bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational Analysis of Therapeutic Neuroadaptation to Chronic Antidepressant in a Model of the Monoaminergic Neurotransmitter and Stress Hormone Systems
Authors: Camacho Mariam Bonyadi , Vijitbenjaronk Warut D. , Anastasio Thomas J 
Published: May 2019

AbstractThe clinical practice of selective serotonin reuptake inhibitor (SSRI) augmentation relies heavily on clinical judgment and trial-and-error. Unfortunately, the drug combinations prescribed today fail to provide relief for all treatment-resistant depressed patients. In order to identify potentially more effective treatments, we developed a computational model of the monoaminergic neurotransmitter and stress-steroid systems that neuroadapts to chronic administration of combinations of antidepressant drugs and hormones by adjusting the strengths of its transmitter-system components (TSCs). We used the model to screen 60 chronically administered drug/hormone pairs and triples, and identified as potentially therapeutic those combinations that raised the monoamines (serotonin, norepinephrine, and dopamine) but lowered cortisol following neuroadaptation in the model. We also evaluated the contributions of individual and pairs of TSCs to therapeutic neuroadaptation with chronic SSRI using sensitivity, correlation, and linear temporal-logic analyses. All three approaches found that therapeutic neuroadaptation to chronic SSRI is an overdetermined process that depends on multiple TSCs, providing a potential explanation for the clinical finding that no single antidepressant regimen alleviates depressive symptoms in all patients.
Fine-scale haplotype structure reveals strong signatures of positive selection in a recombining bacterial pathogen
Authors: Arnold Brian , Sohail Mashaal , Wadsworth Crista , Corander Jukka , Hanage William P. , Sunyaev Shamil , Grad Yonatan H. 
Published: May 2019

ABSTRACTIdentifying the forces that create and shape ecologically meaningful variation in bacteria remains an important challenge. For recombining bacteria, the sign and strength of linkage provide a unique lens into ongoing selection. We show derived alleles less than 300bp apart inNeisseria gonorrhoeaeexhibit more coupling linkage than repulsion linkage, a pattern that cannot be explained by limited recombination or neutrality as these couplings are significantly stronger for nonsynonymous alleles compared to synonymous alleles. While linkage is shaped by many evolutionary processes, extensive simulations show only two distinct forms of positive selection can drive an excess of coupling linkage between neighboring nonsynonymous alleles: directional selection on introgressed alleles or selection that maintains distinct haplotypes in the presence of recombination. Our results establish a framework for identifying patterns of selection in fine-scale haplotype structure that indicate specific ecological processes in species that recombine with distantly related lineages or possess coexisting adaptive haplotypes.
Differential Functions of Splicing Factors in Breast-Cancer Initiation and Metastasis
Authors: Das Shipra , Akerman Martin , Park SungHee , Brugioli Mattia , Geier Adam , Kesarwani Anil K. , Fan Martin , Leclair Nathan , Urbanski Laura , Lin Kuan-Ting , Hu Chenle , Hua Xingan , George Joshy , Muthuswamy Senthil K. , Krainer Adrian R. , Anczuków Olga 
Published: May 2019

SUMMARYMisregulation of alternative splicing is a hallmark of human tumors; yet to what extent and how it contributes to malignancy are only beginning to be unraveled. Here, we define which members of the splicing factor SR and SR-like families contribute to breast cancer, and uncover differences and redundancies in their targets and biological functions. We first identify splicing factors frequently altered in human breast tumors, and then assay their oncogenic functions using breast organoid models. Importantly we demonstrate that not all splicing factors affect mammary tumorigenesis. Specifically, upregulation of either SRSF4, SRSF6 or TRA2β promotes cell transformation and invasion. By characterizing the targets of theses oncogenic factors, we identify a shared set of spliced genes associated with well-established cancer hallmarks. Finally, we demonstrate that the splicing factor TRA2β is regulated by the MYC oncogene, plays a role in metastasis maintenancein vivo, and its levels correlate with breast-cancer-patient survival.
Why high yield QTLs did not succeed in preventing yield stagnation in rice?
Authors: Xiong Dongliang 
Published: May 2019

