bluuebunny/crossref_metadata_2025_split huggingface dataset:
Benchmarking Time-Series Data Discretization on Inference Methods
Authors: Li Yuezhe , Jann Tiffany , Vera-Licona Paola 
Published: August 2018

AbstractThe rapid development in quantitatively measuring DNA, RNA, and protein has generated a great interest in the development of reverse-engineering methods, that is, data-driven approaches to infer the network structure or dynamical model of the system. Many reverse-engineering methods require discrete quantitative data as input, while many experimental data are continuous. Some studies have started to reveal the impact that the choice of data discretization has on the performance of reverse-engineering methods. However, more comprehensive studies are still greatly needed to systematically and quantitatively understand the impact that discretization methods have on inference methods. Furthermore, there is an urgent need for systematic comparative methods that can help select between discretization methods. In this work, we consider 4 published intracellular networks inferred with their respective time-series datasets. We discretized the data using different discretization methods. Across all datasets, changing the data discretization to a more appropriate one improved the reverse-engineering methods’ performance. We observed no universal best discretization method across different time-series datasets. Thus, we propose DiscreeTest, a two-step evaluation metric for ranking discretization methods for time-series data. The underlying assumption of DiscreeTest is that an optimal discretization method should preserve the dynamic patterns observed in the original data across all variables. We used the same datasets and networks to show that DiscreeTest is able to identify an appropriate discretization among several candidate methods. To our knowledge, this is the first time that a method for benchmarking and selecting an appropriate discretization method for time-series data has been proposed.AvailabilityAll the datasets, reverse-engineering methods and source code used in this paper are available in Vera-Licona’s lab Github repository: https://github.com/VeraLiconaResearchGroup/Benchmarking_TSDiscretizations
Interspecies malate-pyruvate shuttle drives amino acid exchange in organohalide-respiring microbial communities
Authors: Wang Po-Hsiang , Correia Kevin , Ho Han-Chen , Venayak Naveen , Nemr Kayla , Flick Robert , Mahadevan Radhakrishnan , Edwards Elizabeth A. 
Published: August 2018

AbstractMost microorganisms in the biosphere live in communities and develop coordinated metabolisms via trading metabolites. In this study, we sought to deconstruct the metabolic interdependency in organohalide-respiring microbial communities enriched withDehalobacter restrictus(Dhb), using a complementary approach of computational metabolic modeling and experimental validation.Dhbpossesses a complete set of genes for amino acid biosynthesis yet requires amino acid supplementation. We reconciled this discrepancy using Flux Balance Analysis with consideration for cofactor availability, enzyme promiscuity, and shared protein expression patterns of severalDhbstrains. Experimentally,13C incorporation assays, growth assays, and metabolite analysis of strain PER-K23 cultures were performed to validate the model predictions. The model resolved thatDhb’s amino acid dependency results from restricted NADPH regeneration and diagnosed that malate supplementation can replenish intracellular NADPH using malic enzyme. Interestingly, we observed unexpected export of glutamate and pyruvate in parallel to malate consumption in the strain PER-K23 cultures. Further experiments onDhb-enriched consortium ACT-3 suggested an interspecies malate-pyruvate shuttle betweenDhband a glutamate-auxotrophicBacteroidessp., reminiscent of the mitochondrial malate shunt pathway in eukaryotic cells. Altogether, this study reveals that redox constraints and metabolic complementarity are important driving forces for amino acid exchange in anaerobic microbial communities.
Synthetic chromosome fusion: effects on genome structure and function
Authors: Luo Jingchuan , Vale-Silva Luis A. , Raghavan Adhithi R. , Mercy Guillaume , Heldrich Jonna , Sun Xiaoji , Li Mingyu , Zhang Weimin , Agmon Neta , Yang Kun , Cai Jitong , Stracquadanio Giovanni , Thierry Agnès , Zhao Yu , Coelho Camila , Lauer Stephanie , Ahn Ju Young , Adoff Greg , D’Avino Andrew , Berger Henri , Chen Yi , Chickering Michael , Fishman Oren , Greeno Rebeca Vergara , Kim Sangmin , Kim Sunghan , Lim Hong Seo , Im Jay , Meyer Lauren , Moyer Allison , Annadanam Surekha , Murphy Natalie A. , Natov Peter , Nimer Maisa , Radley Arthur , Tripathy Arushi , Wang Tony , Wilkerson Nick , Zheng Tony , Zhou Vivian , Zeller Karen , Kaback David B. , Bader Joel S. , Mitchell Leslie A. , Mozziconacci Julien , Koszul Romain , Hochwagen Andreas , Boeke Jef D. 
Published: August 2018

