimens and post-remission consolidation for treatment of newly diagnosed primary CNS lymphoma: meta-analysis of clinical trials
Authors: Yu Junyao , Du Huaping , Ye Xueshi , Zhang Lifei , Xiao Haowen 
Published: January 2021

AbstractWith the exception of high-dose methotrexate (HD-MTX), there is currently no defined standard treatment for newly diagnosed primary central nervous system lymphoma (PCNSL). This review focused on first-line induction and consolidation treatment of PCNSL and aimed to determine the optimal combination of HD-MTX and the long-term beneficial consolidation methods. A comprehensive literature search of MEDLINE identified 1407 studies, among which 31 studies met the inclusion criteria. The meta-analysis was performed by using Stata SE version 15. Forest plots were generated to report combined outcomes like the complete response rate (CRR), overall survival, and progression-free survival. We also conducted univariate regression analyses of the baseline characteristics to identify the source of heterogeneity. Pooled analysis showed a CRR of 41% across all HD-MTX-based regimens, and three- and four-drug regimens had better CRRs than HD-MTX monotherapy. In all combinations based on HD-MTX, the HD-MTX + procarbazine + vincristine (MPV) regimen showed pooled CRRs of 63% and 58% with and without rituximab, respectively, followed by the rituximab + HD-MTX + temozolomide regimen, which showed a pooled CRR of 60%. Pooled PFS and OS showed that post-remission consolidation with autologous stem cell transplantation (ASCT) was associated with the best survival outcome, with a pooled 2-year OS of 80%, a 2-year PFS of 74%, a 5-year OS of 77%, and a 5-year PFS of 63%. Next, whole-brain radiation therapy (WBRT) + chemotherapy showed a pooled 2-year OS of 72%, 2-year PFS of 56%, 5-year OS of 55%, and 5-year PFS of 41%, with no detectable CR heterogeneity throughout the entire treatment process. In HD-MTX-based therapy of newly diagnosed PCNSL, MPV with or without rituximab can be chosen as the inductive regimen, and the rituximab + HD-MTX + temozolomide regimen is also a practical choice. Based on our study, high-dose chemotherapy supported by ASCT is an efficacious approach for consolidation. Consolidation with WBRT + chemotherapy can be another feasible approach.
Transcriptomic responses of Microcystis aeruginosa under electromagnetic radiation exposure
Authors: Tang Chao , Zhang Ziyan , Tian Shen , Cai Peng 
Published: January 2021

AbstractElectromagnetic radiation is an important environmental factor. It has a potential threat to public health and ecological environment. However, the mechanism by which electromagnetic radiation exerts these biological effects remains unclear. In this study, the effect of Microcystis aeruginosa under electromagnetic radiation (1.8 GHz, 40 V/m) was studied by using transcriptomics. A total of 306 differentially expressed genes, including 121 upregulated and 185 downregulated genes, were obtained in this study. The differentially expressed genes were significantly enriched in the ribosome, oxidative phosphorylation and carbon fixation pathways, indicating that electromagnetic radiation may inhibit protein synthesis and affect cyanobacterial energy metabolism and photosynthesis. The total ATP synthase activity and ATP content significantly increased, whereas H+K+-ATPase activity showed no significant changes. Our results suggest that the energy metabolism pathway may respond positively to electromagnetic radiation. In the future, systematic studies on the effects of electromagnetic radiation based on different intensities, frequencies, and exposure times are warranted; to deeply understand and reveal the target and mechanism of action of electromagnetic exposure on organisms.
The Drosophila melanogaster Neprilysin Nepl15 is involved in lipid and carbohydrate storage
Authors: Banerjee Surya , Woods Christine , Burnett Micheal , Park Scarlet J. , Ja William W. , Curtiss Jennifer 
Published: January 2021

