bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes of Three- Versus Six-Monthly Dispensing of Antiretroviral Treatment (ART) for Stable HIV Patients in Community ART Refill Groups: A Cluster-Randomized Trial in Zimbabwe
Authors: Fatti Geoffrey , Ngorima-Mabhena Nicoletta , Mothibi Eula , Muzenda Trish , Choto Regis , Kasu Tonderai , Tafuma Taurayi A. , Mahachi Nyika , Takarinda Kudakwashe C. , Apollo Tsitsi , Mugurungi Owen , Chasela Charles , Hoffman Risa M. , Grimwood Ashraf 
Published: February 2020

Introduction:
Multimonth dispensing (MMD) of antiretroviral treatment (ART) aims to reduce patient-related barriers to access long-term treatment and improve health system efficiency. However, randomized evidence of its clinical effectiveness is lacking. We compared MMD within community ART refill groups (CARGs) vs. standard-of-care facility-based ART delivery in Zimbabwe.

Methods:
A three-arm, cluster-randomized, pragmatic noninferiority trial was performed. Thirty health care facilities and associated CARGs were allocated to either ART collected three-monthly at facility (3MF, control); ART delivered three-monthly in CARGs (3MC); or ART delivered six-monthly in CARGs (6MC). Stable adults receiving ART ≥six months with baseline viral load (VL) <1000 copies/ml were eligible. Retention in ART care (primary outcome) and viral suppression (VS) 12 months after enrollment were compared, using regression models specified for clustering (ClinicalTrials.gov: NCT03238846).

Results:
4800 participants were recruited, 1919, 1335, and 1546 in arms 3MF, 3MC, and 6MC, respectively. For retention, the prespecified noninferiority limit (-3.25%, risk difference [RD]) was met for comparisons between all arms, 3MC (94.8%) vs. 3MF (93.0%), adjusted RD = 1.1% (95% CI: -0.5% to 2.8%); 6MC (95.5%) vs. 3MF: aRD = 1.2% (95% CI: -1.0% to 3.6%); and 6MC vs. 3MC: aRD = 0.1% (95% CI: -2.4% to 2.6%). VL completion at 12 months was 49%, 45%, and 8% in 3MF, 3MC, and 6MC, respectively. VS in 3MC (99.7%) was high and not different to 3MF (99.1%), relative risk = 1.0 (95% CI: 1.0-1.0). VS was marginally reduced in 6MC (92.9%) vs. 3MF, relative risk = 0.9 (95% CI: 0.9-1.0).

Conclusion:
Retention in CARGs receiving three- and six-monthly MMD was noninferior versus standard-of-care facility-based ART delivery. VS in 3MC was high. VS in six-monthly CARGs requires further evaluation.
Simultaneous Restoration of Swallowing and Voice Function With Ileocolon Free Flap
Authors: Lo Torto Federico , Ribuffo Diego , Manrique Oscar J. , Ciudad Pedro , Mouchammed Agko , Maruccia Michele , Nicoli Fabio , Turriziani Gianmarco , Chen Hung-Chi 
Published: February 2020

Background:
Free ileocolon flap is a reliable technique allowing simultaneous restoration of swallowing and speech. The aim is to report our 6-year experience in a single center.

Methods:
Thirty-seven patients treated between 2010 and 2015 were included in the study. Swallowing and speech function were evaluated in 27 patients with a 7-point and 5-point Likert scale, respectively. Moreover, 12 of them consented to voice spectrum analysis (VSA).

Results:
Complications noted were: aspiration (3), esophagocutaneous fistula (2), and stricture (1). Seven patients experienced self-limited diarrhea. Regarding swallowing function, 77.8% scored ≥5 on Likert scale whereas speech Likert scale showed excellent results (score >12) in 74%. VSA demonstrated mean phonation time of 10.75 seconds, mean frequency of 131 Hz and mean dynamic range of 56 dB.

