bluuebunny/crossref_metadata_2025 huggingface dataset:
Putting on the Garber Style? Better Not
Authors: Howson Colin
Published: June 2017

This article argues that not only are there serious internal difficulties with both Garber’s and later ‘Garber-style’ solutions of the old-evidence problem, including a recent proposal of Hartmann and Fitelson, but Garber-style approaches in general cannot solve the problem. It also follows the earlier lead of Rosenkrantz in pointing out that, despite the appearance to the contrary which inspired Garber’s nonclassical development of the Bayesian theory, there is a straightforward, classically Bayesian, solution.
Recent progress on the Tate conjecture
Authors: Totaro Burt
Published: June 2017

We survey the history of the Tate conjecture on algebraic cycles. The conjecture is closely related with other big problems in arithmetic and algebraic geometry, including the Hodge and Birch–Swinnerton-Dyer conjectures. We conclude by discussing the recent proof of the Tate conjecture for K3 surfaces over finite fields.
SANDPUMA: ensemble predictions of nonribosomal peptide chemistry reveal biosynthetic diversity across Actinobacteria
Authors: Chevrette Marc G , Aicheler Fabian , Kohlbacher Oliver , Currie Cameron R , Medema Marnix H
Published: June 2017

Nonribosomally synthesized peptides (NRPs) are natural products with widespread applications in medicine and biotechnology. Many algorithms have been developed to predict the substrate specificities of nonribosomal peptide synthetase adenylation (A) domains from DNA sequences, which enables prioritization and dereplication, and integration with other data types in discovery efforts. However, insufficient training data and a lack of clarity regarding prediction quality have impeded optimal use. Here, we introduce prediCAT, a new phylogenetics-inspired algorithm, which quantitatively estimates the degree of predictability of each A-domain. We then systematically benchmarked all algorithms on a newly gathered, independent test set of 434 A-domain sequences, showing that active-site-motif-based algorithms outperform whole-domain-based methods. Subsequently, we developed SANDPUMA, a powerful ensemble algorithm, based on newly trained versions of all high-performing algorithms, which significantly outperforms individual methods. Finally, we deployed SANDPUMA in a systematic investigation of 7635 Actinobacteria genomes, suggesting that NRP chemical diversity is much higher than previously estimated. SANDPUMA has been integrated into the widely used antiSMASH biosynthetic gene cluster analysis pipeline and is also available as an open-source, standalone tool.

Availability and implementation

SANDPUMA is freely available at https://bitbucket.org/chevrm/sandpuma and as a docker image at https://hub.docker.com/r/chevrm/sandpuma/ under the GNU Public License 3 (GPL3).

Supplementary information

Supplementary data are available at Bioinformatics online.
BPP: a sequence-based algorithm for branch point prediction
Authors: Zhang Qing , Fan Xiaodan , Wang Yejun , Sun Ming-an , Shao Jianlin , Guo Dianjing
Published: June 2017

Motivation

Although high-throughput sequencing methods have been proposed to identify splicing branch points in the human genome, these methods can only detect a small fraction of the branch points subject to the sequencing depth, experimental cost and the expression level of the mRNA. An accurate computational model for branch point prediction is therefore an ongoing objective in human genome research.

Results

We here propose a novel branch point prediction algorithm that utilizes information on the branch point sequence and the polypyrimidine tract. Using experimentally validated data, we demonstrate that our proposed method outperforms existing methods.

Availability and implementation

https://github.com/zhqingit/BPP.

Supplementary information

Supplementary data are available at Bioinformatics online.
Formalizing drug indications on the road to therapeutic intent
Authors: Nelson Stuart J , Oprea Tudor I , Ursu Oleg , Bologa Cristian G , Zaveri Amrapali , Holmes Jayme , Yang Jeremy J , Mathias Stephen L , Mani Subramani , Tuttle Mark S , Dumontier Michel
Published: June 2017

Therapeutic intent, the reason behind the choice of a therapy and the context in which a given approach should be used, is an important aspect of medical practice. There are unmet needs with respect to current electronic mapping of drug indications. For example, the active ingredient sildenafil has 2 distinct indications, which differ solely on dosage strength. In progressing toward a practice of precision medicine, there is a need to capture and structure therapeutic intent for computational reuse, thus enabling more sophisticated decision-support tools and a possible mechanism for computer-aided drug repurposing. The indications for drugs, such as those expressed in the Structured Product Labels approved by the US Food and Drug Administration, appears to be a tractable area for developing an application ontology of therapeutic intent.
Shunt-Dependent Hydrocephalus After Aneurysmal Subarachnoid Hemorrhage: Predictors and Long-Term Functional Outcomes
Authors: Paisan Gabriella M , Ding Dale , Starke Robert M , Crowley R Webster , Liu Kenneth C
Published: June 2017

BACKGROUND

Although chronic hydrocephalus requiring shunt placement is a known sequela of aneurysmal subarachnoid hemorrhage (aSAH), its effect on long-term functional outcomes is incompletely understood.

OBJECTIVE

To identify predictors of shunt-dependent hydrocephalus and shunt complications after aSAH and determine the effect of shunt dependence on functional outcomes in aSAH patients.

METHODS

We evaluated a database of patients treated for aSAH at a single center from 2000 to 2015. Favorable and unfavorable outcomes were defined as modified Rankin Scale grades 0 to 2 and 3 to 6, respectively. We performed statistical analyses to identify variables associated with shunt-dependent hydrocephalus, unfavorable outcome, and shunt complication.