AbstractThe prototypical M13 peptidase, human Neprilysin, functions as a transmembrane “ectoenzyme” that cleaves neuropeptides that regulate e.g. glucose metabolism, and has been linked to type 2 diabetes. The M13 family has undergone a remarkable, and conserved, expansion in the Drosophila genus. Here, we describe the function of Drosophila melanogaster Neprilysin-like 15 (Nepl15). Nepl15 is likely to be a secreted protein, rather than a transmembrane protein. Nepl15 has changes in critical catalytic residues that are conserved across the Drosophila genus and likely renders the Nepl15 protein catalytically inactive. Nevertheless, a knockout of the Nepl15 gene reveals a reduction in triglyceride and glycogen storage, with the effects likely occurring during the larval feeding period. Conversely, flies overexpressing Nepl15 store more triglycerides and glycogen. Protein modeling suggests that Nepl15 is able to bind and sequester peptide targets of catalytically active Drosophila M13 family members, peptides that are conserved in humans and Drosophila, potentially providing a novel mechanism for regulating the activity of neuropeptides in the context of lipid and carbohydrate homeostasis.
Sharpness recognition based on synergy between bio-inspired nociceptors and tactile mechanoreceptors
Authors: Parvizi-Fard Adel , Salimi-Nezhad Nima , Amiri Mahmood , Falotico Egidio , Laschi Cecilia 
Published: January 2021

AbstractTouch and pain sensations are complementary aspects of daily life that convey crucial information about the environment while also providing protection to our body. Technological advancements in prosthesis design and control mechanisms assist amputees to regain lost function but often they have no meaningful tactile feedback or perception. In the present study, we propose a bio-inspired tactile system with a population of 23 digital afferents: 12 RA-I, 6 SA-I, and 5 nociceptors. Indeed, the functional concept of the nociceptor is implemented on the FPGA for the first time. One of the main features of biological tactile afferents is that their distal axon branches in the skin, creating complex receptive fields. Given these physiological observations, the bio-inspired afferents are randomly connected to the several neighboring mechanoreceptors with different weights to form their own receptive field. To test the performance of the proposed neuromorphic chip in sharpness detection, a robotic system with three-degree of freedom equipped with the tactile sensor indents the 3D-printed objects. Spike responses of the biomimetic afferents are then collected for analysis by rate and temporal coding algorithms. In this way, the impact of the innervation mechanism and collaboration of afferents and nociceptors on sharpness recognition are investigated. Our findings suggest that the synergy between sensory afferents and nociceptors conveys more information about tactile stimuli which in turn leads to the robustness of the proposed neuromorphic system against damage to the taxels or afferents. Moreover, it is illustrated that spiking activity of the biomimetic nociceptors is amplified as the sharpness increases which can be considered as a feedback mechanism for prosthesis protection. This neuromorphic approach advances the development of prosthesis to include the sensory feedback and to distinguish innocuous (non-painful) and noxious (painful) stimuli.
Utility of T2-weighted MRI texture analysis in assessment of peripheral zone prostate cancer aggressiveness: a single-arm, multicenter study
Authors: Nketiah Gabriel A. , Elschot Mattijs , Scheenen Tom W. , Maas Marnix C. , Bathen Tone F. , Selnæs Kirsten M. ,   The PCa-MAP Consortium, Attenberger Ulrike I. , Baltzer Pascal A. T. , Bathen Tone F. , Fütterer Jurgen J. , Haider Masoom A. , Helbich Thomas H. , Kiefer Berthold , Maas Marnix C. , Macura Katarzyna J. , Margolis Daniel J. A. , Padhani Anwar R. , Polanec Stephen H. , Praet Marleen , Scheenen Tom W. , Schoenberg Stefan O. , Selnæs Kirsten M. , van der Kwast Theodorus H. , Villeirs Geert M. , Viset Trond , von Busch Heninrich 
Published: January 2021

AbstractT2-weighted (T2W) MRI provides high spatial resolution and tissue-specific contrast, but it is predominantly used for qualitative evaluation of prostate anatomy and anomalies. This retrospective multicenter study evaluated the potential of T2W image-derived textural features for quantitative assessment of peripheral zone prostate cancer (PCa) aggressiveness. A standardized preoperative multiparametric MRI was performed on 87 PCa patients across 6 institutions. T2W intensity and apparent diffusion coefficient (ADC) histogram, and T2W textural features were computed from tumor volumes annotated based on whole-mount histology. Spearman correlations were used to evaluate association between textural features and PCa grade groups (i.e. 1–5). Feature utility in differentiating and classifying low-(grade group 1) vs. intermediate/high-(grade group ≥ 2) aggressive cancers was evaluated using Mann–Whitney U-tests, and a support vector machine classifier employing “hold-one-institution-out” cross-validation scheme, respectively. Textural features indicating image homogeneity and disorder/complexity correlated significantly (p < 0.05) with PCa grade groups. In the intermediate/high-aggressive cancers, textural homogeneity and disorder/complexity were significantly lower and higher, respectively, compared to the low-aggressive cancers. The mean classification accuracy across the centers was highest for the combined ADC and T2W intensity-textural features (84%) compared to ADC histogram (75%), T2W histogram (72%), T2W textural (72%) features alone or T2W histogram and texture (77%), T2W and ADC histogram (79%) combined. Texture analysis of T2W images provides quantitative information or features that are associated with peripheral zone PCa aggressiveness and can augment their classification.
A directional 3D neurite outgrowth model for studying motor axon biology and disease
Authors: Spijkers Xandor M. , Pasteuning-Vuhman Svetlana , Dorleijn Jennifa C. , Vulto Paul , Wevers Nienke R. , Pasterkamp R. Jeroen 
Published: January 2021