SUMMARYAs part of the Synthetic Yeast 2.0 (Sc2.0) project, we designed and synthesized synthetic chromosome I. The total length of synI is ∼21.4% shorter than wild-type chromosome I, the smallest chromosome inSaccharomyces cerevisiae. SynI was designed for attachment to another synthetic chromosome due to concerns of potential instability and karyotype imbalance. We used a variation of a previously developed, robust CRISPR-Cas9 method to fuse chromosome I to other chromosome arms of varying length: chrIXR (84kb), chrIIIR (202kb) and chrIVR (1Mb). All fusion chromosome strains grew like wild-type so we decided to attach synI to synIII. Through the investigation of three-dimensional structures of fusion chromosome strains, unexpected loops and twisted structures were formed in chrIII-I and chrIX-III-I fusion chromosomes, which depend on silencing protein Sir3. These results suggest a previously unappreciated 3D interaction betweenHMRand the adjacent telomere. We used these fusion chromosomes to show that axial element Red1 binding in meiosis is not strictly chromosome size dependent even though Red1 binding is enriched on the three smallest chromosomes in wild-type yeast, and we discovered an unexpected role for centromeres in Red1 binding patterns.
Comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide-based inhibitor design
Authors: Musyoka Thommas M. , Njuguna Joyce N. , Bishop Özlem Tastan 
Published: August 2018

AbstractFalcipains are major cysteine proteases ofPlasmodium falciparumessential in hemoglobin digestion. Several inhibitors blocking their activity have been identified, yet none of them has been approved for malaria treatment. For selective therapeutic targeting of these plasmodial proteases, identification of sequence and structure differences with homologous human cathepsins is necessary. The protein substrate processing activity of these proteases is tightly controlled in space and time via a prodomain segment occluding the active site making it inaccessible. Here, we utilisedin silicoapproaches to determine sequence and structure variations between the prodomain regions of plasmodial proteins and human cathepsins. Hot spot residues, key for maintaining structural integrity of the prodomains as well as conferring their inhibitory activity, were identified via residue interaction analysis. Information gathered was used to design short peptides able to mimic the prodomain activity on plasmodial proteases whilst showing selectivity on human cathepsins. Inhibitory potency was highly dependent on peptide amino acid composition and length. Our current results show that despite the conserved structural and catalytic mechanism of human cathepsins and plasmodial proteases, significant differences between the two groups exist and may be valuable in the development of novel antimalarial peptide inhibitors.
Functional Genomics Screen with Pooled shRNA Library and Gene Expression Profiling with Extracts of Azadirachta indica Identify Potential Pathways for Therapeutic Targets in Head and Neck Squamous Cell Carcinoma
Authors: Krishnan Neeraja M , Katoh Hiroto , Palve Vinayak , Pareek Manisha , Sato Reiko , Ishikawa Shumpei , Panda Binay 
Published: August 2018

AbstractTumor suppression by the extracts of Azadirachta indica (neem) works via anti-proliferation, cell cycle arrest, and apoptosis, demonstrated previously using cancer cell lines and live animal models. However, very little is known about the molecular targets and pathways that the neem extracts and the associated compounds act through. Here, we address this using a genome-wide functional pooled shRNA screen on head and neck squamous cell carcinoma cell line treated with crude neem leaf extracts, known for their anti-tumorigenic activity. By analyzing differences in global clonal sizes of the shRNA-infected cells cultured under no treatment and treatment with neem leaf extract conditions, assayed using next-generation sequencing, we found 225 genes affected the cancer cell growth in the shRNA-infected cells treated with neem extract. Pathway enrichment analyses of whole-genome gene expression data from cells temporally treated with neem extract revealed important roles played by the TGF-β pathway and HSF-1-related gene network. Our results indicate that neem extract simultaneously affects various important molecular signaling pathways in head and neck cancer cells, some of which may be therapeutic targets for this devastating tumor.
Rho-mediated gene transcription promotes BRAF inhibitor resistance in de-differentiated melanoma cells
Authors: Misek SA , Appleton KM , Dexheimer TS , Lisabeth EM , Lo RS , Larsen SD , Gallo KA , Neubig RR 
Published: August 2018