RESULTS

Of the 888 aSAH patients, 116 had shunt-dependent hydrocephalus (13%). Older age (P = .001), intraventricular hemorrhage (IVH) (P = .004), higher World Federation of Neurological Surgeons (WFNS) grade (P < .001), surgical aneurysm treatment (P = .002), and angiographic vasospasm (P = .005) were independent predictors of shunt-dependent hydrocephalus in multivariable analysis. Functional outcome was evaluable in 527 aSAH patients (mean follow-up 18.6 mo), with an unfavorable outcome rate of 17%. Shunt placement (P < .001), shunt infection (P = .041), older age (P < .001), and higher WFNS grade (P = .043) were independently associated with an unfavorable outcome in multivariable analysis. Of the shunt-dependent patients, 18% had a shunt-related complication. Higher WFNS grade (P = .011), posterior circulation aneurysm (P = .018), and angiographic vasospasm (P = .008) were independent predictors of shunt complications in multivariable analysis.

CONCLUSION

aSAH patients with shunt-dependent hydrocephalus have significantly poorer long-term functional outcomes. Patients with risk factors for post-aSAH shunt dependence may benefit from increased surveillance, although the effect of such measures is not defined in this study.
Searches for new Milky Way satellites from the first two years of data of the Subaru/Hyper Suprime-Cam survey: Discovery of Cetus III
Authors: Homma Daisuke , Chiba Masashi , Okamoto Sakurako , Komiyama Yutaka , Tanaka Masayuki , Tanaka Mikito , Ishigaki Miho N , Hayashi Kohei , Arimoto Nobuo , Garmilla José A , Lupton Robert H , Strauss Michael A , Miyazaki Satoshi , Wang Shiang-Yu , Murayama Hitoshi
Published: June 2017

We present the results from a search for new Milky Way (MW) satellites from the first two years of data from the Hyper Suprime-Cam (HSC) Subaru Strategic Program (SSP) ∼300 deg2 and report the discovery of a highly compelling ultra-faint dwarf galaxy candidate in Cetus. This is the second ultra-faint dwarf we have discovered after Virgo I reported in our previous paper. This satellite, Cetus III, has been identified as a statistically significant (10.7 σ) spatial overdensity of star-like objects, which are selected from a relevant isochrone filter designed for a metal-poor and old stellar population. This stellar system is located at a heliocentric distance of 251$^{+24}_{-11}\:$kpc with a most likely absolute magnitude of MV = −2.4 ± 0.6 mag estimated from a Monte Carlo analysis. Cetus III is extended with a half-light radius of $r_h = 90^{+42}_{-17}\:$pc, suggesting that this is a faint dwarf satellite in the MW located beyond the detection limit of the Sloan Digital Sky Survey. Further spectroscopic studies are needed to assess the nature of this stellar system. We also revisit and update the parameters for Virgo I, finding $M_V = -0.33^{+0.75}_{-0.87}\:$mag and $r_h = 47^{+19}_{-13}\:$pc. Using simulations of Λ-dominated cold dark matter models, we predict that we should find one or two new MW satellites from ∼300 deg2 HSC-SSP data, in rough agreement with the discovery rate so far. The further survey and completion of HSC-SSP over ∼1400 deg2 will provide robust insights into the missing satellites problem.
A Case Study of High-Velocity, Persistent Geotropic Nystagmus: Is This BPPV?
Authors: Schubert Michael C. , Dunlap Pamela M. , Whitney Susan L.
Published: June 2017

Background and Purpose:

Deciphering the cause for a persistent, direction-changing geotropic nystagmus can be difficult. Migraine and light cupula are two possible causes, though can be confused with benign paroxysmal positional vertigo (BPPV) affecting the horizontal semicircular canal. In migraine, the persistent geotropic nystagmus tends to be slow; in light cupula, the nystagmus has been illustrated to beat in the direction opposite that of prone positioning.

Case Description:

Here we describe a patient with initial occurrence then recurrence of a high velocity (≥30 deg/sec), persistent direction-changing geotropic nystagmus and vertigo with an intensity variable based on head position, which was difficult to manage. This patient did not have migraine. The case presented uniquely as it was unlikely due to canalithiasis of the horizontal semicircular canal yet the presentation was not clearly related to the light cupula phenomena either.

Intervention:

In this case, the physical therapist attempted to use the barbeque roll canalith repositioning maneuver (CRM) even though the direction-changing geotropic nystagmus was persistent. The nystagmus did not resolve during the clinic visit.

Outcomes and Discussion:

The persistent, high velocity geotropic nystagmus resolved within 1 week, however, this resolution was likely spontaneous and not due to the CRM intervention. Our case suggests that physical therapists assessing persistent geotropic nystagmus should wait long enough for the nystagmus to stop (∼2 minutes), test for fatigue by repeating the positional nystagmus tests, incorporate a head flexion component as part of the positional testing, and attempt to identify a null point.

Video Abstract available for additional insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A178).
Clinical Outcome Measures for Lateropulsion Poststroke: An Updated Systematic Review
Authors: Koter Ryan , Regan Sara , Clark Caitlin , Huang Vicki , Mosley Melissa , Wyant Erin , Cook Chad , Hoder Jeffrey
Published: June 2017

Background and Purpose:

Contraversive Lateropulsion, also referred to as contraversive pushing, pusher behavior, and pusher syndrome, can be associated with increased hospital length of stay, increased health care costs, and delayed outcomes in persons with stroke. The purpose of this updated systematic review was to identify scales used to classify contraversive lateropulsion, investigate literature that addresses their clinimetric properties, and create a resource for clinicians recommending use in clinical practice.