AbstractWe report a method to generate a 3D motor neuron model with segregated and directed axonal outgrowth. iPSC-derived motor neurons are cultured in extracellular matrix gel in a microfluidic platform. Neurons extend their axons into an adjacent layer of gel, whereas dendrites and soma remain predominantly in the somal compartment, as verified by immunofluorescent staining. Axonal outgrowth could be precisely quantified and was shown to respond to the chemotherapeutic drug vincristine in a highly reproducible dose-dependent manner. The model was shown susceptible to excitotoxicity upon exposure with excess glutamate and showed formation of stress granules upon excess glutamate or sodium arsenite exposure, mimicking processes common in motor neuron diseases. Importantly, outgrowing axons could be attracted and repelled through a gradient of axonal guidance cues, such as semaphorins. The platform comprises 40 chips arranged underneath a microtiter plate providing both throughput and compatibility to standard laboratory equipment. The model will thus prove ideal for studying axonal biology and disease, drug discovery and regenerative medicine.
Dlx5-augmentation in neural crest cells reveals early development and differentiation potential of mouse apical head mesenchyme
Authors: Vu Tri H. , Takechi Masaki , Shimizu Miki , Kitazawa Taro , Higashiyama Hiroki , Iwase Akiyasu , Kurihara Hiroki , Iseki Sachiko 
Published: January 2021

AbstractNeural crest cells (NCCs) give rise to various tissues including neurons, pigment cells, bone and cartilage in the head. Distal-less homeobox 5 (Dlx5) is involved in both jaw patterning and differentiation of NCC-derivatives. In this study, we investigated the differentiation potential of head mesenchyme by forcing Dlx5 to be expressed in mouse NCC (NCCDlx5). In NCCDlx5 mice, differentiation of dermis and pigment cells were enhanced with ectopic cartilage (ec) and heterotopic bone (hb) in different layers at the cranial vertex. The ec and hb were derived from the early migrating mesenchyme (EMM), the non-skeletogenic cell population located above skeletogenic supraorbital mesenchyme (SOM). The ec developed within Foxc1+-dura mater with increased PDGFRα signalling, and the hb formed with upregulation of BMP and WNT/β-catenin signallings in Dermo1+-dermal layer from E11.5. Since dermal cells express Runx2 and Msx2 in the control, osteogenic potential in dermal cells seemed to be inhibited by an anti-osteogenic function of Msx2 in normal context. We propose that, after the non-skeletogenic commitment, the EMM is divided into dermis and meninges by E11.5 in normal development. Two distinct responses of the EMM, chondrogenesis and osteogenesis, to Dlx5-augmentation in the NCCDlx5 strongly support this idea.
The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells
Authors: Nagai Yurie , Mimura Naoya , Rizq Ola , Isshiki Yusuke , Oshima Motohiko , Rizk Mohamed , Saraya Atsunori , Koide Shuhei , Nakajima-Takagi Yaeko , Miyota Makiko , Chiba Tetsuhiro , Oshima-Hasegawa Nagisa , Muto Tomoya , Tsukamoto Shokichi , Mitsukawa Shio , Takeda Yusuke , Ohwada Chikako , Takeuchi Masahiro , Iseki Tohru , Nakaseko Chiaki , Lennox William , Sheedy Josephine , Weetall Marla , Yokote Koutaro , Iwama Atsushi , Sakaida Emiko 
Published: January 2021