AbstractOver half of cutaneous melanoma tumors have BRAFV600E/Kmutations. Acquired resistance to BRAF inhibitors (BRAFi) remains a major hurdle in attaining durable therapeutic responses. In this study we demonstrate that approximately 50-60% of melanoma cell lines with vemurafenib resistance acquiredin vitroshow activation of RhoA family GTPases. In BRAFi-resistant melanoma cell lines and tumors, activation of RhoA is correlated with decreased expression of melanocyte lineage genes. Using a machine learning approach, we built gene expression-based models to predict drug sensitivity for 265 common anti-cancer compounds. We then projected these signatures onto the collection of TCGA cutaneous melanoma and found that poorly differentiated tumors were predicted to have increased sensitivity to multiple Rho kinase (ROCK) inhibitors. Two transcriptional effectors downstream of Rho, MRTF and YAP1, are activated in the RhoHighBRAFi-resistant cell lines, and resistant cells are more sensitive to inhibition of these transcriptional mechanisms. Taken together, these results support the concept of targeting Rho-regulated gene transcription pathways as a promising therapy approach to restore sensitivity to BRAFi-resistant tumors or as a combination therapy to prevent the onset of drug resistance.
Mechanism of replication-coupled DNA-protein crosslink proteolysis by SPRTN and the proteasome
Authors: Gao Alan , Larsen Nicolai B. , Sparks Justin L. , Gallina Irene , Mann Matthias , Räschle Markus , Walter Johannes C. , Duxin Julien P. 
Published: August 2018

SummaryDNA-protein crosslinks (DPCs) are bulky DNA lesions that interfere with DNA metabolism and therefore threaten genomic integrity. Recent studies implicate the metalloprotease SPRTN in S-phase removal of DPCs, but how SPRTN activity is coupled to DNA replication is unknown. Using Xenopus egg extracts that recapitulate replication-coupled DPC proteolysis, we show that DPCs can be degraded by SPRTN or the proteasome, which act as independent DPC proteases. Proteasome recruitment requires DPC polyubiquitylation, which is triggered by single-stranded DNA, a byproduct of DNA replication. In contrast, SPRTN-mediated DPC degradation is independent of DPC polyubiquitylation but requires polymerase extension of a nascent strand to the lesion. Thus, SPRTN and proteasome activities are coupled to DNA replication by distinct mechanisms and together promote replication across immovable protein barriers.HighlightsThe proteasome, in addition to SPRTN, degrades DPCs during DNA replicationProteasome-dependent DPC degradation requires DPC ubiquitylationDPC ubiquitylation is triggered by ssDNA and does not require the replisomeSPRTN-dependent DPC degradation is a post-replicative process
Increased influence of periphery on central visual processing in humans during walking
Authors: Cao Liyu , Händel Barbara 
Published: August 2018

AbstractCognitive processes are almost exclusively investigated under highly controlled settings while voluntary body movements are suppressed. However, recent animal work suggests differences in sensory processing between movement states by showing drastically changed neural responses in early visual areas between locomotion and stillness. Does locomotion also modulate visual cortical activity in humans and what are its perceptual consequences? Here, we present converging neurophysiological and behavioural evidence that walking leads to an increased influence of peripheral stimuli on central visual input. This modulation of visual processing due to walking is encompassed by a change in alpha oscillations, which is suggestive of an attentional shift to the periphery during walking. Overall, our study shows that strategies of sensory information processing can differ between movement states. This finding further demonstrates that a comprehensive understanding of human perception and cognition critically depends on the consideration of natural behaviour.
Carbon monoxide, a retrograde messenger generated in post-synaptic mushroom body neurons evokes non-canonical dopamine release
Authors: Ueno Kohei , Morstein Johannes , Ofusa Kyoko , Naganos Shintaro , Suzuki-Sawano Ema , Minegishi Saika , Rezgui Samir P. , Kitagishi Hiroaki , Michel Brian W. , Chang Christopher J. , Horiuchi Junjiro , Saitoe Minoru 
Published: August 2018