Methods:

Three databases were searched for articles from inception to March 2017. The search strategy followed Cochrane Collaboration guidelines. The Consensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist was applied to evaluate methodological quality.

Results:

Four hundred three records were screened. Seven studies met inclusion criteria. Four scales were identified: the Scale for Contraversive Pushing (SCP), the Modified Scale for Contraversive Pushing (M-SCP), the Burke Lateropulsion Scale (BLS), and the Swedish Scale for Contraversive Pushing (S-SCP). Psychometric property investigation was most robust for the SCP and the BLS. Cross-cultural validity has not been fully investigated in scales used outside of their country of origin.

Discussion and Conclusions:

The BLS is recommended for identifying contraversive lateropulsion. The scale assesses the presence of contraversive lateropulsion across several functional tasks, from rolling to walking, and is the only scale originally written in English. The BLS is the only tool to receive ratings greater than poor for reliability and responsiveness. The BLS should be implemented as soon as contraversive lateropulsion is suspected to guide frontline clinicians' initial plan of care, allow objective identification of change over time, and facilitate easier investigation of interventional efficacy.

Video Abstract available for additional insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A177).
Effectiveness of Prenatal Screening and Treatment to Prevent Congenital Syphilis, Louisiana and Florida, 2013–2014
Authors: Matthias James M. , Rahman Mohammad M. , Newman Daniel R. , Peterman Thomas A.
Published: June 2017

Background

From 2012 to 2014, rates of congenital syphilis increased in Louisiana and Florida. We evaluated the effectiveness of early (first or second) and third trimester syphilis screening for the prevention of congenital syphilis in these high-morbidity states.

Methods

Reported syphilis cases among pregnant women in Louisiana and Florida during January 1, 2013, to December 31, 2014, were reviewed for documented screening for syphilis in the first 2 trimesters and third trimester. Pregnant women with syphilis were linked to congenital syphilis records and stratified by whether the pregnancy led to a reported congenital syphilis case.

Results

Seven hundred ten pregnant women with syphilis in Louisiana and Florida were linked to 155 congenital syphilis cases. Three hundred seventy (52%) pregnant women with syphilis were staged as early syphilis (n = 270) or high-titer late or unknown duration-latent syphilis (n = 100), and 109 (70% of the total) were linked to congenital syphilis cases. Screening in the first 2 trimesters identified 513 pregnant women who tested positive for syphilis, and 470 (92%) potential congenital syphilis were averted. One hundred nine pregnant women tested positive for syphilis in the third trimester, and 85 (78%) had babies without congenital syphilis. During their pregnancy, 85 (12%) women tested negative at least once, and 55 (65%) had babies with congenital syphilis. Thirty-nine women had no reported syphilis screening 30 days or longer before delivery.

Conclusions

Screening for syphilis both early and in the third trimester prevented many pregnant women with syphilis from having a baby with congenital syphilis. Preventing all congenital syphilis would likely require preventing all syphilis among women.
Missed Opportunities for Chlamydia Screening in Title X Family Planning Clinics
Authors: Salomon Sarah Goldenkranz , Torrone Elizabeth , Nakatsukasa-Ono Wendy , Fine David N.
Published: June 2017

Background

Annual chlamydia (CT) screening is recommended for women younger than 25 years, yet less than half of young women seeking health care are screened annually. We analyzed Title X family planning service data from the Northwest United States to assess factors associated with missed opportunities for CT screening. Our primary hypothesis was screening coverage is higher during annual preventive health visits compared to other visit types. Study objectives were: (1) identify gaps in screening coverage by patient demographics, visit characteristics, and clinic measures; and (2) examine the association between visit type and CT screening by controlling for other covariates and stratifying by state.

Methods

Calendar year 2011 Title X visit records (n = 180,856) were aggregated to the patient level (n = 112,926) to assess CT screening coverage by all characteristics. Screening variation was explored by bivariate and multivariate Poisson regression. Adjusted models for each state estimated association between comprehensive examination and screening controlling for confounders.

Results

Clinic and visit characteristics were associated with CT screening. Coverage ranged from 45% in Washington to 80% in Alaska. Only 34% of patients visited for a routine comprehensive examination. Visit type was associated with screening; 75% of patients who had a comprehensive examination were screened versus 34% of those without a comprehensive examination (unadjusted PR, 2.18; 95% confidence interval, 2.16–2.21). The association between comprehensive examination and CT screening varied significantly by state (interaction term, P < 0.001).

Conclusions

Missed screening opportunities are common among women who access brief appointments for specific needs but do not seek routine preventive care, particularly in some states. Structural interventions may help address these systematically missed opportunities.
Trichomonas vaginalis Prevalence and Correlates in Women and Men Attending STI Clinics in Western Canada
Authors: Gratrix Jennifer , Plitt Sabrina , Turnbull LeeAnn , Smyczek Petra , Brandley Judith , Scarrott Ron , Naidu Prenilla , Bertholet Lindsay , Chernesky Max , Read Ron , Singh Ameeta E.
Published: June 2017

Trichomonas vaginalis prevalence (2.8%) in female sexually transmitted infection clinic attendees was within the prevalence of chlamydia (5.8%) and gonorrhea (1.8%), while being very low for male attendees (0.2%). Correlates among women were indigenous ethnicity, other ethnicity, and being symptomatic.
Hydrogen Sulfide in Exhaled Gases From Ventilated Septic Neonates and Children: A Preliminary Report
Authors: Bee Natalie , White Ruth , Petros Andy J.
Published: June 2017

Objectives:

There is increasing interest in hydrogen sulfide as a marker of pathologic conditions or predictors of outcome. We speculate that as hydrogen sulfide is a diffusible molecule, if there is an increase in plasma hydrogen sulfide in sepsis, it may accumulate in the alveolar space and be detected in exhaled gas. We wished to determine whether we could detect hydrogen sulfide in exhaled gases of ventilated children and neonates and if the levels changed in sepsis.