Conclusion:
In experienced hands, the ileocolon flap is safe and effective, particularly in patients with long-life expectancy, providing good swallowing and speech function without further procedures/prostheses.
Sleep Deprivation alters the influence of biological sex on active-phase sleep behavior
Authors: Nichols India , Vincent Scott , Hesse September , Ehlen J. Christopher , Brager Allison , Paul Ketema 
Published: February 2020

AbstractPoor sleep is a hazard of daily life that oftentimes cannot be avoided. Gender differences in daily sleep and wake patterns are widely reported; however, it remains unclear how biological sex, which is comprised of genetic and endocrine components, directly influences sleep regulatory processes. In the majority of model systems studied thus far, sex differences in daily sleep amount are predominant during the active (wake) phase of the sleep-wake cycle. The pervasiveness of sex differences in sleep amount throughout phylogeny suggests a strong underlying genetic component. The goal of the current study is to determine if sex differences in active-phase sleep amount are dependent on sex chromosomes in mice.Sleep was examined in the four-core genotype (FCG) mouse model, whose sex chromosome complement (XY, XX) is independent of sex phenotype (male or female). In this line, sex phenotype is determined by the presence or absence of theSrygene, which is dissociated from the Y chromosome. Polysomnographic sleep recordings were obtained from gonadectomized (GDX) FCG mice to examine spontaneous sleep states and the ability to recover from sleep loss. We report that during the active-phase, the presence of theSrygene accounts for most sex differences during spontaneous sleep; however, during recovery from sleep loss, sex differences in sleep amount are partially driven by sex chromosome complement. These results suggest that genetic factors on the sex chromosomes encode the homeostatic response to sleep loss.
Imaging cell lineage with a synthetic digital recording system
Authors: Chow Ke-Huan K. , Budde Mark W. , Granados Alejandro A. , Cabrera Maria , Yoon Shinae , Cho Soomin , Huang Ting-hao , Koulena Noushin , Frieda Kirsten L. , Cai Long , Lois Carlos , Elowitz Michael B. 
Published: February 2020

AbstractMulticellular development depends on the differentiation of cells into specific fates with precise spatial organization. Lineage history plays a pivotal role in cell fate decisions, but is inaccessible in most contexts. Engineering cells to actively record lineage information in a format readablein situwould provide a spatially resolved view of lineage in diverse developmental processes. Here, we introduce a serine integrase-based recording system that allowsin situreadout, and demonstrate its ability to reconstruct lineage relationships in cultured stem cells and flies. The system, termed intMEMOIR, employs an array of independent three-state genetic memory elements that can recombine stochastically and irreversibly, allowing up to 59,049 distinct digital states. intMEMOIR accurately reconstructed lineage trees in stem cells and enabled simultaneous analysis of single cell clonal history, spatial position, and gene expression inDrosophilabrain sections. These results establish a foundation for microscopy-readable clonal analysis and recording in diverse systems.One sentence summaryA new genetic editing system termed intMEMOIR reveals the lineage histories of individual cells directly within their native tissue context.
Machine Learning Based Refined Differential Gene Expression Analysis of Pediatric Sepsis
Authors: Abbas Mostafa , EL-Manzalawy Yasser 
Published: February 2020

AbstractBackgroundDifferential expression (DE) analysis of transcriptomic data enables genome-wide analysis of gene expression changes associated with biological conditions of interest. Such analysis often provide a wide list of genes that are differentially expressed between two or more groups. In general, identified differentially expressed genes (DEGs) can be subject to further downstream analysis for obtaining more biological insights such as determining enriched functional pathways or gene ontologies. Furthermore, DEGs are treated as candidate biomarkers and a small set of DEGs might be identified as biomarkers using either biological knowledge or data-driven approaches.MethodsIn this work, we present a novel approach for identifying biomarkers from a list of DEGs by re-ranking them according to the Minimum Redundancy Maximum Relevance (MRMR) criteria using repeated cross-validation feature selection procedure.ResultsUsing gene expression profiles for 199 children with sepsis and septic shock, we identify 108 DEGs and propose a 10-gene signature for reliably predicting pediatric sepsis mortality with an estimated Area Under ROC (AUC) score of 0.89.ConclusionsMachine learning based refinement of DE analysis is a promising tool for prioritizing DEGs and discovering biomarkers from gene expression profiles. Moreover, our reported 10-gene signature for pediatric sepsis mortality may facilitate the development of reliable diagnosis and prognosis biomarkers for sepsis.
Ketogenic Diet Prevents Heart Failure from Defective Mitochondrial Pyruvate Metabolism
Authors: McCommis Kyle S. , Kovacs Attila , Weinheimer Carla J. , Shew Trevor M. , Koves Timothy R. , Ilkayeva Olga R. , Kamm Dakota R. , Pyles Kelly D. , King M. Todd , Veech Richard L. , DeBosch Brian J. , Muoio Deborah M. , Gross Richard W. , Finck Brian N. 
Published: February 2020