AbstractThe novel small molecule PTC596 inhibits microtubule polymerization and its clinical development has been initiated for some solid cancers. We herein investigated the preclinical efficacy of PTC596 alone and in combination with proteasome inhibitors in the treatment of multiple myeloma (MM). PTC596 inhibited the proliferation of MM cell lines as well as primary MM samples in vitro, and this was confirmed with MM cell lines in vivo. PTC596 synergized with bortezomib or carfilzomib to inhibit the growth of MM cells in vitro. The combination treatment of PTC596 with bortezomib exerted synergistic effects in a xenograft model of human MM cell lines in immunodeficient mice and exhibited acceptable tolerability. Mechanistically, treatment with PTC596 induced cell cycle arrest at G2/M phase followed by apoptotic cell death, associated with the inhibition of microtubule polymerization. RNA sequence analysis also revealed that PTC596 and the combination with bortezomib affected the cell cycle and apoptosis in MM cells. Importantly, endoplasmic reticulum stress induced by bortezomib was enhanced by PTC596, providing an underlying mechanism of action of the combination therapy. Our results indicate that PTC596 alone and in combination with proteasome inhibition are potential novel therapeutic options to improve outcomes in patients with MM.
Efficacy of biorational insecticides against Bemisia tabaci (Genn.) and their selectivity for its parasitoid Encarsia formosa Gahan on Bt cotton
Authors: Gogi Muhammad Dildar , Syed Ali Hassan , Atta Bilal , Sufyan Muhammad , Arif Muhammad Jalal , Arshad Muhammad , Nawaz Ahmad , Khan Muhammad Ahsan , Mukhtar Adeel , Liburd Oscar Emanuel 
Published: January 2021

AbstractThe toxicity of seven biorational insecticides [five insect growth regulators (Buprofezin, Fenoxycarb, Pyriproxyfen, Methoxyfenozide, and Tebufenozide) and two oil-extracts of neem and bitter gourd seeds] againstBemisia tabaciand their selectivity for its parasitoid,Encarsia formosawere evaluated in laboratory and field conditions for 2 years (2018–2019) in Pakistan. Toxicity results demonstrate that Pyriproxyfen, Buprofezin, and Fenoxycarb proved to be effective (80–91% mortality and 66.3–84.2% population-reduction) againstB. tabacifollowed by Methoxyfenozide, Tebufenozide (50–75% mortality and 47.8–52.4% population-reduction), and then oil-extracts of neem and bitter gourd (25–50% mortality and 36.5–39.8% population-reduction) in the laboratory [72 h post-application exposure interval (PAEI)] and field trails (168 h PAEI), respectively. All tested biorationals, except Methoxyfenozide [(slightly-harmful/Class-II), i.e., causing mortality of parasitoids between a range of 25–50%] and Tebufenozide [(moderately-harmful/Class-III), i.e., causing mortality of parasitoids between the ranges of 51–75%], proved harmless/Class-I biorationals at PAEI of 7-days in the field (parasitism-reduction < 25%) and 3-days in the lab (effect < 30%). In laboratory bioassays, exposure of parasitized-pseudopupae and adult-parasitoids to neem and bitter gourd oils demonstrated that these compounds proved harmless/Class-I biorationals (< 30% mortality). Alternatively, Pyriproxyfen, Buprofezin, Fenoxycarb, Methoxyfenozide, and Tebufenozide were slightly-harmful biorationals (30–79% mortality) against the respective stages ofE. formosa. We conclude that most of the tested biorationals proved harmless or slightly harmful toE. formosa, except tebufenozide after PAEI of 7-days (168 h) in the field and, therefore, may be used strategically in Integrated Pest Management (IPM) ofB. tabaci.
Loss of Parkinson’s susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis
Authors: Lebovitz Chandra , Wretham Nicole , Osooly Maryam , Milne Katy , Dash Tia , Thornton Shelby , Tessier-Cloutier Basile , Sathiyaseelan Paalini , Bortnik Svetlana , Go Nancy Erro , Halvorsen Elizabeth , Cederberg Rachel A. , Chow Norman , Dos Santos Nancy , Bennewith Kevin L. , Nelson Brad H. , Bally Marcel B. , Lam Wan L. , Gorski Sharon M. 
Published: January 2021