Design:

Prospective, observational study.

Setting:

The study was conducted across three intensive care units, pediatric, neonatal and cardiac in a large tertiary children’s hospital.

Patients:

We studied ventilated children and neonates with sepsis, defined by having two or more systemic inflammatory response syndrome criteria and one organ failure or suspected infection. A control group of ventilated non-septic patients was also included.

Intervention:

A portable gas chromatograph (OralChroma; Envin Scientific, Chester, United Kingdom) was used to measure H2S in parts per billion.

Measurements and Main Results:

A 1-2 mL sample of expired gas was taken from the endotracheal tube and analyzed. A repeat sample was taken after 30 minutes and a further single daily sample up to a maximum of 5 days or until the patient was extubated. WBC and C-reactive protein were measured around the time of gas sampling. Each group contained 20 subjects. Levels of H2S were significantly higher in septic patients (Mann Whitney U-test;p< 0.0001) and trended to control levels over five days. C- reactive protein levels were also significantly raised (p< 0.001) and mirrored the decrease in H2S levels.

Conclusion:

Hydrogen sulfide can be detected in expired pulmonary gases in very low concentrations of parts per billion. Significantly higher levels are seen in septic patients compared with controls. The pattern of response was similar to that ofC-reactive protein.
Selective Serotonin Reuptake Inhibitor-Induced Hyponatremia: Clinical Implications and Therapeutic Alternatives
Authors: Varela Piñón María , Adán-Manes Jaime
Published: June 2017

Background

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed among the general population. Despite their benign side effect profile, these drugs can cause significant adverse effects in elderly patients, including severe hyponatremia. We report 1 case of SSRI-induced hyponatremia and review therapeutic alternatives.

Case

We present an 81-year-old male patient treated with sertraline and furosemide who presented with a recent-onset symptomatic hyponatremia. Low sodium levels persisted for more than 1 week after furosemide had been discontinued. Sertraline was then replaced with a nonserotonergic antidepressant (bupropion), leading to a full recovery.

Conclusions

Although SSRIs are the first treatment option for elderly depressed patients, they should be prescribed cautiously in this population because of the risk of potentially severe adverse effects such as hyponatremia. Particularly vulnerable patients could benefit from being prescribed nonserotonergic antidepressants from the start.
Aripiprazole-Related Diurnal Enuresis in Children: 2 Cases (Aripiprazole-Related Enuresis)
Authors: Gunes Serkan
Published: June 2017

Aripiprazole is an atypical antipsychotic with dopaminergic and serotonergic effects. Enuresis as an adverse effect has been reported with aripiprazole use in children with autism spectrum disorders. Here, we report 2 cases without autism spectrum disorders who developed diurnal enuresis after starting aripiprazole and ceased after discontinuation of the medication.
The “Forgotten” Treatment of Alcohol Withdrawal Delirium With Electroconvulsive Therapy: Successful Use in a Very Prolonged and Severe Case
Authors: Kranaster Laura , Aksay Suna Su , Bumb Jan Malte , Janke Christoph , Sartorius Alexander
Published: June 2017

Objective

Alcohol withdrawal delirium (AWD) is a notorious complication in alcohol withdrawal. Usually, the symptomatic treatment is efficacious; however, some patients show treatment resistance or a prolonged course of AWD.

Method

We report the case of a patient with a prolonged and severest form of AWD. Even 11 weeks after admission, he received approximately 100 mg diazepam per week to manage the symptoms of withdrawal delirium.

Results

A treatment course of electroconvulsive therapy was initiated, which allowed a complete tapering off of benzodiazepines during electroconvulsive therapy without adverse effects.

Conclusions

The reported case might contribute to alternative approaches reserved for severest forms of prolonged AWD.
Sleep Disturbance as a Precursor of Severe Regression in Kleefstra Syndrome Suggests a Need for Firm and Rapid Pharmacological Treatment
Authors: Vermeulen Karlijn , Staal Wouter G. , Janzing Joost G. , van Bokhoven Hans , Egger Jos I.M. , Kleefstra Tjitske
Published: June 2017

Intellectual disability is frequently accompanied by psychiatric symptoms that require pharmacological interventions. Treatment guidelines often provide a general treatment approach for these symptoms in intellectual disability. However, this may not always be the best strategy, as illustrated here in Kleefstra syndrome. We present 3 patients showing severe regression after sleep disturbances. If these are treated with care as usual (eg, behavioral programs and sleep medication) deterioration is likely to follow. It is observed that rapid treatment with relatively high dosages of antipsychotics contributes to restore sleep, halt further regression, and improve daily life functioning.
Unexpected Early Proteomic Changes in Alzheimer’s Disease Model Mice Synaptosomes
Authors: Ball Kerri , Pisconti Addolorata , Grounds Kelly , Old William M. , Stowell Michael H. B.
Published: June 2017