AbstractRice plays a vital role in global food security, and its yield needs to be increased to meet escalating demand. Although many high yield quantitative trait loci (QTLs) have been identified in the last decades, rice grain yield in the main rice-producing countries is stagnating since the middle of the 1990s. By summarizing the yield performance of high-yielding QTL lines, we found that almost all the high-yielding QTL introduced lines had no practical usage in current high yield breeding programs, due mainly to their low absolute grain yield. Further analysis showed that scientists primarily focused on spikelets number per panicle alone rather than other yield traits, and, in most of the studies, the yield increase was referenced to very old cultivars. By analyzing the yield traits correlations across cultivars in both field and pot conditions, and yield traits correlations across different eco-sites using the same cultivars, we demonstrated that the rice high yield will be rarely achieved by using single-trait approaches due to the traits trade-offs. Building on this, several recommendations are provided to the next generation of biotechnological breeding in rice.
Identification of NAD-dependent xylitol dehydrogenase fromGluconobacter oxydansWSH-003
Authors: Liu Li , Zeng Weizhu , Du Guocheng , Chen Jian , Zhou Jingwen 
Published: May 2019

AbstractGluconobacter oxydansplays important role in conversion of D-sorbitol to L-sorbose, which is an essential intermediate for industrial-scale production of vitamin C. In the fermentation process, some D-sorbitol could be converted to D-fructose and other byproducts by uncertain dehydrogenases. Genome sequencing has revealed the presence of diverse genes encoding dehydrogenases inG. oxydans. However, the characteristics of most of these dehydrogenases remain unclear. Therefore, analyses of these unknown dehydrogenases could be useful for identifying those related to the production of D-fructose and other byproducts. Accordingly, dehydrogenases inG. oxydansWSH-003, an industrial strain used for vitamin C production, were examined. An NAD-dependent dehydrogenase, which was annotated as xylitol dehydrogenase 2, was identified, codon-optimized, and expressed inEscherichia coliBL21 (DE3) cells. The enzyme exhibited high preference for NAD+as the cofactor, while no activity with NADP+, FAD, or PQQ was noted. Although this enzyme presented high similarity with NAD-dependent xylitol dehydrogenase, it showed high activity to catalyze D-sorbitol to D-fructose. Unlike the optimum temperature and pH for most of the known NAD-dependent xylitol dehydrogenases (30°C–40°C and about 6–8, respectively), those for the identified enzyme were 57°C and 12, respectively. TheKmandVmaxof the identified dehydrogenase towards L-sorbitol were 4.92 μM and 196.08 μM/min, respectively. Thus, xylitol dehydrogenase 2 can be useful for cofactor NADH regeneration under alkaline conditions or its knockout can improve the conversion ratio of D-sorbitol to L-sorbose.ImportanceProduction of L-sorbose from D-sorbitol byGluconobacter oxydansis the first step for industrial scale production of L-ascorbic acid.G. oxydanscontains a lot of different dehydrogenases, among which only several are responsible for the conversion of D-sorbitol to L-sorbose, while others may responsible for the accumulation of byproducts, thus decreased the yield of L-sorbose on D-sorbitol. Therefore, a new xylitol dehydrogenase has been identified from 44 dehydrogenases ofG.oxydans. Optimum temperature and pH of the xylitol dehydrogenase are different to most of the known ones. Knock-out of the dehydrogenase may improve the conversion ratio of D-sorbitol to L-sorbose. Besides, the enzyme exhibits high preference for NAD+and have potential to be used for cofactor regeneration.
Acute phase protein, α – 1- acid glycoprotein (AGP-1), has differential effects on TLR-2 and TLR-4 mediated responses
Authors: Sumanth Mosale Seetharam , Abhilasha Kandahalli Venkataranganayaka , Jacob Shancy Petsel , Chaithra Vyala Hanumanthareddy , Basrur Venkatesha , Willard Belinda , McIntyre Thomas M. , Prabhu K. Sandeep , Marathe Gopal K. 
Published: May 2019

