bluuebunny/crossref_metadata_2025_split huggingface dataset:
FLT-PET At 6 Weeks Predicts Response Assessed by CT at 12 Weeks in Melanoma Patients Treated With Pembrolizumab
Authors: Yeh Randy , Trager Megan H. , Rizk Emanuelle M. , Finkel Grace G. , Barker Luke W. , Carvajal Richard D. , Geskin Larisa J. , Schwartz Gary K. , Schwartz Lawrence , Dercle Laurent , Saenger Yvonne M. 
Published: February 2020

Purpose
Investigate the ability of 18F-fluorothymidine (FLT) PET combined with CT at 6 weeks to predict treatment response at 12 weeks after treatment with pembrolizumab.

Methods
Five patients with unresectable stage IV melanoma were included in this single-institution pilot study. Patients underwent FLT-PET/CT (baseline and 6 weeks) and CT (baseline and 12 weeks). FLT-PET/CT response and CT response were assessed using PET Response Criteria in Solid Tumors and immune Response Evaluation Criteria in Solid Tumors, respectively. Patients were categorized as responders (complete response, partial response) and nonresponders (stable disease, progressive disease). Agreement between 6-week FLT-PET/CT and 12-week CT was calculated using Cohen kappa's agreement. Eight baseline FLT-PET/CT parameters were extracted: SUVmax, SUVpeak, SUVSD, SUVmean, proliferative tumor volume, total lesion proliferation, bone marrow–to–liver SUVmax ratio, and spleen-to-liver SUVmax ratio. Eight delta-parameters were extracted at 6 weeks by calculating variation in FLT uptake as percentage change from baseline.

Results
Agreement between 6-week FLT-PET/CT and 12-week CT was kappa = 0.615, P = 0.025. Three of 5 patients were categorized as responders on CT by immune Response Evaluation Criteria in Solid Tumors. At baseline, responders had a lower mean proliferative tumor volume and a higher bone marrow–to–liver SUVmax ratio. At 6 weeks, responders demonstrated a decrease in tumor volume and tumor proliferation.

Conclusions
Our study illustrates the potential for FLT-PET/CT as an early predictor of response for patients with metastatic melanoma on anti-PD1 immunotherapy. Larger studies are indicated to confirm these findings.
Generation of GGTA1−/−β2M−/−CIITA−/− Pigs Using CRISPR/Cas9 Technology to Alleviate Xenogeneic Immune Reactions
Authors: Fu Rui , Fang Minghui , Xu Kai , Ren Jilong , Zou Jun , Su Long , Chen Xinxin , An PeiPei , Yu Dawei , Ka Meina , Hai Tang , Li Ziyi , Li Wei , Yang Yongguang , Zhou Qi , Hu Zheng 
Published: February 2020

Background.
Xenogeneic organ transplantation has been proposed as a potential approach to fundamentally solve organ shortage problem. Xenogeneic immune responses across species is one of the major obstacles for clinic application of xeno-organ transplantation. The generation of glycoprotein galactosyltransferase α 1, 3 (GGTA1) knockout pigs has greatly contributed to the reduction of hyperacute xenograft rejection. However, severe xenograft rejection can still be induced by xenoimmune responses to the porcine major histocompatibility complex antigens swine leukocyte antigen class I and class II.

Methods.
We simultaneously depleted GGTA1, β2-microglobulin (β2M), and major histocompatibility complex class II transactivator (CIITA) genes using clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins technology in Bamma pig fibroblast cells, which were further used to generate GGTA1
−/−
β2M
−/−
CIITA
−/− triple knockout (GBC-3KO) pigs by nuclear transfer.

Results.
The genotype of GBC-3KO pigs was confirmed by polymerase chain reaction and Sanger sequencing, and the loss of expression of α-1,3-galactose, SLA-I, and SLA-II was demonstrated by flow cytometric analysis using fluorescent-conjugated lectin from bandeiraea simplicifolia, anti-β2-microglobulin, and swine leukocyte antigen class II DR antibodies. Furthermore, mixed lymphocyte reaction assay revealed that peripheral blood mononuclear cells from GBC-3KO pigs were significantly less effective than (WT) pig peripheral blood mononuclear cells in inducing human CD3+CD4+ and CD3+CD8+ T-cell activation and proliferation. In addition, GBC-3KO pig skin grafts showed a significantly prolonged survival in immunocompetent C57BL/6 mice, when compared with wild-type pig skin grafts.

