bluuebunny/crossref_metadata_2025_split huggingface dataset:
Menopausal hormone therapy and mild cognitive impairment: a randomized, placebo-controlled trial
Authors: Yoon Byung-Koo , Chin Juhee , Kim Jong-Won , Shin Myung-Hee , Ahn Soohyun , Lee Dong-Yun , Seo Sang Won , Na Duk L. 
Published: May 2018

Abstract

Objective:
The aim of the study was to explore the therapeutic potential of menopausal hormone therapy (MHT) in women with mild cognitive impairment (MCI).

Methods:
Thirty-seven postmenopausal women (age range: 57-82 y) with multiple-domain, amnestic subtype MCI were randomly assigned to either placebo (n = 18) or MHT (n = 19) for 24 months (percutaneous estradiol [E2] gel [0.1%, 2 mg/d] and oral micronized progesterone [MP4] [100 mg/d]). All participants received donepezil, and apolipoprotein E genotype was determined. The primary endpoint was general cognitive function: Alzheimer's disease Assessment Scale, cognitive subscale, the Korean version of Mini-Mental State Examination (K-MMSE), and the Korean version of the Montreal Cognitive Assessment (MoCA_K) were performed in-person every 6 months.

Results:
Twenty-one participants (placebo 13, MHT 8) completed the trial (56.8%). Progression rates to dementia were 52.9% (9/17) in the placebo group and 44.4% (8/18) in the MHT group. Within-group analysis showed that all three tests significantly worsened during the trial in the placebo, but not the MHT groups. Analysis adjusted for ε4 allele demonstrated that MHT significantly reduced deterioration of MoCA_K score, a sensitive tool for assessing global cognition in MCI (P = 0.0261). Compared with the control group, both MoCA_K (P = 0.043; mean difference, 3.85; 95% CI, −0.46 to 8.16) and K-MMSE (P = 0.0319; mean difference, 3.26; 95% CI, 0.04-6.48) scores were significantly better at 24 months in the MHT group.

Conclusions:
Long-term MHT using percutaneous E2 gel and oral MP4 might attenuate cognitive decline in postmenopausal women with MCI.
D-amino acid-mediated translation arrest is modulated by the identity of the incoming aminoacyl-tRNA
Authors: Fleisher Rachel C. , Cornish Virginia W. , Gonzalez Ruben L. 
Published: May 2018

AbstractA complete understanding of the determinants that restrict D-amino acid incorporation by the ribosome, which is of interest to both basic biologists as well as the protein engineering community, remains elusive. Previously, we demonstrated that D-amino acids are successfully incorporated into the C-terminus of the nascent polypeptide chain. Ribosomes carrying the resulting peptidyl-D-aminoacyl-tRNA (peptidyl-D-aa-tRNA) donor substrate, however, partition into subpopulations that either undergo translation arrest through inactivation of the ribosomal peptidyl-transferase center (PTC) or remain translationally competent. The proportion of each subpopulation is determined by the identity of the D-amino acid sidechain. Here, we demonstrate that the identity of the aminoacyl-tRNA (aa-tRNA) acceptor substrate that is delivered to ribosomes carrying a peptidyl-D-aa-tRNA donor further modulates this partitioning. Our discovery demonstrates that it is the pairing of the peptidyl-D-aa-tRNA donor and the aa-tRNA acceptor that determines the activity of the PTC. Moreover, we provide evidence that both the amino acid and tRNA components of the aa-tRNA donor contribute synergistically to the extent of arrest. The results of this work deepen our understanding of the mechanism of D-amino acid-mediated translation arrest and how cells avoid this precarious obstacle, reveal similarities to other translation arrest mechanisms involving the PTC, and provide a new route for improving the yields of engineered proteins containing D-amino acids.
Autonomous functionality of an upstream open reading frame in polycistronic mammalian mRNAs
Authors: Kitano Shohei , Pratt Gabriel , Takao Keizo , Aizawa Yasunori 
Published: May 2018