AbstractAlpha-1-acid glycoprotein (AGP-1) is a major positive acute phase glycoprotein with unknown functions that likely plays a role in inflammation. We tested its involvement in a variety of inflammatory responses using human AGP-1 purified to apparent homogeneity and confirmed its identity by immunoblotting and mass spectrometry. AGP-1 alone upregulated MAPK signaling in murine peritoneal macrophages. However, when given in combination with TLR ligands, AGP-1 selectively augmented MAPK activation induced by ligands of TLR-2 (Braun lipoprotein) but not TLR-4 (lipopolysaccharide).In vivotreatment of AGP-1 in a murine model of sepsis with or without TLR-2 or TLR-4 ligands, selectively potentiated TLR-2-mediated mortality, but was without significant effect on TLR-4-mediated mortality. Furthermore,in vitro, AGP-1 selectively potentiated TLR-2 mediated adhesion of human primary immune cell, neutrophils. Hence, our studies highlight a new role for the acute phase protein AGP-1 in sepsis via its interaction with TLR-2 signaling mechanisms to selectively promote responsiveness to one of the two major gram-negative endotoxins, contributing to the complicated pathobiology of sepsis.
Peptides derived of kunitz-type serine protease inhibitor as potential vaccine against experimental schistosomiasis
Authors: Hernández-Goenaga Juan , López-Abán Julio , Protasio Anna V. , Vicente Santiago Belén , del Olmo Esther , Vanegas Magnolia , Fernández-Soto Pedro , Alfonso Patarroyo Manuel , Muro Antonio 
Published: May 2019

AbstractSchistosomiasis is a significant public health problem in sub-Saharan Africa, China, South-East Asia and regions of South and central America affecting about 189 million people. Kunitz-type serine protease inhibitors have been identified as important players in the interaction of other flatworm parasites with their mammalian hosts. Here, we evaluate the protective efficacy of chemically synthesized of T- and B-cell peptide epitopes derived from a kunitz protein fromSchistosoma mansoni. Putative kunitz-type protease inhibitor proteins were identified in theS. mansonigenome and their expression analyzed by RNA-seq. Gene expression analyses showed that the kunitz protein Smp_147730 (Syn. Smp_311670) was dramatically and significantly up-regulated in schistosomula and adult worms when compared to the invading cercariae. T- and B-cell epitopes were predicted using bioinformatics tools, chemically synthesized and formulated in the Adjuvant Adaptation (ADAD) vaccination system. BALB/c mice were vaccinated and challenged withS. mansonicercariae. Kunitz peptides were highly protective in vaccinated BALB/c mice showing significant reductions in recovery of adult females (89-91%), and in the numbers of eggs trapped in the livers (77-81%) and guts (57-77%) of mice. Moreover, liver lesions were significantly reduced in vaccinated mice (64-65%) compared to infected control mice. The vaccination regime was well tolerated with both peptides. We propose the use of these peptides, alone or in combination, as reliable candidates for vaccination against schistosomiasis.
Comparison of Vitek® 2, three different gradient strip tests and broth microdilution for detecting vanB-positive Enterococcus faecium isolates with low vancomycin MICs
Authors: Klare Ingo , Bender Jennifer K. , Fleige Carola , Kriebel Nancy , Hamprecht Axel , Gatermann Sören , Werner Guido 
Published: May 2019

AbstractObjectivesIn 2018, EUCAST issued a warning regarding unreliable results of gradient strip tests for confirming vancomycin resistance in enterococci. We compared the performance of various diagnostic standard and confirmatory tests to identify and determine vanB-type vancomycin resistance.MethodsWe analysed a collection of vanB-positive E. faecium isolates (n = 68) with low level vancomycin minimal inhibitory concentrations (MICs) and compared the performance of Vitek® 2 (bioMérieux), of broth microdilution and of three different gradient strip test providers (Oxoid, Liofilchem, bioMérieux). For the latter we compared the standard procedure vs. a protocol with increased inoculum, a rich agar medium and a longer incubation time (“macromethod”).ResultsThe sensitivity of Vitek® 2 was 81% of vanB-isolates compared to 72% for broth microdilution and 61 – 63% for the three gradient strip tests using standard conditions. The “macromethod” substantially improved performance of all strip tests resulting in a sensitivity of 89 – 96% at 48h readout.ConclusionsThe “macromethod” provided the overall best performance for recognition of vanB E. faecium. We therefore propose to adapt the EUCAST warning and to recommend the “macromethod” with an additional 48h readout or a confirmation by a vanB-specific PCR from culture.
Mesenchymal expression of activated K-ras yields Noonan Syndrome-like bone defects that are rescued by mid-gestational MEK inhibition
Authors: Nedelcu Simona , Kobayashi Tatsuya , Stanciu Monica , Kronenberg Henry M. , Lees Jacqueline A. 
Published: May 2019