Conclusions.
Taken together, these results demonstrate that elimination of GGTA1, β2M, and CIITA genes in pigs can effectively alleviate xenogeneic immune responses and prolong pig organ survival in xenogenesis. We believe that this work will facilitate future research in xenotransplantation.
Identification of potential biomarkers in subtypes of epithelial ovarian cancer
Authors: Singh Rinki , Som Anup 
Published: February 2020

ABSTRACTEpithelial ovarian cancer (EOC) is the most lethal gynecological cancer. Due to the lack of specific symptoms, ∼80% of epithelial ovarian cancer is diagnosed at an advanced stage and often metastasize to the distant organ. Epithelial ovarian cancer is a heterogeneous disease that is classified into four major histological subtypes namely, serous carcinoma (SC), endometrioid carcinoma (EC), mucinous carcinoma (MC), and clear cell carcinoma (CCC). Ovarian cancer treatment is complicated due to the heterogeneity of the tumors. Patients with different subtypes respond differently to the same treatment and also have different prognoses. This diversity extends to various clinical outcomes of the disease. Thus, identifying new reliable potential biomarkers irrespective of their subtypes is an urgent need for the diagnosis and prognosis of epithelial ovarian cancer. In this study, we performed comparative gene expression analysis for identifying potential biomarkers in four histological subtypes of epithelial ovarian cancer (EOC) that include serous, endometrioid, mucinous, and clear cell carcinomas. Differentially expressed genes (DEGs) between cancerous and normal tissue samples were identified by considering the criteria of absolute logarithmic fold change |log2fc|>1 and adjusted p (padj) value<0.05. Pathway enrichment analysis of the DEGs showed that pathways in cancer, PI3K-AKT signaling pathway, RAP1 signaling pathway, cell cycle, cell adhesion molecules, and proteoglycans in cancer were common among the selected cancer subtypes. Further, we constructed the co-expression network of DEGs and identified 15 candidate genes. Finally, based on the survival analysis of the candidate genes, a total of nine genes namely ASPM, CDCA8, CENPM, CEP55, HMMR, RACGAP1, TPX2, UBE2C, and ZWINT with significant prognostic value was proposed as the potential biomarker.
IL-6 signalling protects zebrafish larvae duringStaphylococcus epidermidisinfection in a novel bath immersion model
Authors: Dhanagovind PT , Kujur Prabeer K. , Swain Rajeeb K. , Banerjee Sanjita 
Published: February 2020

AbstractHost immune responses toStaphylococcus epidermidis, a frequent cause of nosocomial infections, are not well understood. We have established a novel bath immersion model of this infection in zebrafish larvae.S.epidermidisinfection activates Tlr-2 signalling pathway by upregulation oftlr-2. Macrophages play a primary role in the host immune response and are involved in clearance of infection in the larvae. There is marked inflammation characterised by heightened NF-κB signalling and elevation of several pro-inflammatory cytokines. Infected larvae show rapid upregulation ofil-1bandtnf-atranscripts and relatively slower elevation ofil-6transcription. The IL-6 signalling pathway is additionally subject to amplification by elevation of IL-6 signal transducer (il-6st) levels, which negatively correlates with miRNA dre-miR-142-5p expression. Enhanced IL-6 signalling is protective to the host in this model as inhibition of the signalling pathway resulted in increased mortality uponS.epidermidisinfection. Our study describes the host immune responses toS.epidermidisinfection, identifies a likely role for miR-142-5p –il-6stinteraction in modulating this response and establishes the importance of IL-6 signalling in this infection model.
Reducing monocarboxylate transporter MCT1 worsens experimental diabetic peripheral neuropathy
Authors: Jha Mithilesh Kumar , Ament Xanthe Heifetz , Yang Fang , Liu Ying , Polydefkis Michael J. , Pellerin Luc , Morrison Brett M. 
Published: February 2020