SUMMARYUpstream open reading frames (uORFs) are established as cis-acting elements for eukaryotic translation of annotated ORFs (anORFs) located on the same mRNAs. Here, we identified a mammalian uORF with functions that are independent from anORF translation regulation. Bioinformatics screening using ribosome profiling data of human and mouse brains yielded 308 neurologically vital genes from which anORF and uORFs are polycistronically translated in both species. Among them, Arhgef9 contains a uORF named SPICA, which is highly conserved among vertebrates and stably translated only in specific brain regions of mice. Disruption of SPICA translation by ATG-to-TAG substitutions did not perturb translation or function of its anORF product, collybistin. SPICA-null mice displayed abnormal maternal reproductive performance and enhanced anxiety-like behavior, characteristic of ARHGEF9-associated neurological disorders. This study demonstrates that mammalian uORFs can be independent genetic units, revising the prevailing dogma of the monocistronic gene in mammals, and even eukaryotes.
Alternative activation of macrophages is accompanied by chromatin remodeling and short-term dampening of macrophage secondary response
Authors: Tang Mei San , Miraldi Emily R. , Girgis Natasha M. , Bonneau Richard A. , Loke P’ng 
Published: May 2018

AbstractInterleukin-4 (IL-4) activates macrophages to adopt a distinct phenotype associated with clearance of helminth infections and tissue repair. Here, we describe changes in the accessible chromatin landscape following IL-4 stimulation of terminally differentiated mouse peritoneal macrophages. This chromatin remodeling process occurs in both tissue resident and monocyte-derived macrophages, but the regions gaining accessibility post-stimulation are macrophage-specific. PU.1 motif is similarly associated with tissue resident and monocyte-derived IL-4 induced regions, but has macrophage-specific DNA shape and predicted co-factors. In addition, IL-4 stimulation leads to short-term dampening of macrophage secondary response. However, the degree of dampening differs between macrophages derived from different genetic backgrounds. Together, these results lead us to propose that DNA sequence variations can alter parts of the accessible chromatin landscape and differences in secondary responses due to host genetics can contribute to phenotypic variations in immune responses.
ClusterMap: Comparing analyses across multiple Single Cell RNA-Seq profiles
Authors: Gao Xin , Hu Deqing , Gogol Madelaine , Li Hua 
Published: May 2018

AbstractSingle cell RNA-Seq facilitates the characterization of cell type heterogeneity and developmental processes. Further study of single cell profiles across different conditions enables the understanding of biological processes and underlying mechanisms at the sub-population level. However, developing proper methodology to compare multiple scRNA-Seq datasets remains challenging. We have developed ClusterMap, a systematic method and workflow to facilitate the comparison of scRNA profiles across distinct biological contexts. Using hierarchical clustering of the marker genes of each sub-group, ClusterMap matches the sub-types of cells across different samples and provides “similarity” as a metric to quantify the quality of the match. We introduce a purity tree cut method designed specifically for this matching problem. We use Circos plot and regrouping method to visualize the results concisely. Furthermore, we propose a new metric “separability” to summarize sub-population changes among all sample pairs. In three case studies, we demonstrate that ClusterMap has the ability to offer us further insight into the different molecular mechanisms of cellular sub-populations across different conditions. ClusterMap is implemented in R and available at https://github.com/xgaoo/ClusterMap.
Real-time projections of Ebola outbreak size and duration with and without vaccine use in Équateur, Democratic Republic of Congo, as of May 27, 2018
Authors: Kelly J. Daniel , Worden Lee , Wannier Rae , Hoff Nicole A. , Mukadi Patrick , Sinai Cyrus , Ackley Sarah , Chen Xianyun , Gao Daozhou , Selo Bernice , Mossoko Mathais , Okitolonda-Wemakoy Emile , Richardson Eugene T. , Rutherford George W. , Lietman Thomas M. , Muyembe-Tamfum Jean Jacques , Rimoin Anne W. , Porco Travis C. 
Published: May 2018