ABSTRACTActivating germline K-ras mutations cause Noonan syndrome (NS), which is characterized by several developmental deficits including cardiac defects, cognitive delays and skeletal abnormalities. NS patients have increased signaling through the MAPK pathway. To model NS skeletal defects and understand the effect of hyperactive K-ras signaling on normal limb development, we generated a mouse model in which activated K-rasG12D was expressed specifically in mesenchymal progenitors of the limb bud. These mice display short, abnormally mineralized long bones that phenocopy those of NS patients. This defect was first apparent at E14.5, and was characterized by a delay in bone collar formation. Coincident mutation of p53 had no effect on the K-rasG12D induced bone defect, arguing that it is does not result from senescence or apoptosis. Instead, our data revealed profound defects in the development of the committed osteoblasts; their appearance is delayed, concordant with the delay in bone collar formation, and they display an aberrant localization outside of the bone shaft. Additionally, we see growth plate defects including a reduction in the hypertrophic chondrocyte layer. Most importantly, we found that in utero delivery of a MEK inhibitor between E10.5 and E14.5 is sufficient to completely suppress the ability of activated K-ras to induce NS-like long bone defects in embryogenesis. These data define a critical point in mid-gestation in which elevated MAPK signaling impairs growth plate and bone collar formation and yield NS-like limb defects. Moreover, they offer insight into possible therapeutic strategies for skeletal defects in patients with Noonan Syndrome.SIGNIFICANCE STATEMENTNoonan syndrome is a genetic condition that is characterized by various developmental defects including skeletal abnormalities that lead to short stature. These patients carry mutations that activate Ras/MAPK signaling. We have generated a mouse model that recapitulates these Noonan Syndrome-like bone defects. Analysis of these animals establishes the developmental window in which bone formation goes awry, and reveals disruption of an early event that is critical for the longitudinal growth of bones. Additionally, we show that treatment with an inhibitor of Ras/MAPK signaling during this key developmental window is sufficient to completely suppress these Noonan Syndrome-like bone defects. This offers possible therapeutic strategies for skeletal defects in patients with Noonan Syndrome.
Cullin-5 adaptor SPSB1 controls NF-κB activation downstream of multiple signalling pathways
Authors: Georgana Iliana , de Motes Carlos Maluquer 
Published: May 2019

ABSTRACTCullin-RING E3 ubiquitin ligases (CRLs) have emerged as critical regulators of many cellular functions including innate immunity and inflammation. CRLs form multiprotein complexes in which specific adaptor proteins recruit the substrates to be ubiquitylated. Here, we systematically depleted all predicted SOCS-box proteins – the substrate adaptors for the CRL5 family - and assessed the impact on the activation of the NF-κB pathway. Depletion of SPSB1 resulted in a significant increase in NF-κB activation, indicating the importance of SPSB1 as an NF-κB negative regulator. In agreement, overexpression of SPSB1 suppressed NF-κB activity in a potent, dose-dependent manner in response to various agonists. Conversely, the activation of IRF-3, AP-1 and STATs was unaffected by SPSB1, showing its specificity for NF-κB. Mechanistically, SPSB1 suppressed NF-κB activation induced via multiple pathways including Toll-like receptors and RNA and DNA sensing adaptors, but was unable to prevent the phosphorylation and degradation of IκB nor the translocation of p65 into the nucleus. This indicated that SPSB1 exerts its inhibitory activity downstream, or at the level, of the NF-κB heterodimer and in agreement, SPSB1 was found to co-precipitate with p65. Additionally, A549 cells stably expressing SPSB1 presented lower cytokine levels including type I interferon in response to cytokine stimulation and virus infection. Taken together, our results reveal novel regulatory mechanisms in inflammation and innate immune signalling and identify the prominent role of SPSB1 in controlling NF-κB activation, thus providing new opportunities for the therapeutic targeting of NF-κB transcriptional activity.
Quantifying E2F1 protein dynamics in single cells
Authors: Mathey-Prevot Bernard , Parker Bao-Tran , Im Carolyn , Hong Cierra , Dong Peng , Yao Guang , You Lingchong 
Published: May 2019