AbstractPathological links between neurodegenerative disease and cancer are emerging. LRRK2 overactivity contributes to Parkinson’s disease, whereas our previous analyses of public cancer patient data revealed that decreased LRRK2 expression is associated with lung adenocarcinoma (LUAD). The clinical and functional relevance of LRRK2 repression in LUAD is unknown. Here, we investigated associations between LRRK2 expression and clinicopathological variables in LUAD patient data and asked whether LRRK2 knockout promotes murine lung tumorigenesis. In patients, reduced LRRK2 was significantly associated with ongoing smoking and worse survival, as well as signatures of less differentiated LUAD, altered surfactant metabolism and immunosuppression. We identified shared transcriptional signals between LRRK2-low LUAD and postnatal alveolarization in mice, suggesting aberrant activation of a developmental program of alveolar growth and differentiation in these tumors. In a carcinogen-induced murine lung cancer model, multiplex IHC confirmed that LRRK2 was expressed in alveolar type II (AT2) cells, a main LUAD cell-of-origin, while its loss perturbed AT2 cell morphology. LRRK2 knockout in this model significantly increased tumor initiation and size, demonstrating that loss of LRRK2, a key Parkinson’s gene, promotes lung tumorigenesis.
Circulating long non-coding RNAs HOTAIR, Linc-p21, GAS5 and XIST expression profiles in diffuse large B-cell lymphoma: association with R-CHOP responsiveness
Authors: Senousy Mahmoud A. , El-Abd Aya M. , Abdel-Malek Raafat R. , Rizk Sherine M. 
Published: January 2021

AbstractThe reliable identification of diffuse large B-cell lymphoma (DLBCL)-specific targets owns huge implications for its diagnosis and treatment. Long non-coding RNAs (lncRNAs) are implicated in DLBCL pathogenesis; however, circulating DLBCL-related lncRNAs are barely investigated. We investigated plasma lncRNAs; HOTAIR, Linc-p21, GAS5 and XIST as biomarkers for DLBCL diagnosis and responsiveness to R-CHOP therapy. Eighty-four DLBCL patients and thirty-three healthy controls were included. Only plasma HOTAIR, XIST and GAS5 were differentially expressed in DLBCL patients compared to controls. Pretreatment plasma HOTAIR was higher, whereas GAS5 was lower in non-responders than responders to R-CHOP. Plasma GAS5 demonstrated superior diagnostic accuracy (AUC = 0.97) whereas a panel of HOTAIR + GAS5 superiorly discriminated responders from non-responders by ROC analysis. In multivariate analysis, HOTAIR was an independent predictor of non-response. Among patients, plasma HOTAIR, Linc-p21 and XIST were correlated. Plasma GAS5 negatively correlated with International Prognostic Index, whereas HOTAIR positively correlated with performance status, denoting their prognostic potential. We constructed the lncRNAs-related protein–protein interaction networks linked to drug response via bioinformatics analysis. In conclusion, we introduce plasma HOTAIR, GAS5 and XIST as potential non-invasive diagnostic tools for DLBCL, and pretreatment HOTAIR and GAS5 as candidates for evaluating therapy response, with HOTAIR as a predictor of R-CHOP failure. We provide novel surrogates for future predictive studies in personalized medicine.
Phanerozoic radiation of ammonia oxidizing bacteria
Authors: Ward L. M. , Johnston D. T. , Shih P. M. 
Published: January 2021

AbstractThe modern nitrogen cycle consists of a web of microbially mediated redox transformations. Among the most crucial reactions in this cycle is the oxidation of ammonia to nitrite, an obligately aerobic process performed by a limited number of lineages of bacteria (AOB) and archaea (AOA). As this process has an absolute requirement for O2, the timing of its evolution—especially as it relates to the Great Oxygenation Event ~ 2.3 billion years ago—remains contested and is pivotal to our understanding of nutrient cycles. To estimate the antiquity of bacterial ammonia oxidation, we performed phylogenetic and molecular clock analyses of AOB. Surprisingly, bacterial ammonia oxidation appears quite young, with crown group clades having originated during Neoproterozoic time (or later) with major radiations occurring during Paleozoic time. These results place the evolution of AOB broadly coincident with the pervasive oxygenation of the deep ocean. The late evolution AOB challenges earlier interpretations of the ancient nitrogen isotope record, predicts a more substantial role for AOA during Precambrian time, and may have implications for understanding of the size and structure of the biogeochemical nitrogen cycle through geologic time.