AbstractBackgroundAs of May 27, 2018, 54 cases of Ebola virus disease (EVD) were reported in Équateur Province, Democratic Republic of Congo. We used reported case counts and time series from prior outbreaks to estimate the current outbreak size and duration with and without vaccine use.MethodsWe modeled Ebola virus transmission using a stochastic branching process model with a negative binomial distribution, using both estimates of reproduction number R declining from supercritical to subcritical derived from past Ebola outbreaks, as well as a particle filtering method to generate a probabilistic projection of the future course of the outbreak conditioned on its reported trajectory to date; modeled using 0%, 44%, and 62% estimates of vaccination coverage. Additionally, we used the time series for 18 prior Ebola outbreaks from 1976 to 2016 to parameterize a regression model predicting the outbreak size from the number of observed cases from April 4 to May 27.ResultsWith the stochastic transmission model, we projected a median outbreak size of 78 EVD cases (95% credible interval: 52, 125.4), 86 cases (95% credible interval: 53, 174.3), and 91 cases (95% credible interval: 52, 843.5), using 62%, 44%, and 0% estimates of vaccination coverage. With the regression model, we estimated a median size of 85.0 cases (95% prediction interval: 53.5, 216.6).ConclusionsThis outbreak has the potential to be the largest outbreak in DRC since 2007. Vaccines are projected to limit outbreak size and duration but are only part of prevention, control, and care strategies.
General Regulatory Factors control the fidelity of transcription by restricting non-coding and ectopic initiation
Authors: Challal Drice , Barucco Mara , Kubik Slawomir , Feuerbach Frank , Candelli Tito , Geoffroy Hélène , Benaksas Chaima , Shore David , Libri Domenico 
Published: May 2018

ABSTRACTThe fidelity of transcription initiation is essential for accurate gene expression, but the determinants of start site selection are not fully understood. Rap1 and other General Regulatory Factors (GRFs) control the expression of many genes in yeast. We show that depletion of these factors induces widespread ectopic transcription initiation within promoters. This generates many novel non-coding RNAs and transcript isoforms with diverse stability, profoundly altering the coding potential of the transcriptome. Ectopic transcription initiation strongly correlates with altered nucleosome positioning. We show that Rap1 sterically constrains nucleosomes as its mere binding to the DNA can be sufficient for restoration normal nucleosome positioning, transcription initiation and gene expression. These results demonstrate an essential role for GRFs in the fidelity of transcription initiation and in the suppression of pervasive transcription, redefining current models of their function. They have general implications for the mechanism of transcription initiation and the control of gene expression.HIGHLIGHTSRap1, Abf1 and Reb1 control the fidelity of transcription initiation and suppress pervasive transcriptionWidespread ectopic transcription initiation in Rap1-deficient cells induces variegated alterations in gene expressionAltered nucleosome positioning in GRFs-defective cells correlate with ectopic transcription initiation.Rap1 controls nucleosomes positioning and transcription initiation at least partially by a steric hindrance mechanism
Experimentally infection of Cattle with wild types of Peste-des-petits-ruminants Virus – Role in its maintenance and spread
Authors: Couacy-Hymann Emmanuel , Kouadio Valère K. , Koffi Mathurin Y. , Mossoum Arsène , Kouassi Antoinette , Assemian Krou , Godji Privat H. 
Published: May 2018

SummaryPPR is a common and dreadful disease of sheep and goats in tropical regions caused by PPRV which can infect also cattle without any clinical signs but show a seroconversion. However the epidemiological role of cattle in the maintenance and spread of the disease is not known. For the purpose of the present study, cattle were infected with a wild candidate from each of the four lineages of PPRV and placed in separate boxes. Then naive goats were introduced in each specific box for the 30 days duration of the experiment. The results showed that no clinical signs of PPR were recorded from these infected cattle along with the in-contact goats. The nasal and oral swabs remainend negative. However, animals infected with wild types of PPRV from lineages 1, 3, 4 seroconverted with high percentage inhibition (PI %= values. Only two animals out of three with the Nigeria 75/3 strain of lineage 2 (mild strain) did elicit a production of specific anti-PPR antibodies in those cattle but with PI% values around the threshold of the test. Our findings confirm that cattle are dead end hosts for PPRV and do not play an epidemiological role in the maintenance and spread of PPRV. In a PPR surveillance programme, cattle can serve as indicators of PPRV infection.ImportancePeste-ds-ptetis-ruminants (PPR) is a major Transboundary Animal disease (TADs) in the tropical regions which is spreading extensively nowadays to southern and northern of Africa, Turkey in Europ and southwest Asia. PPR virus is very close related to Rinderpest virus (RPV) which has been eradicated from the world. Today FAO, WOAH / OIE and the scientific community have elected PPR to be the second animal disease to be eradicated through The PPR Global Eradication Programme (GEP-PPR). Since PPR infects cattle without any clinical signs but they seroconvert, it is important to explore the role of cattle in the maintenance and spread of PPRV to better understand the epidemiology of the disease which wll help in the the GEP-PPR.
Molecular inactivation of exopolysaccharide biosynthesis inPaenibacillus polymyxaDSM 365 for enhanced 2,3-butanediol production
Authors: Okonkwo Christopher Chukwudi , Ujor Victor , Ezeji Thaddeus Chukwuemeka 
Published: May 2018