We have employed label-free quantitative proteomics of wild-type and Alzheimer’s disease (AD) model mice synaptosomes to investigate proteomic changes occurring during AD progression as a prelude to analysis in humans. More than 4000 proteins were analyzed using multiple analysis tools and statistical criteria. Pathway enrichment identified numerous pathways consistent with the current AD knowledge base, including dysregulation of Glutamate Receptor Signaling, Synaptic Long Term Potentiation and Depression, Rho and Rac Signaling, Calcium Signaling, and Oxidative Phosphorylation and Mitochondrial Dysfunction. Additionally, the data demonstrate that a large number of changes occur in the proteome very early relative to the onset of both traditional disease markers such as amyloid accumulation, tau phosphorylation and cognitive dysfunction. These early changes include a number of dysregulated proteins that have novel associations with AD progression. These results reinforce the importance of mechanistic investigations in early disease progression long before the classical markers of Alzheimer’s disease are observed.
Genome-wide association study of Alcohol Use Disorder Identification Test (AUDIT) scores in 20,328 research participants of European ancestry
Authors: Sanchez-Roige Sandra , Fontanillas Pierre , Elson Sarah L. ,   the 23 and Me Research Team, Gray Joshua C. , Wit Harriet de , Davis Lea K. , MacKillop James , Palmer Abraham A.
Published: June 2017

Genetic factors contribute to the risk for developing alcohol use disorder (AUD). In collaboration with the genetics company 23andMe, Inc., we performed a genome-wide association (GWAS) study of the Alcohol Use Disorder Identification Test (AUDIT), an instrument designed to screen for alcohol misuse over the past year. Our final sample consisted of 20,328 research participants of European ancestry (55.3% females; mean age = 53.8, SD = 16.1) who reported ever using alcohol. Our results showed that the ‘chip-heritability’ of AUDIT score, when treated as a continuous phenotype, was 12%. No loci reached genome-wide significance. The geneADH1C, which has been previously implicated in AUD, was among our most significant associations (4.4 × 10−7; rs141973904). We also detected a suggestive association on chromosome 1 (2.1 × 10−7; rs182344113) near the geneKCNJ9, which has been implicated in mouse models of high ethanol drinking. Using LD score regression, we identified positive genetic correlations between AUDIT score and AUD, high alcohol consumption, and cigarette smoking. We also observed an unexpected positive genetic correlation between AUDIT and educational attainment, and additional unexpected negative correlations with BMI/obesity and attention-deficit/hyperactivity disorder (ADHD). We conclude that conducting a genetic study using data from a population unselected for AUD and responding to an online questionnaire may represent a cost-effective strategy for elucidating the etiology of AUD.
Real-time detection of condensin-driven DNA compaction reveals a multistep binding mechanism
Authors: Eeftens Jorine M. , Bisht Shveta , Kerssemakers Jacob , Haering Christian H. , Dekker Cees
Published: June 2017

Condensin, a conserved member of the SMC protein family of ring-shaped multi-subunit protein complexes, is essential for structuring and compacting chromosomes. Despite its key role, its molecular mechanism has remained largely unknown. Here, we employ single-molecule magnetic tweezers to measure, in real-time, the compaction of individual DNA molecules by the budding yeast condensin complex. We show that compaction proceeds in large (~200nm) steps, driving DNA molecules into a fully condensed state against forces of up to 2pN. Compaction can be reversed by applying high forces or adding buffer of high ionic strength. While condensin can stably bind DNA in the absence of ATP, ATP hydrolysis by the SMC subunits is required for rendering the association salt-insensitive and for subsequent compaction. Our results indicate that the condensin reaction cycle involves two distinct steps, where condensin first binds DNA through electrostatic interactions before using ATP hydrolysis to encircle the DNA topologically within its ring structure, which initiates DNA compaction. The finding that both binding modes are essential for its DNA compaction activity has important implications for understanding the mechanism of chromosome compaction.
Bacteria defend against phages through type IV pilus glycosylation
Authors: Harvey Hanjeong , Bondy-Denomy Joseph , Marquis Hélène , Sztanko Kristina M. , Davidson Alan R. , Burrows Lori L.
Published: June 2017

Bacterial surface structures such as type IV pili are common receptors for phage. Strains of the opportunistic pathogenPseudomonas aeruginosaexpress one of five different major type IV pilin alleles, two of which are glycosylated with either lipopolysaccharide O-antigen units or polymers of D-arabinofuranose. Here we show that both these post-translational modifications protectP. aeruginosafrom a variety of pilus-specific phages. We identified a phage capable of infecting strains expressing both non-glycosylated and glycosylated pilins, and through construction of a chimeric phage, traced this ability to its unique tail proteins. Alteration of pilin sequence, or masking of binding sites by glycosylation, both block phage infection. The energy invested by prokaryotes in glycosylating thousands of pilin subunits is thus explained by the protection against phage predation provided by these common decorations.