ABSTRACTThe myocardium is metabolically flexible and can use fatty acids, glucose, lactate/pyruvate, ketones, or amino acids to fuel mechanical work. However, impaired metabolic flexibility is associated with cardiac dysfunction in conditions including diabetes and heart failure. The mitochondrial pyruvate carrier (MPC) is required for pyruvate metabolism and is composed of a hetero-oligomer of two proteins known as MPC1 and MPC2. Interestingly, MPC1 and MPC2 expression is downregulated in failing human hearts and in a mouse model of heart failure. Mice with cardiac-specific deletion of MPC2 (CS-MPC2-/-) exhibited loss of both MPC2 and MPC1 proteins and reduced pyruvate-stimulated mitochondrial respiration. CS-MPC2-/- mice exhibited normal cardiac size and function at 6-weeks old, but progressively developed cardiac dilation and contractile dysfunction thereafter. Feeding CS-MPC2-/- mice a ketogenic diet (KD) completely prevented or reversed the cardiac remodeling and dysfunction. Other diets with higher fat content and enough carbohydrate to limit ketosis also improved heart failure in CS-MPC2-/- mice, but direct ketone body provisioning provided only minor improvements in cardiac remodeling. Finally, KD was also able to prevent further remodeling in an ischemic, pressure-overload mouse model of heart failure. In conclusion, loss of mitochondrial pyruvate utilization leads to dilated cardiomyopathy that can be corrected by a ketogenic diet.
Transcriptional control of parallel-acting pathways that remove discrete presynaptic proteins in remodeling neurons
Authors: Miller-Fleming Tyne W. , Cuentas-Condori Andrea , Manning Laura , Palumbos Sierra , Richmond Janet E. , Miller David M. 
Published: February 2020

ABSTRACTSynapses are actively dismantled to mediate circuit refinement, but the developmental pathways that regulate synaptic disassembly are largely unknown. We have previously shown that the epithelial sodium channel UNC-8 triggers an activity-dependent mechanism that drives the removal of presynaptic proteins liprin-α/SYD-2, Synaptobrevin/SNB-1, RAB-3 and Endophilin/UNC-57 in remodeling GABAergic neurons inC. elegans(Miller-Fleming et al., 2016). Here, we report that the transcription factor Iroquois/IRX-1 regulates UNC-8 expression as well as an additional pathway, independent of UNC-8, that functions in parallel to dismantle functional presynaptic terminals. We show that the additional IRX-1-regulated pathway is selectively required for the removal of the presynaptic proteins, Munc13/UNC-13 and ELKS, which normally mediate synaptic vesicle fusion and neurotransmitter release. Our findings are notable because they highlight the key role of transcriptional regulation in synapse elimination and reveal parallel-acting pathways that orchestrate synaptic disassembly by removing specific active zone proteins.
Clinical and genomic epidemiology of carbapenem-non-susceptibleCitrobacterspp. at a tertiary healthcare center over two decades
Authors: Babiker Ahmed , Evans Daniel R. , Griffith Marissa P. , McElheny Christi L. , Hassan Mohamed , Clarke Lloyd G. , Mettus Roberta T. , Harrison Lee H. , Doi Yohei , Shields Ryan K. , Van Tyne Daria 
Published: February 2020

AbstractCarbapenem-non-susceptibleCitrobacterspp. (CNSC) are increasingly recognized as healthcare-associated pathogens. Information regarding their clinical epidemiology, genetic diversity, and mechanisms of carbapenem resistance is lacking. We examined microbiology records of adult patients at the University of Pittsburgh Medical Center (UMPC) Presbyterian Hospital (PUH) from 2000-2018 for CNSC, as defined by ertapenem non-susceptibility. Over this timeframe, the proportion of CNSC increased from 4% to 10% (P=0.03), as did carbapenem daily defined doses/1000 patient days (6.52 to 34.5, R2=0.831,P<0.001), which correlated with the observed increase in CNSC (lag=0 years, R2=0.660). Twenty CNSC isolates from 19 patients at PUH and other UPMC hospitals were available for further analysis, including whole-genome short-read sequencing and additional antimicrobial susceptibility testing. Of the 19 patients, nearly all acquired CNSC in the healthcare setting and over half had polymicrobial cultures containing at least one other organism. Among the 20 CNSC isolates,C. freundiiwas the predominant species identified (60%). CNSC genomes were compared with genomes of carbapenem-susceptibleCitrobacterspp. from UPMC, and with other publicly available CNSC genomes. Isolates encoding carbapenemases (blaKPC-2,blaKPC-3, andblaNDM-1) were also long-read sequenced, and their carbapenemase-encoding plasmid sequences were compared with one another and with publicly available sequences. Phylogenetic analysis of 102 UPMCCitrobacterspp. genomes showed that CNSC from our setting did not cluster together. Similarly, a global phylogeny of 64 CNSC genomes showed a diverse population structure. Our findings suggest that both local and global CNSC populations are genetically diverse, and that CNSC harbor carbapenemase-encoding plasmids found in otherEnterobacterales.
“Polar mutagenesis of bacterial transcriptional units using Cas12a”
Authors: Graffeuil Antoine , Uhlin Bernt Eric , Cisneros David A. 
Published: February 2020