AbstractFormation of Exopolysaccharides (EPS) during 2,3-butanediol (2,3-BD) fermentation byPaenibacillus polymyxadecreases 2,3-BD yield, increases medium viscosity and impacts 2,3-BD downstream processing. Therefore, additional purification steps are required to rid the fermentation broth of EPS prior to 2,3-BD purification, which adds to the production cost. To eliminate EPS production during 2,3-BD fermentation, we explored a metabolic engineering strategy to disable the EPS production pathway ofP. polymyxa, thereby increasing 2,3-BD yield and productivity. The levansucrase gene which encodes levansucrase, the enzyme responsible for EPS biosynthesis inP. polymyxa, was successfully disrupted. The resultingP. polymyxalevansucrase null mutant showed 34% and 54% increases in growth with 6.4- and 2.4-folds decrease in EPS formation in sucrose and glucose cultures, respectively. The observed decrease in EPS formation by the levansucrase null mutant may account for the 27% and 4% increase in 2,3-BD yield, and 4% and 128% increases in 2,3-BD productivity when grown on sucrose and glucose media, respectively. Genetic stability of the levansucrase null mutant was further evaluated. Interestingly, the levansucrase null mutant remained genetically stable over fifty generations with no observable decrease in growth and 2,3- BD formation with or without antibiotic supplementations. Collectively, our results show thatP. polymyxalevansucrase null mutant has potential for improving 2,3-BD yield, and ultimately, the economics of large-scale microbial 2,3-BD production.
Investigating the efficacy of triple artemisinin-based combination therapies (TACTs) for treatingPlasmodium falciparummalaria patients using mathematical modelling
Authors: Dini Saber , Zaloumis Sophie , Cao Pengxing , Price Ric N , Fowkes Freya J.I. , McCaw James M , Simpson Julie A 
Published: May 2018

AbstractThe first line treatment for uncomplicated falciparum malaria is artemisinin-based combination therapy (ACT), which consists of an artemisinin derivative co-administered with a longer acting partner drug. However, the spread ofPlasmodium falciparumresistant to both artemisinin and its partner drugs poses a major global threat to malaria control activities. Novel strategies are needed to retard and reverse the spread of these resistant parasites. One such strategy is triple artemisinin-based combination therapy (TACT). We developed a mechanistic within-host mathematical model to investigate the efficacy of a TACT (dihydroartemisinin-piperaquine-mefloquine - DHA-PQ-MQ), for use in South-East Asia, where DHA and PQ resistance are now increasingly prevalent. Comprehensive model simulations were used to explore the degree to which the underlying resistance influences the parasitological outcomes. The effect of MQ dosing on the efficacy of TACT was quantified at varying degrees of DHA and PQ resistance. To incorporate interactions between drugs, a novel model is presented for the combined effect of DHA-PQ-MQ, which illustrates how the interactions can influence treatment efficacy. When combined with a standard regimen of DHA and PQ, the administration of three 8.3 mg/kg doses of MQ was sufficient to achieve parasitological efficacy greater than that currently recommended by WHO guidelines.
Conservation and Divergence in the Asexual Sporulation Gene Regulatory Network Across a Genus of Filamentous Fungi
Authors: Wu Ming-Yueh , Mead Matthew E. , Lee Mi-Kyung , Kim Sun-Chang , Rokas Antonis , Yu Jae-Hyuk 
Published: May 2018