ABSTRACTDopaminergic neurons innervate extensive areas of the brain and release dopamine (DA) onto a wide range of target neurons. However, DA release is also precisely regulated, and inDrosophila,DA is released specifically onto mushroom body (MB) neurons, which have been coincidentally activated by cholinergic and glutamatergic inputs. The mechanism for this precise release has been unclear. Here we found that coincidentally activated MB neurons generate carbon monoxide (CO) which functions as a retrograde signal evoking local DA release from presynaptic terminals. CO production depends on activity of heme oxygenase in post-synaptic MB neurons, and CO-evoked DA release requires Ca2+efflux through ryanodine receptors in DA terminals. CO is only produced in MB areas receiving coincident activation, and removal of CO using scavengers blocks DA release. We propose that DA neurons utilize two distinct modes of transmission to produce global and local DA signaling.SIGNIFICANCE STATEMENTDopamine (DA) is needed for various higher brain functions including memory formation. However, DA neurons form extensive synaptic connections, while memory formation requires highly specific and localized DA release. Here we identify a mechanism through which DA release from presynaptic terminals is controlled by postsynaptic activity. Postsynaptic neurons activated by cholinergic and glutamatergic inputs generate carbon monoxide, which acts as a retrograde messenger inducing presynaptic DA release. Released DA is required for memory-associated plasticity. Our work identifies a novel mechanism that restricts DA release to the specific postsynaptic sites that require DA during memory formation.
A Novel Scavenging Tool for Cancer Biomarker Discovery based on the Blood-Circulating Nanoparticle Protein Corona
Authors: Hadjidemetriou Marilena , Al-ahmady Zahraa , Buggio Maurizio , Swift Joe , Kostarelos Kostas 
Published: August 2018

AbstractThe prominent discrepancy between the significant investment towards plasma biomarker discovery and the very low number of biomarkers currently in clinical use stresses the need for novel discovery technologies. The discovery of protein biomarkers present in human blood by proteomics is tremendously challenging, owing to the large dynamic concentration range of blood proteins. Here, we describe the use of blood-circulating lipid-based nanoparticles (NPs) as a scavenging tool to comprehensively analyse the blood circulation proteome. We aimed to exploit the spontaneous interaction of NPs with plasma proteins once injected in the bloodstream, known as ‘protein corona’ and to facilitate the discovery of previously unreported biomarker molecules for cancer diagnostics. We employed two different tumor models, a subcutaneous melanoma model (B16-F10) and human lung carcinoma xenograft model (A549) and comprehensively compared by mass spectrometry the in vivo protein coronas formed onto clinically used liposomes, intravenously administered in healthy and tumor-bearing mice. The results obtained demonstrated the ability of blood-circulating liposomes to surface-capture and amplify low molecular weight (MW) and low abundant tumor specific proteins (intracellular products of tissue leakage) that could not be detected by plasma analysis, performed in comparison. Most strikingly, the NP (liposomal) corona formed in the xenograft model was found to consist of murine host response proteins, as well as human proteins released from the inoculated and growing human cancer cells. This study offers direct evidence that the in vivo NP protein corona could be deemed as a valuable tool of the blood proteome in experimental disease models to allow the discovery of potential biomarkers.ToC Graphic
Tuberculosis in the military: Trends in notification and treatment outcomes within the Zimbabwe Defence Forces, Dependants and Communities 2010-2015
Authors: Muringazuva Caroline , Owiti Philip , Edwards Jeffrey , Mutetse Godfrey N , Dobbie Munyaradzi , Chimedza Jasper 
Published: August 2018