AbstractBacterial genes are often organized in functionally related transcriptional units or operons. One such example is thefimAICDFGHoperon, which codes for type I fimbriae inEscherichia coli. We tested the hypothesis that markerless polar mutations could be efficiently engineered using CRISPR/Cas12a in thefimoperon. Cas12a-mediated engineering of a terminator sequence inside thefimAgene occurred with efficiencies between 10 and 30%, whilst other types of mutations, such as a 97 bp deletion, occurred with 100% efficiency. Our results showed that some of the obtained mutants, including one with a single base substitution at thefimlocus, had decreased mRNA levels offimA, suggesting that the regulation of thefimoperon was disrupted. We corroborated the polar effect of these mutants by phenotypic assays and quantitative PCR, showing up to a 43 fold decrease in expression of genes downstreamfimA. We believe this strategy could be useful in engineering the transcriptional shut-down of multiple genes in one single step. For bio-production inE. coli, this opens the possibility of inhibiting competing metabolic routes.
A CURE for physiological characterization of bacterioplankton in liquid culture
Authors: Lanclos V. Celeste , Coelho Jordan T. , Hyer Alex J. , Brooks Mindy M. , Savoie Emily R. , Kosiba Scott , Thrash J. Cameron 
Published: February 2020

ABSTRACTBacterial characterization is an important aspect of microbiology that includes experimentally determining growth rates, environmental conditions conducive to growth, and the types of energy sources microorganisms can use. Researchers use this information to help understand and predict an organism’s ecological distribution and environmental functions. Microbiology students generally conduct bacterial characterization experiments in their coursework; however they are frequently restricted to model organisms without ecological relevance and for which the results have been known for decades. We present a course-based undergraduate research experience (CURE) curriculum to involve students in characterization of previously untested, ecologically relevant bacterioplankton cultures to identify the carbon substrates used for growth, as well as the temperature and salinity ranges conducive to growth. Students use these results to connect their organism’s physiology to the isolation environment. This curriculum also exposes students to advanced microbiology methods such as flow cytometry for measuring cell concentrations, teaches them to use the programming language R for data plotting, and emphasizes scientific communication through writing, speaking, poster creation/presentation, and social media. This CURE is an attractive introduction to scientific research and was successfully tested with 147 students during the fall semester of 2018.
AmpliCI: A High-resolution Model-Based Approach for Denoising Illumina Amplicon Data
Authors: Peng Xiyu , Dorman Karin 
Published: February 2020

AbstractMotivationNext-generation amplicon sequencing is a powerful tool for investigating microbial communities. One main challenge is to distinguish true biological variants from errors caused by PCR and sequencing. In the traditional analysis pipeline, such errors are eliminated by clustering reads within a sequence similarity threshold, usually 97%, and constructing operational taxonomic units, but the arbitrary threshold leads to low resolution and high false positive rates. Recently developed “denoising” methods have proven able to resolve single-nucleotide amplicon variants, but they still miss low frequency sequences, especially those near abundant variants, because they ignore the sequencing quality information.ResultsWe introduce AmpliCI, a reference-free, model-based method for rapidly resolving the number, abundance and identity of error-free sequences in massive Illumina amplicon datasets. AmpliCI takes into account quality information and allows the data, not an arbitrary threshold or an external database, to drive conclusions. AmpliCI estimates a finite mixture model, using a greedy strategy to gradually select error-free sequences and approximately maximize the likelihood. We show that AmpliCI is superior to three popular denoising methods, with acceptable computation time and memory usage.AvailabilitySource code available athttps://github.com/DormanLab/AmpliCI
Cryo-EM structures of HKU2 and SADS-CoV spike glycoproteins and insights into coronavirus evolution
Authors: Yu Jinfang , Qiao Shuyuan , Guo Runyu , Wang Xinquan 
Published: February 2020