SIGNIFICANCE

Post-translational modification of bacterial and archaeal surface structures such as pili and flagella is widespread, but the function of these decorations is not clear. We propose that predation by bacteriophages that use these structures as receptors selects for strains that mask potential phage binding sites using glycosylation. Phages are of significant interest as alternative treatments for antibiotic-resistant pathogens, but the ways in which phage interact with host receptors are not well understood. We show that specific phage tail proteins allow for infection of strains with glycosylated pili, providing a foundation for the creation of designer phages that can circumvent first-line bacterial defenses.
A single cell transcriptional roadmap for cardiopharyngeal fate diversification
Authors: Wang Wei , Niu Xiang , Stuart Tim , Jullian Estelle , Mauck William , Kelly Robert G. , Satija Rahul , Christiaen Lionel
Published: June 2017

In vertebrates, multipotent progenitors located in the pharyngeal mesoderm form cardiomyocytes and branchiomeric head muscles, but the dynamic gene expression programs and mechanisms underlying cardiopharyngeal multipotency and heart vs. head muscle fate choices remain elusive. Here, we used single cell genomics in the simple chordate model Ciona, to reconstruct developmental trajectories forming first and second heart lineages, and pharyngeal muscle precursors, and characterize the molecular underpinnings of cardiopharyngeal fate choices. We show that FGF-MAPK signaling maintains multipotency and promotes the pharyngeal muscle fate, whereas signal termination permits the deployment of a pan-cardiac program, shared by the first and second lineages, to define heart identity. In the second heart lineage, a Tbx1/10-Dach pathway actively suppresses the first heart lineage program, conditioning later cell diversity in the beating heart. Finally, cross-species comparisons between Ciona and the mouse evoke the deep evolutionary origins of cardiopharyngeal networks in chordates.
Campylobacter jejunitranscriptome changes during loss of culturability in water
Authors: Bronowski Christina , Mustafa Kasem , Goodhead Ian B. , James Chloe E. , Nelson Charlotte , Lucaci Anita , Wigley Paul , Humphrey Tom J. , Williams Nicola J. , Winstanley Craig
Published: June 2017

Background

The natural environment serves as a potential reservoir forCampylobacter,the leading cause of bacterial gastroenteritis in humans. However, little is understood about the mechanisms underlying variations in survival characteristics between different strains ofC. jejuniin natural environments, including water.

Results

We identified threeCampylobacter jejunistrains that exhibited variability in their ability to retain culturability after suspension in water at two different temperatures (4°C and 25°C). Of the three, strainsC. jejuniM1 exhibited the most rapid loss of culturability whilst retaining viability. Using RNAseq transcriptomics, we characterised C.jejuniM1 gene expression in response to suspension in water by analyzing bacterial suspensions recovered immediately after introduction into water (Time 0), and from two sampling time/temperature combinations where considerable loss of culturability was evident, namely (i) after 24 h at 25°C, and (ii) after 72 h at 4°C. Transcript data were compared with a culture-grown control. Some gene expression characteristics were shared amongst the three populations recovered from water, with more genes being up-regulated than down. Many of the up-regulated genes were identified in the Time 0 sample, whereas the majority of down-regulated genes occurred in the 25°C (24 h) sample.

Conclusions

Variations in expression were found amongst genes associated with oxygen tolerance, starvation and osmotic stress. However, we also found upregulation of flagellar assembly genes, accompanied by down-regulation of genes involved in chemotaxis. Our data also suggested a switch from secretion via thesecsystem to via thetatsystem, and that the quorum sensing geneluxSmay be implicated in the survival of strain M1 in water. Variations in gene expression also occurred in accessory genome regions. Our data suggest that despite the loss of culturability,C. jejuniM1 remains viable and adapts via specific changes in gene expression.
Association study of schizophrenia with variants in miR-137 binding sites
Authors: Curtis David , Emmett Warren
Published: June 2017

There is strong cumulative evidence for the involvement of miR-137 and its targets in the aetiology of schizophrenia. Here we test whether variants, especially rare variants, in miR137 binding sites are associated with schizophrenia in an exome-sequenced sample of 4225 cases and 5834 controls. A weighted burden test using 372 variants was significant at p=0.024. The sample size is too small to implicate individual variants or genes but overall this finding provides further support for the hypothesis that disruption of miR-137 binding sites can increase the risk of schizophrenia, perhaps by leading to over-expression of the target gene. These findings could be followed up by genotyping these variants in larger samples and by experimentally testing whether they do indeed effect expression. When carrying out exome sequencing it is important to include UTRs so that disruption of microRNA bindings sites can be detected.
Phenotypic consequences of RNA polymerase dysregulation inEscherichia coli
Authors: Sarkar Paramita , Switzer Amy , Peters Christine , Pogliano Joe , Wigneshweraraj Sivaramesh
Published: June 2017

Many bacterial adaptive responses to changes in growth conditions due to biotic and abiotic factors involve reprogramming of gene expression at the transcription level. The bacterial RNA polymerase (RNAP), which catalyzes transcription, can thus be considered as the major mediator of cellular adaptive strategies. But how do bacteria respond if a stress factor directly compromises the activity of the RNAP? We used a phage-derived small protein to specifically perturb bacterial RNAP activity in exponentially growingEscherichia coli. Using cytological profiling, tracking RNAP behavior at single-molecule level and transcriptome analysis, we reveal that adaptation to conditions that directly perturb bacterial RNAP performance can result in a biphasic growth behavior and thereby confer the ‘adapted’ bacterial cells an enhanced ability to tolerate diverse antibacterial stresses. The results imply that while synthetic transcriptional rewiring may confer bacteria with the intended desirable properties, such approaches may also collaterally allow them to acquire undesirable traits.
The genetic overlap between mood disorders and cardio-metabolic diseases: A systematic review of genome wide and candidate gene studies
Authors: Amare Azmeraw T. , Schubert Klaus Oliver , Cohen-Woods Sarah , Baune Bernhard T.
Published: June 2017