AbstractBackgroundHistorically, tuberculosis (TB) has been responsible for significant disease burden among the military both during peace and conflict. A routine review of Zimbabwe Defence Force (ZDF) data showed 36% of reported deaths could be attributed to TB. We conducted a study to determine the TB trends and outcomes among patients managed in ZDF health facilities between 2010-2015.MethodsRetrospective cohort study of TB patients (military and dependents). Data were extracted from ZDF TB registers and analyzed for trends in notification and outcomes. Independent factors associated with unfavourable TB treatment outcomes were modeled using multivariable regression.ResultsOf the total 1298 TB patients, 84% were males, median age 37 years and 92% from Army facilities. Ninety three percentage had pulmonary TB, 87% were new patients and 68% HIV co-infected (97% on antiretroviral therapy[ART]). Number of TB cases reduced two-fold between 2010-2015 (317 vs 115). Treatment outcomes remained relatively stable with overall treatment success of 81%, 9.9% deaths, 0.2% loss to follow up, 2.2% treatment failure, 6.6% not evaluated. Clients who were HIV-positive and not on ART were 3.81 times likely to have unfavourable outcome.ConclusionThis is the first study of TB in an African defence force showed decreasing trends in notified TB cases. Though treatment success was comparable over time, it still fell below international targets. Being HIV-positive (even with ART) was associated with increased unfavourable outcomes. Continued monitoring, evaluation and increased support of the TB programme within this high risk population is recommended.
Non-invasive spinal electro-magnetic stimulation (SEMS): a tool for evaluation and modulation of lower limb spinal-muscular transmission in healthy adults
Authors: Arvanian Victor L. , Petrosyan Hayk , Zou Chuancai , Leone Cynthia , Zaidi Mohammad , Hou Wei , Tesfa Asrat , Fahmy Magda , Kaufman Mark , Sisto Sue A. 
Published: August 2018

AbstractObjectiveOur earlier electrophysiological recordings using animal models revealed diminished transmission through spared fibers to motoneurons and leg muscles after incomplete spinal cord injury (SCI). Administration of spinal electro-magnetic stimulation (SEMS) at specific parameters induced transient improvement of transmission at neuro-muscular circuitry in SCI animals. In the current human study, we sought translate this knowledge to establish optimal parameters of SEMS for (i) neurophysiological evaluation via Compound Motor Action Potential (CMAP); and (ii) modulation at neuro-muscular circuitry via H-reflex and M-wave response in 12 healthy adults.MethodsSEMS application was with a coil positioned over T12-S1 spinal levels. SEMS-evoked CMAP-responses were wirelessly measured simultaneously from biceps femoris (BF), semitendinosus (ST), vastus lateralis (VL), soleus (SOL), medial gastrocnemius (MG) and lateral gastrocnemius (LG) muscles. We also examined effects of SEMS trains on H-reflex and M-wave responses. H-reflexes and M-waves were measured simultaneously from SOL, MG and LG muscles and evoked by peripheral electrical stimulation of tibial nerves before and after each SEMS session.ResultsSpinal levels for SEMS application to evoke CMAP-responses in corresponding muscles and amplitude/latency of these responses have been established. SEMS applied over L4-S1 spinal levels at 0.2 Hz rate for 30 min induced facilitation of H-reflexes and M-responses. Facilitation lasted for at least 1 hour after stopping SEMS and was associated with a decrease in threshold intensity and leftward shift of recruitment curve for H-reflex and M-wave. SEMS did not alter TMS-evoked responses in hand muscles.ConclusionSEMS is a novel, non-invasive approach for sustained neuromodulation of H-reflex and M-wave responses in triceps surae muscle group. The parameters of SEMS application established in this study for evaluation and neuromodulation of neural pathways innervating leg muscles in healthy individuals may be used as a reference for neurophysiological evaluation and long-lasting plasticity of the lower limb spino-neuromuscular circuitry in individuals with SCI.
Nanopore-based DNA sequencing in clinical microbiology: preliminary assessment of basic requirements
Authors: Harstad Håvard , Ahmad Rafi , Bredberg Anders 
Published: August 2018

AbstractAimIdentify basic requirements for a metagenomic nanopore sequencing protocol permitting frequent application in a clinical microbiology daily routine diagnostic setting.BackgroundNanopore sequencing with the Oxford Nanopore Technologies MinION device has a potential to markedly improve clinical diagnosis of infections. Reports have emerged recently that it may provide direct-from-clinical-sample information; for example, with urine samples, bronchial tuberculosis samples and orthopedic prostheses. However, the ideal protocol for clinical use remains to be determined, especially relating to detection of relevant pathogen quantities and to finding a reasonable level of economic costs.ResultsMinION can provide qualitatively and quantitatively correct identification of multiple species in metagenomics samples. For detection of clinically relevant quantities of bacteria (on a nanogram DNA level) there is a need for carrier DNA. Importantly, high-purity DNA and a naïve MinION flow cell seem to be critical parameters.ConclusionsOur results suggest that high-purity clinical sample DNA, addition of carrier DNA and a naïve flow cell are critical factors for clinical use of MinION. A relatively high error rate may limit detection of antimicrobial resistance genes, and a realistic level of costs will require availability of a price-reduced and single-use flowcell.