AbstractDiabetic peripheral neuropathy (DPN) is one of the most common complications in diabetic patients. Though the exact mechanism for DPN is unknown, it clearly involves metabolic dysfunction and energy failure in multiple cells within the peripheral nervous system (PNS). Lactate is an alternate source of metabolic energy that is increasingly recognized for its role in supporting neurons. The primary transporter for lactate in the nervous system, monocarboxylate transporter-1 (MCT1), has been shown to be critical for peripheral nerve regeneration and metabolic support to neurons/axons. In this study, MCT1 was reduced in both sciatic nerve and dorsal root ganglia in wild-type mice treated with streptozotocin (STZ), a common model of type-1 diabetes. Heterozygous MCT1 null mice treated with STZ developed a more severe DPN compared to wild-type mice, as measured by greater axonal demyelination, decreased peripheral nerve function, and increased numbness to innocuous low-threshold mechanical stimulation. Given that MCT1 inhibitors are being developed as both immunosuppressive and chemotherapeutic medications, our results suggest that clinical development in patients with diabetes should proceed with caution. Collectively, our findings uncover an important role for MCT1 in DPN and provide a potential lead toward developing novel treatments for this currently untreatable disease.
Sp8regulatory function in the limb bud ectoderm
Authors: Pérez-Gómez Rocío , Fernández-Guerrero Marc , Campa Víctor , Lopez-Gimenez Juan F. , Rada-Iglesias Alvaro , Ros Maria A. 
Published: February 2020

ABSTRACTSp8 and Sp6 are two closely related Sp genes expressed in the limb ectoderm where they regulate proximo-distal and dorso-ventral patterning. Mouse genetics revealed that they act together in a dose-dependent manner but with Sp8 making a much greater contribution. Here, we combine ChIP-seq and RNA-seq genome-wide analyses to investigate the Sp8 regulatory network and mechanism of action. We find that Sp8 predominantly binds to putative distal enhancers to activate crucial limb patterning genes, includingFgf8, En1, Sp6andRspo2. Sp8 exerts its regulatory function by directly binding DNA at Sp consensus sequences or indirectly through Dlx5 interaction. Overall, our work underscores Sp8 master regulatory functions and supports a model in which it cooperates with other Dlx and Sp cofactors to regulate target genes. We believe that this model could help to properly understand the molecular basis of congenital malformations.Impact SentenceIn the limb ectoderm, Sp8 regulates master genes through a dual mechanism: directly binding DNA at Sp consensus sequences and indirectly engaging through Dlx5 interaction.
Genetic variance in fitness and its cross-sex covariance predict adaptation during experimental evolution
Authors: Koch Eva L. , Sbilordo Sonja H. , Guillaume Frédéric 
Published: February 2020

AbstractIn presence of rapid environmental changes, it is of particular importance to assess the adaptive potential of populations, which is mostly determined by the additive genetic variation (VA) in fitness. In this study we usedTribolium castaneum(red flour beetles) to investigate its adaptive potential in three new environmental conditions (Dry, Hot, Hot-Dry). We tested for potential constraints that might limit adaptation, including negative genetic covariance between female and male fitness. Based on VAestimates for fitness, we expected the highest relative fitness increase in the most stressful condition Hot-Dry and similar increases in single stress conditions Dry and Hot. High adaptive potential in females in Hot was reduced by a negative covariance with male fitness. We tested adaptation to the three conditions after 20 generations of experimental evolution and found that observed adaptation mainly matched our predictions. Given that body size is commonly used as a proxy for fitness, we also tested how this trait and its genetic variance (including non-additive genetic variance) were impacted by environmental stress. In both traits, variances were sex and condition dependent, but they differed in their variance composition, cross-sex and cross-environment genetic covariances, as well as in the environmental impact on VA.
Hypoxia-inducible lipid droplet-associated interacts with DGAT1 and promotes lipid storage in hepatocytes
Authors: de la Rosa Rodriguez Montserrat A. , Gemmink Anne , van Weeghel Michel , Aoun Marie Louise , Warnecke Christina , Singh Rajat , Borst Jan Willem , Kersten Sander 
Published: February 2020