Meta-analyses of genome-wide association studies (meta-GWAS) and candidate gene studies have identified genetic variants associated with cardiovascular diseases, metabolic diseases, and mood disorders. Although previous efforts were successful for individual disease conditions (single disease), limited information exists on shared genetic risk between these disorders. This article presents a detailed review and analysis of cardio-metabolic diseases risk (CMD-R) genes that are also associated with mood disorders. Firstly, we reviewed meta-GWA studies published until January 2016, for the diseases “type 2 diabetes, coronary artery disease, hypertension” and/or for the risk factors “blood pressure, obesity, plasma lipid levels, insulin and glucose related traits”. We then searched the literature for published associations of these CMD-R genes with mood disorders. We considered studies that reported a significant association of at least one of the CMD-R genes and “depressive disorder” OR “depressive symptoms” OR “bipolar disorder” OR “lithium treatment”, OR “serotonin reuptake inhibitors treatment”. Our review revealed 24 potential pleiotropic genes that are likely to be shared between mood disorders and CMD-Rs. These genes includeMTHFR,CACNA1D,CACNB2,GNAS,ADRB1,NCAN,REST,FTO,POMC,BDNF,CREB,ITIH4,LEP,GSK3B,SLC18A1,TLR4,PPP1R1B,APOE,CRY2,HTR1A,ADRA2A,TCF7L2,MTNR1B, andIGF1. A pathway analysis of these genes revealed significant pathways: corticotrophin-releasing hormone signaling, AMPK signaling, cAMP-mediated or G-protein coupled receptor signaling, axonal guidance signaling, serotonin and dopamine receptors signaling, dopamine-DARPP32 feedback in cAMP signaling, circadian rhythm signaling and leptin signaling. Our findings provide insights in to the shared biological mechanisms of mood disorders and cardio-metabolic diseases.
Amyloid accumulation drives proteome-wide alterations in mouse models of Alzheimer’s disease like pathology
Authors: Savas Jeffrey N. , Wang Yi-Zhi , DeNardo Laura A. , Martinez-Bartolome Salvador , McClatchy Daniel B. , Hark Timothy J. , Shanks Natalie F. , Cozzolino Kira A. , Lavallée-Adam Mathieu , Smukowski Samuel N. , Park Sung Kyu , Kelly Jeffery W. , Koo Edward H. , Nakagawa Terunaga , Masliah Eliezer , Ghosh Anirvan , Yates John R.
Published: June 2017

Amyloid beta (Aβ) peptides impair multiple cellular pathways in the brain and play a causative role in Alzheimer’s disease (AD) pathology, but how the brain proteome is remodeled during this process is unknown. To identify new protein networks associated with AD-like pathology, we performed global quantitative proteomic analysis in three mouse models at pre- and post-symptomatic ages. Our analysis revealed a robust and consistent increase in Apolipoprotein E (ApoE) levels in nearly all transgenic brain regions with increased Aβ levels. Taken together with prior findings on ApoE driving Aβ accumulation, this analysis points to a pathological dysregulation of the ApoE-Aβ axis. We also found dysregulation of protein networks involved in excitatory synaptic transmission consistent with AD pathophysiology. Targeted analysis of the AMPA receptor complex revealed a specific loss of TARPγ-2, a key AMPA receptor trafficking protein. Expression of TARPγ-2in vivoin hAPP transgenic mice led to a restoration of AMPA currents. This database of proteome alterations represents a unique resource for the identification of protein alterations responsible for AD.

Highlights

Proteomic analysis of mouse brains with AD-like pathology reveals stark remodeling

Proteomic evidence points to a dysregulation of ApoE levels associated with Aβ clearance rather than production

Co-expression analysis found distinctly impaired synapse and mitochondria modules

In-depth analyses of AMPAR complex points to loss of TARPγ-2, which may compromise synapses in AD

eTOC Blurb

Proteome-wide profiling of brain tissue from three mouse models of AD-like pathology reveals Aβ, brain region, and age dependent alterations of protein levels. This resource provides a new global protein expression atlas for the Alzheimer’s disease research community.
Triazavirine supramolecular complexes as modifiers of the peptide oligomeric structure
Authors: Shvetsov Alexey V. , Zabrodskaya Yana A. , Nekrasov Peter A. , Egorov Vladimir V.
Published: June 2017

In this study we present molecular dynamics simulations of the antiviral drug triazavirine, that affects formation of amyloid-like fibrils of the model peptide (SI). According to our simulations, triazavirine is able to form linear supramolecular structures which can act as shields and prevent interactions between SI monomers. This model, as validated by simulations, provides an adequate explanation of triazavirine’s mechanism of action as it pertains to SI peptide fibril formation.
An evolutionarily young defense metabolite influences the root growth of plants via the ancient TOR signaling pathway
Authors: Malinovsky F.G. , Thomsen M-L.F. , Nintemann S.J. , Jagd L.M. , Bourgine B. , Burow M. , Kliebenstein D. J.
Published: June 2017

To optimize fitness a plant should monitor its metabolism to appropriately control growth and defense. Primary metabolism can be measured by the universally conserved TOR (Target of Rapamycin) pathway to balance growth and development with the available energy and nutrients. Recent work suggests that plants may measure defense metabolites to potentially provide a strategy ensuring fast reallocation of resources to coordinate plant growth and defense. There is little understanding of mechanisms enabling defense metabolite signaling. To identify mechanisms of defense metabolite signaling, we used glucosinolates, an important class of plant defense metabolites. We report novel signaling properties specific to one distinct glucosinolate, 3- hydroxypropyl glucosinolate across plants and fungi. This defense metabolite, or derived compounds, reversibly inhibits root growth and development. 3-hydroxypropyl glucosinolate signaling functions via genes in the ancient TOR pathway. Thus, plants might link evolutionarily new defense metabolites to ancient signaling pathways to optimize energy allocation.
Karyotype stability and unbiased fractionation in the paleo-allotetraploidCucurbitagenomes
Authors: Sun Honghe , Wu Shan , Zhang Guoyu , Jiao Chen , Guo Shaogui , Ren Yi , Zhang Jie , Zhang Haiying , Gong Guoyi , Jia Zhangcai , Zhang Fan , Tian Jiaxing , Lucas William J. , Doyle Jeff J. , Li Haizhen , Fei Zhangjun , Xu Yong
Published: June 2017