AbstractThe Rb/E2F pathway plays a central role in regulating cell-fate decisions and cell-cycle progression. The E2F1 protein, a major effector of the pathway, is regulated via a combination of transcriptional, translational and posttranslational constraints. Elucidating the regulation and impact of the Rb/E2F pathway requires direct measurement of E2F1 dynamics in single cells. To this end, we have engineered fluorescent E2F1 protein reporters to enable live detection and quantification in single cells. The reporter constructs expressed an E2F1-Venus fusion protein under the regulation of the mouse or human E2F1 promoter and contained or excluded the 3’UTR of the E2F1 gene, a sequence that contains miRNA regulatory regions that modulate expression of the protein. Expression of the reporter protein was highly dynamic during the cell cycle: there was no or little fluorescent signal in G0, but levels steadily increased during late G1 and peaked during mid to late S phase before returning to baseline before the onset of mitosis. The absence of the E2F1 3’UTR in the constructs led to considerably higher steady-state levels of the fusion protein, which although normally regulated, exhibited a slightly less complex dynamic profile during the cell cycle or genotoxic stress. Lastly, the presence or absence of Rb failed to impact in substantial ways the overall detection and levels of the reporters.
Symmetric arrangement of mitochondria:plasma membrane contacts between adjacent photoreceptor cells regulated by Opa1
Authors: Meschede Ingrid P. , Seabra Miguel C. , Futter Clare E. , Votruba Marcela , Cheetham Michael E. , Burgoyne Thomas 
Published: May 2019

AbstractMitochondria are known to play an essential role in photoreceptor function and wellbeing that enables normal healthy vision. Within photoreceptors they are elongated and extend most of the length inner segment, where they supply energy for protein synthesis and the phototransduction machinery in the outer segment as well as acting as a calcium store. Here we examined the arrangement of the mitochondria within the inner segment in detail using 3D electron microscopy techniques and show they are tethered to the plasma membrane in a highly specialised arrangement. This includes mitochondria running alongside each other in neighbouring inner segments, with evidence of alignment of the cristae openings. As the pathway by which photoreceptors meet their high energy demands is not fully understood, we propose this to be a mechanism to share metabolites and assist in maintaining homeostasis across the photoreceptor cell layer. In the extracellular space between photoreceptors, Müller glial processes were identified. Due to the often close proximity to the inner segment mitochondria, they may too play a role in the inner segment mitochondrial arrangement as well as metabolite shuttling. OPA1 is an important factor in mitochondrial homeostasis, including cristae remodelling; therefore, we examined the photoreceptors of a heterozygousOpa1knock-out mouse model. The cristae structure in theOpa1+/−photoreceptors was not greatly affected, but there were morphological abnormalities and a reduction in mitochondria in contact with the inner segment plasma membrane. This indicates the importance of key regulators in maintaining this specialised photoreceptor mitochondrial arrangement.
The conformational and mutational landscape of the ubiquitin-like marker for the autophagosome formation in cancer
Authors: Fas Burcu Aykac , Kumar Mukesh , Sora Valentina , Mashkoor Maliha , Lambrughi Matteo , Tiberti Matteo , Papaleo Elena 
Published: May 2019

AbstractAutophagy is a cellular process to recycle damaged cellular components and its modulation can be exploited for disease treatments. A key autophagy player is a ubiquitin-like protein, LC3B. Compelling evidence attests the role of autophagy and LC3B in different cancer types. Many LC3B structures have been solved, but a comprehensive study, including dynamics, has not been yet undertaken. To address this knowledge gap, we assessed ten physical models for molecular dynamics for their capabilities to describe the structural ensemble of LC3B in solution using different metrics and comparison with NMR data. With the resulting LC3B ensembles, we characterized the impact of 26 missense mutations from Pan-Cancer studies with different approaches. Our findings shed light on driver or neutral mutations in LC3B, providing an atlas of its modifications in cancer. Our framework could be used to assess the pathogenicity of mutations by accounting for the different aspects of protein structure and function altered by mutational events.