AbstractA new porcine coronavirus SADS-CoV was recently identified from suckling piglets with severe diarrhea in southern China and its genome sequence is most identical (~95% identity) to that of bat α-coronavirus HKU2. It again indicates bats are the natural reservoir of many coronaviruses that have great potential for cross-species transmission to animals and humans by recombination and/or mutation. Here we report the cryo-EM structures of HKU2 and SADS-CoV spike glycoprotein trimers at 2.38 Å and 2.83 Å resolution, respectively. HKU2 and SADS-CoV spikes exhibit very high structural similarity, with subtle differences mainly distributed in the NTD and CTD of the S1 subunit responsible for cell attachment and receptor binding. We systematically analyzed and compared the NTD, CTD, SD1 and SD2 domains of the S1 subunit and the S2 subunit of HKU2 spike with those of α-, β-, γ-, and δ-coronavirus spikes. The results show that the NTD and CTD of HKU2/SADS-CoV are probably the most ancestral in the evolution of spike. Although the S2 subunit mediating membrane fusion is highly conserved, the connecting region after fusion peptide in HKU2/SADS-CoV S2 subunit also adopts a conformation distinct from other coronaviruses. These results structurally demonstrate a close evolutionary relationship between HKU2 /SADS-CoV and β-coronavirus spikes and provide new insights into the evolution and cross-species transmission of coronaviruses.
Prebiotically-relevant low polyion multivalency can improve functionality of membraneless compartments
Authors: Cakmak Fatma Pir , Choi Saehyun , Meyer McCauley O. , Bevilacqua Philip C. , Keating Christine D. 
Published: February 2020

AbstractMultivalent polyions can undergo complex coacervation, producing membraneless compartments that accumulate ribozymes and enhance catalysis, and offering a mechanism for functional prebiotic compartmentalization in the origins of life. Here, we evaluated the impact of low, prebiotically-relevant polyion multivalency in coacervate performance as functional compartments. As model polyions, we used positively and negatively charged homopeptides with one to 100 residues, and adenosine mono-, di-, and triphosphate nucleotides. Polycation/polyanion pairs were tested for coacervation, and resulting membraneless compartments were analyzed for salt resistance, ability to provide a distinct internal microenvironment (apparent local pH, RNA partitioning), and effect on RNA structure formation. We find that coacervates formed by phase separation of the relatively shorter polyions more effectively generated distinct pH microenvironments, accumulated RNA, and preserved duplexes. Hence, reduced multivalency polyions are not only viable as functional compartments for prebiotic chemistries, but they can offer advantages over higher molecular weight analogues.
Barriers to coexistence limit the poleward range of a globally-distributed plant
Authors: Armitage David W. , Jones Stuart E. 
Published: February 2020

AbstractSpecies’ poleward ranges are thought to be primarily limited by climatic constraints rather than biotic interactions such as competition. However, theory suggests that a species’ tolerance to competition is reduced in harsh environments, such as at the extremes of its climatic niche. This implies that under certain conditions, interspecific competition near species’ range margins can prevent the establishment of populations into otherwise tolerable environments and results in geographic distributions being shaped by the interaction of climate and competition. We test this prediction by challenging an experimentally-parameterized mechanistic competition model to predict the poleward range boundaries of two widely co-occurring and ecologically-similar aquatic duckweed plants. We show that simple, mechanistic ecological niche models which include competition and thermal response terms best predict the northern range limits of our study species, outperforming competition-free mechanistic models and matching the predictive ability of popular statistical niche models fit to occurrence records. Next, using the theoretical framework of modern coexistence theory, we show that relative nonlinearity in competitors’ responses to temperature fluctuations maintains coexistence at the subordinate competitor’s poleward range boundary, highlighting the importance of this underappreciated fluctuation-dependent coexistence mechanism. Our results demonstrate the predictive utility of mechanistic niche models and support a more nuanced, interactive role of climate and species interactions in determining range boundaries, which may help explain the conflicting results from previous tests of classic range limit theory and contribute to a more mechanistic understanding of range dynamics under global change.