ABSTRACTLipid droplets (LD) are dynamic organelles that can expand and shrink, driven by fluctuations in the rate of triglyceride synthesis and degradation. Triglyceride synthesis, storage in LD, and degradation are governed by a complex set of LD-associated proteins. One of these LD-associated proteins, hypoxia-inducible lipid droplet-associated (HILPDA), was found to impair LD breakdown by inhibiting adipose triglyceride lipase. Here we characterized the physiological role and mechanism of action of HILPDA in hepatocytes. Expression of HILPDA was induced by fatty acids in several hepatoma cell lines. Hepatocyte-specific deficiency of HILPDA in mice modestly but significantly reduced hepatic triglycerides in mice with non-alcoholic fatty liver disease. Similarly, deficiency of HILPDA in mouse precision-cut liver slices and primary hepatocytes reduced lipid storage and accumulation of fluorescently-labelled fatty acids in LD, respectively, which was independent of adipose triglyceride lipase. Fluorescence microscopy showed that HILPDA partly colocalizes with LD and with the endoplasmic reticulum, is especially abundant in perinuclear areas, and mainly associates with newly added fatty acids. Real-time fluorescence live-cell imaging further revealed that HILPDA preferentially localizes to LD that are being remodelled. Mechanistically, HILPDA overexpression increased lipid storage in human hepatoma cells concomitant with an increase in DGAT activity and DGAT1 protein levels. Finally, confocal microscopy and Förster resonance energy transfer-fluorescence lifetime imaging microscopy analysis indicated that HILPDA colocalizes and physically interacts with DGAT1. Overall, our data indicate that HILPDA physically interacts with DGAT1 and increases DGAT activity. These findings suggest a novel mechanism in hepatocytes that links elevated fatty acid levels to stimulation of triglyceride synthesis and storage.
Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance
Authors: Huoh Yu-San , Wu Bin , Park Sehoon , Yang Darren , Bansal Kushagra , Greenwald Emily , Wong Wesley P. , Mathis Diane , Hur Sun 
Published: February 2020

ABSTRACTAggregate-like biomolecular assemblies are emerging as new conformational states with functionality. Aire, a transcription factor essential for central T cell tolerance, is known to form large aggregate-like assemblies visualized as nuclear foci. We demonstrate that Aire utilizes Caspase Activation Recruitment Domain (CARD) to form filamentous homo-multimersin vitro, and this assembly mediates foci formation and transcriptional activity. However, CARD-mediated multimerization is a double-edged sword as it also makes Aire susceptible to interaction with PML bodies, sites of many nuclear processes including protein quality control of nuclear aggregates. Several loss-of-function Aire mutants, including those causing autoimmune polyendocrine syndrome type-1, form foci with increased PML body association. Directing Aire to PML bodies impairs Aire’s transcriptional activity, while dispersing PML bodies with a viral antagonist restores it. Thus, our study reveals a new regulatory role of PML bodies in Aire function and highlights the interplay between nuclear aggregate-like assemblies and PML-mediated quality control.
Network analysis of workshop activities reveals increasing transdisciplinarity of German biodiversity research community
Authors: Geschke Jonas , Lutz Martina , Vohland Katrin 
Published: February 2020

AbstractBoundary spanning activities in the biodiversity science-policy interface are urgently needed. Effective science communication and uptake of scientific findings by policymakers is crucial for a successful, cross-scale policy implementation. For this, national platforms promoting knowledge exchange between different stakeholder groups are key. Established in 2009, the Network-Forum on Biodiversity Research Germany (NeFo) until 2018 has organized more than 40 workshops bringing together actors from science, policy and society. In this paper, we present a network and cluster analysis of these NeFo workshops. Based on this, we discuss the importance of science-policy interface projects and networks as knowledge brokers and boundary organizations, as well as challenges in using network analysis as a tool for evaluating workshop impacts. Based on the network analysis outcomes as well as experiences in the conduction of workshops, recommendations to strengthen the innovation impact of networking efforts are drawn.
Chemical and structural investigation of the paroxetine-human serotonin transporter complex
Authors: Coleman Jonathan A. , Navratna Vikas , Antermite Daniele , Yang Dongxue , Bull James A. , Gouaux Eric 
Published: February 2020

ABSTRACTAntidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand the binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation. Such modifications to SERT have led to questions about the relationships of these structures to thebona fideconformation and inhibitor binding poses of the wild-type transporter. To address these concerns, we characterized wild-type SERT with truncated N- and C-termini and thermostabilized variants of SERT bound with paroxetine using x-ray crystallography, single particle cryo-EM and biochemical techniques. Moreover, using a C–H functionalization approach to synthesize enantiopure analogues, we replaced the halide of the fluorophenyl group in paroxetine with either bromine or iodine. We then exploited the anomalous scattering of Br and I to define the pose of the respective paroxetine analog. These structures provide mutually consistent insights into how paroxetine and its analogs bind to the central substrate-binding site of SERT, stabilize the outward-open conformation, and inhibit serotonin transport.
FL-QSAR: a federated learning based QSAR prototype for collaborative drug discovery
Authors: Chen Shaoqi , Xue Dongyu , Chuai Guohui , Yang Qiang , Liu Qi 
Published: February 2020

AbstractMotivationQuantitative structure-activity relationship (QSAR) analysis is commonly used in drug discovery. Collaborations among pharmaceutical institutions can lead to a better performance in QSAR prediction, however, intellectual property and related financial interests remain substantially hindering inter-institutional collaborations in QSAR modeling for drug discovery.ResultsFor the first time, we verified the feasibility of applying the horizontal federated learning (HFL), which is a recently developed collaborative and privacy-preserving learning framework to perform QSAR analysis. A prototype platform of federated-learning-based QSAR modeling for collaborative drug discovery, i.e, FL-QSAR, is presented accordingly. We first compared the HFL framework with a classic privacy-preserving computation framework, i.e., secure multiparty computation (MPC) to indicate its difference from various perspective. Then we compared FL-QSAR with the public collaboration in terms of QSAR modeling. Our extensive experiments demonstrated that (1) collaboration by FL-QSAR outperforms a single client using only its private data, and (2) collaboration by FL-QSAR achieves almost the same performance as that of collaboration via cleartext learning algorithms using all shared information. Taking together, our results indicate that FL-QSAR under the HFL framework provides an efficient solution to break the barriers between pharmaceutical institutions in QSAR modeling, therefore promote the development of collaborative and privacy-preserving drug discovery with extendable ability to other privacy-related biomedical areas.Availability and implementationThe source codes of the federated learning simulation and FL-QSAR are available on the GitHub:https://github.com/bm2-lab/FL-QSAR
Bidirectional sex-dependent regulation of α6 and β3 nicotinic acetylcholine receptors by protein kinase Cε
Authors: Moen Janna K. , DeBaker Margot C. , Myjak Julia E. , Wickman Kevin , Lee Anna M. 
Published: February 2020

AbstractNicotine and alcohol are the most commonly abused substances worldwide, and comorbid nicotine and alcohol addiction is highly prevalent. Nicotinic acetylcholine receptors (nAChRs) containing the α6 and β3 subunits are expressed in neural reward circuits and are critical for both nicotine and alcohol reward. nAChRs are dynamically regulated by signaling molecules such as protein kinase C epsilon (PKCε), which impact transcription of α6 and β3 subunit mRNA (Chrna6andChrnb3, respectively). Previous work found decreased expression ofChrna6andChrnb3transcripts in the ventral midbrain of male PKCε−/−mice, who also consume less nicotine and alcohol compared to wild-type (WT) littermates. Here, we show that female PKCε−/−mice have enhanced expression ofChrna6andChrnb3transcripts in the ventral midbrain, which functionally impacts nAChR-dependent behavior, as female but not male PKCε−/−mice exhibit locomotor hypersensitivity to nicotine. Female PKCε−/−mice show no differences in alcohol-induced sedation compared to WT littermates, while male PKCε−/−have enhanced sedation compared to WT mice, a phenotype that has previously been reported in α6−/−mice. Female PKCε−/−mice also show reduced depression-like behavior in response to systemic injections of varenicline compared to WT littermates, and this effect was absent in male mice. Additionally, we found that female PKCε−/−mice show altered alcohol and nicotine consumption patterns in chronic voluntary two bottle choice assays. Our data reveal a bidirectional effect of sex in the transcriptional regulation of nicotinic receptors by PKCε, and highlight the importance of studying both sexes in preclinical animal models.