AbstractAsexual sporulation is fundamental to the ecology and lifestyle of filamentous fungi and can facilitate both plant and human infection. InAspergillus, the production of asexual spores is primarily governed by the BrlA→AbaA→WetA regulatory cascade. The final step in this cascade is controlled by the WetA protein and not only governs the morphological differentiation of spores but also the production and deposition of diverse metabolites into spores. While WetA is conserved across the genusAspergillus, the structure and degree of conservation of thewetAgene regulatory network (GRN) remains largely unknown. We carried out comparative transcriptome analyses betweenwetAnull mutant and wild type asexual spores in three representative species spanning the diversity of the genusAspergillus:A. nidulans, A. flavus, andA. fumigatus. We discovered that WetA regulates asexual sporulation in all three species via a negative feedback loop that represses BrlA, the cascade’s first step. Furthermore, ChIP-seq experiments inA. nidulansasexual spores suggest that WetA is a DNA-binding protein that interacts with a novel regulatory motif. Several global regulators known to bridge spore production and the production of secondary metabolites show species-specific regulatory patterns in our data. These results suggest that the BrlA→AbaA→WetA cascade’s regulatory role in cellular and chemical asexual spore development is functionally conserved, but that thewetA-associated GRN has diverged duringAspergillusevolution.
Structure of monomeric full-length ARC sheds light on molecular flexibility, protein interactions, and functional modalities
Authors: Hallin Erik I. , Eriksen Maria S. , Baryshnikov Sergei , Nikolaienko Oleksii , Grødem Sverre , Hosokawa Tomohisa , Hayashi Yasunori , Bramham Clive R. , Kursula Petri 
Published: May 2018

AbstractThe activity-regulated cytoskeleton-associated protein (ARC) is critical for long-term synaptic plasticity and memory formation. Acting as a protein interaction hub, ARC regulates diverse signalling events in postsynaptic neurons. A protein interaction site is present in the ARC C-terminal domain (CTD), a bilobar structure homologous to the retroviral Gag capsid domain. However, knowledge of the 3-dimensional structure of full-length ARC is required to elucidate its molecular function. We purified recombinant monomeric full-length ARC and analyzed its structure using small-angle X-ray scattering and synchrotron radiation circular dichroism spectroscopy. In solution, monomeric ARC has a compact, closed structure, in which the oppositely charged N-terminal domain (NTD) and CTD are juxtaposed, and the flexible linker between them is not extended. The modelled structure of ARC is supported by intramolecular live-cell FRET imaging in rat hippocampal slices. Peptides from several postsynaptic proteins, including stargazin, bind to the N-lobe, but not to the C-lobe, of the bilobar CTD. This interaction does not induce large-scale conformational changes in the CTD or flanking unfolded regions. The ARC NTD contains long helices, predicted to form an anti-parallel coiled coil; binding of ARC to phospholipid membranes requires the NTD. Our data support a role for the ARC NTD in oligomerization as well as lipid membrane binding. These findings have important implications for the structural organization of ARC in distinct functional modalities, such as postsynaptic signal transduction and virus-like capsid formation.
Necroptosis and apoptosis contribute to cisplatin and aminoglycoside ototoxicity
Authors: Ruhl Douglas , Du Ting-Ting , Choi Jeong-Hwan , Li Sihan , Reed Robert , Freeman Michael , Hashisaki George , Lukens John R. , Shin Jung-Bum 
Published: May 2018

AbstractOtotoxic side effects of cisplatin and aminoglycosides have been extensively studied, but no therapy is available to date. Sensory hair cells, upon exposure to cisplatin or aminoglycosides, undergo apoptotic and necrotic cell death. Blocking these cell death pathways has therapeutic potential in theory, but incomplete protection and lack of therapeutic targets in the case of necrosis, has hampered the development of clinically applicable drugs. Over the past decade, a novel form of necrosis, termed necroptosis, was established as an alternative cell death pathway. Necroptosis is distinguished from passive necrotic cell death, in that it follows a cellular program, involving the receptor-interacting protein kinases 1 and 3 (RIPK1 and 3). In this study, we used pharmacological and genetic intervention to test the relative contributions of necroptosis and caspase-8-mediated apoptosis towards cisplatin and aminoglycoside ototoxicity. We find that ex vivo, only apoptosis contributes to cisplatin and aminoglycoside ototoxicity, while in vivo, both necroptosis and apoptosis are involved. Inhibition of necroptosis and apoptosis using pharmacological compounds is thus a viable strategy to ameliorate aminoglycoside and cisplatin ototoxicity.Significance statementThe clinical application of cisplatin and aminoglycosides is limited due to ototoxic side effects. Here, using pharmaceutical and genetic intervention, we present evidence that two types of programmed cell death, apoptosis and necroptosis, contribute to aminoglycoside and cisplatin ototoxicity. Key molecular factors mediating necroptosis are well characterized and druggable, presenting new avenues for pharmaceutical intervention.