TheCucurbitagenus contains several economically important species in the Cucurbitaceae family. Interspecific hybrids betweenC. maximaandC. moschataare widely used as rootstocks for other cucurbit crops. We report high-quality genome sequences ofC. maximaandC. moschataand provide evidence supporting an allotetraploidization event inCucurbita. We are able to partition the genome into two homoeologous subgenomes based on different genetic distances to melon, cucumber and watermelon in the Benincaseae tribe. We estimate that the two diploid progenitors successively diverged from Benincaseae around 31 and 26 million years ago (Mya), and the allotetraploidization happened earlier than 3 Mya, whenC. maximaandC. moschatadiverged. The subgenomes have largely maintained the chromosome structures of their diploid progenitors. Such long-term karyotype stability after polyploidization is uncommon in plant polyploids. The two subgenomes have retained similar numbers of genes, and neither subgenome is globally dominant in gene expression. Allele-specific expression analysis in theC. maxima×C. moschatainterspecific F1hybrid and the two parents indicates the predominance oftrans-regulatory effects underlying expression divergence of the parents, and detects transgressive gene expression changes in the hybrid correlated with heterosis in important agronomic traits. Our study provides insights into plant genome evolution and valuable resources for genetic improvement of cucurbit crops.
N-Benzylnicotinamide and N-benzyl-1,4-dihydronicotinamide: useful models for NAD+ and NADH
Authors: Moore John M. , Hall Jasmine M. , Dilling Wendell L. , Jensen Anton W. , Squattrito Philip J. , Giolando Patrick , Kirschbaum Kristin
Published: June 2017

3-Aminocarbonyl-1-benzylpyridinium bromide (N-benzylnicotinamide, BNA), C13H13N2O+·Br−, (I), and 1-benzyl-1,4-dihydropyridine-3-carboxamide (N-benzyl-1,4-dihydronicotinamide, rBNA), C13H14N2O, (II), are valuable model compounds used to study the enzymatic cofactors NAD(P)+ and NAD(P)H. BNA was crystallized successfully and its structure determined for the first time, while a low-temperature high-resolution structure of rBNA was obtained. Together, these structures provide the most detailed view of the reactive portions of NAD(P)+ and NAD(P)H. The amide group in BNA is rotated 8.4 (4)° out of the plane of the pyridine ring, while the two rings display a dihedral angle of 70.48 (17)°. In the rBNA structure, the dihydropyridine ring is essentially planar, indicating significant delocalization of the formal double bonds, and the amide group is coplanar with the ring [dihedral angle = 4.35 (9)°]. This rBNA conformation may lower the transition-state energy of an ene reaction between a substrate double bond and the dihydropyridine ring. The transition state would involve one atom of the double bond binding to the carbon ortho to both the ring N atom and the amide substituent of the dihydropyridine ring, while the other end of the double bond accepts an H atom from the methylene group para to the N atom.
Recombinant ACHT1 fromArabidopsis thaliana: crystallization and X-ray crystallographic analysis
Authors: Pan Weimin , Wang Junchao , Yang Ye , Liu Lin , Zhang Min
Published: June 2017

Thioredoxins (Trxs) play important roles in chloroplasts by linking photosynthetic light reactions to a series of plastid functions. They execute their function by regulating the oxidation and reduction of disulfide bonds. ACHT1 (atypical cysteine/histidine-rich Trx1) is a thylakoid-associated thioredoxin-type protein found in theArabidopsis thalianachloroplast. Recombinant ACHT1 protein was overexpressed inEscherichia coli, purified and crystallized by the vapour-diffusion method. The crystal diffracted to 1.7 Å resolution and a complete X-ray data set was collected. Preliminary crystallographic analysis suggested that the crystals belonged to space groupC2221, with unit-cell parametersa = 102.7,b= 100.6,c= 92.8 Å.
Crystal structure of a family 6 cellobiohydrolase from the basidiomycetePhanerochaete chrysosporium
Authors: Tachioka Mikako , Nakamura Akihiko , Ishida Takuya , Igarashi Kiyohiko , Samejima Masahiro
Published: June 2017

Cellobiohydrolases belonging to glycoside hydrolase family 6 (CBH II, Cel6A) play key roles in the hydrolysis of crystalline cellulose. CBH II from the white-rot fungusPhanerochaete chrysosporium(PcCel6A) consists of a catalytic domain (CD) and a carbohydrate-binding module connected by a linker peptide, like other known fungal cellobiohydrolases. In the present study, the CD ofPcCel6A was crystallized without ligands, andp-nitrophenyl β-D-cellotrioside (pNPG3) was soaked into the crystals. The determined structures of the ligand-free andpNPG3-soaked crystals revealed that binding of cellobiose at substrate subsites +1 and +2 induces a conformational change of the N-terminal and C-terminal loops, switching the tunnel-shaped active site from the open to the closed form.