bluuebunny/crossref_metadata_2025 huggingface dataset:
Balance between Transmitter Availability and Dopamine D2 Receptors in Prefrontal Cortex Influences Memory Functioning
Authors: Papenberg Goran , Karalija Nina , Salami Alireza , Rieckmann Anna , Andersson Micael , Axelsson Jan , Riklund Katrine , Lindenberger Ulman , Lövdén Martin , Nyberg Lars , Bäckman Lars
Published: June 2019

Insufficient or excessive dopaminergic tone impairs cognitive performance. We examine whether the balance between transmitter availability and dopamine (DA) D2 receptors (D2DRs) is important for successful memory performance in a large sample of adults (n = 175, 64–68 years). The Catechol-O-Methyltransferase polymorphism served as genetic proxy for endogenous prefrontal DA availability, and D2DRs in dorsolateral prefrontal cortex (dlPFC) were measured with [11C]raclopride-PET. Individuals for whom D2DR status matched DA availability showed higher levels of episodic and working-memory performance than individuals with insufficient or excessive DA availability relative to the number of receptors. A similar pattern restricted to episodic memory was observed for D2DRs in caudate. Functional magnetic resonance imaging data acquired during working-memory performance confirmed the importance of a balanced DA system for load-dependent brain activity in dlPFC. Our data suggest that the inverted-U–shaped function relating DA signaling to cognition is modulated by a dynamic association between DA availability and receptor status.
Seeing the Unexpected: How Brains Read Communicative Intent through Kinematics
Authors: Trujillo James P , Simanova Irina , Özyürek Asli , Bekkering Harold
Published: June 2019

Social interaction requires us to recognize subtle cues in behavior, such as kinematic differences in actions and gestures produced with different social intentions. Neuroscientific studies indicate that the putative mirror neuron system (pMNS) in the premotor cortex and mentalizing system (MS) in the medial prefrontal cortex support inferences about contextually unusual actions. However, little is known regarding the brain dynamics of these systems when viewing communicatively exaggerated kinematics. In an event-related functional magnetic resonance imaging experiment, 28 participants viewed stick-light videos of pantomime gestures, recorded in a previous study, which contained varying degrees of communicative exaggeration. Participants made either social or nonsocial classifications of the videos. Using participant responses and pantomime kinematics, we modeled the probability of each video being classified as communicative. Interregion connectivity and activity were modulated by kinematic exaggeration, depending on the task. In the Social Task, communicativeness of the gesture increased activation of several pMNS and MS regions and modulated top-down coupling from the MS to the pMNS, but engagement of the pMNS and MS was not found in the nonsocial task. Our results suggest that expectation violations can be a key cue for inferring communicative intention, extending previous findings from wholly unexpected actions to more subtle social signaling.
Skin and Soft Tissue Infection in People Living With Human Immunodeficiency Virus in a Large, Urban, Public Healthcare System in Houston, Texas, 2009–2014
Authors: Hemmige Vagish , Arias Cesar A , Pasalar Siavash , Giordano Thomas P
Published: June 2019

Background

Skin and soft tissue infections (SSTIs) disproportionately impact patients with human immunodeficiency virus (HIV). Recent declines in the incidence of SSTIs have been noted in the non-HIV population. We sought to study the epidemiology and microbiology of SSTIs in a population of 8597 patients followed for HIV primary care in a large, urban county system from January 2009 to December 2014.

Methods

SSTIs were identified from the electronic medical record by use of International Classification of Diseases-9 billing codes. Charts were reviewed to confirm each patient’s diagnosis of acute SSTI and abstract culture and susceptibility data. We calculated the yearly SSTI incidences using Poisson regression with clustering by patient.

Results

There were 2202 SSTIs identified. Of 503 (22.8%) cultured SSTIs, 332 (66.0%) recovered Staphylococcus aureus as a pathogen, of which 287/332 (86.4%) featured S. aureus as the sole isolated organism. Among the S. aureus isolates that exhibited antibiotic susceptibilities, 231/331 (69.8%) were methicillin resistant, and the proportion did not change by year. The observed incidence of SSTI was 78.0 per 1000 person-years (95% confidence interval 72.9–83.4) and declined from 96.0 infections per 1000 person-years in 2009 to 56.5 infections per 1000 person-years in 2014 (P < .001). Other significant predictors of SSTI incidences in both univariate as well as multivariate analyses included a low CD4 count, high viral load, and not being a Spanish-speaking Hispanic.

Conclusions

SSTIs remain a significant problem in the outpatients living with HIV, although rates of SSTIs appear to have declined by approximately 40% between 2009 and 2014.
Safety and Clinical Outcomes of an Equine-derived Heptavalent Botulinum Antitoxin Treatment for Confirmed or Suspected Botulism in the United States
Authors: Richardson Jason S , Parrera Geraldine S , Astacio Hugo , Sahota Harpreet , Anderson Deborah M , Hall Christine , Babinchak Tim
Published: June 2019

Background

Botulism is a rare, life-threatening paralytic illness. Botulism Antitoxin Heptavalent (A,B,C,D,E,F,G)-(Equine) (BAT) manufactured by Emergent BioSolutions Canada Inc is an equine-derived heptavalent botulinum antitoxin product indicated for the treatment of symptomatic botulism following documented or suspected exposure to botulinum neurotoxin serotypes A-G in adults and pediatric patients. BAT product was US-licensed in 2013.

Methods

In the United States, from October 2014 through July 2017, safety and clinical outcomes data were collected under a registry for patients treated with BAT product.

Results

Registry patients had a median age of 51 years (range, 32 days to 92 years). Among 162 patients, 7 (4.3%) experienced BAT product–related serious adverse events, including 1 (0.6%) report each of pneumonia, pneumonia aspiration, ventricular tachycardia, upper gastrointestinal hemorrhage, anaphylactic reaction, acute kidney injury, and acute myocardial infarction. Thirty-one (19.1%) patients had 41 BAT product–related adverse events. Six (3.7%) deaths were reported in the registry. All deaths were attributed to the underlying illness and were assessed as unlikely related to BAT product. Among 113 (69.8%) patients with a final diagnosis of botulism, those treated early (≤2 days) spent fewer days in the hospital (5 vs 15.5 days), in the intensive care unit (ICU) (4 vs 12 days), and on mechanical ventilation (6 vs 14.5 days) than those treated late (>2 days), respectively.

Conclusions

BAT product was well tolerated in patients. Treatment with BAT product at ≤2 days of symptom onset was associated with shorter hospital and ICU stays, and shorter duration and need for mechanical ventilation, showing clinical benefit associated with early treatment.
Faecal Micro-RNAs in Inflammatory Bowel Diseases
Authors: Verdier Julien , Breunig Irene Raphaela , Ohse Margarete Clara , Roubrocks Silvia , Kleinfeld Sandra , Roy Sanchari , Streetz Konrad , Trautwein Christian , Roderburg Christoph , Sellge Gernot
Published: June 2019

Background and Aims

Faecal biomarkers are used as indicators of disease activity in inflammatory bowel diseases [IBD], which include Crohn’s disease [CD] and ulcerative colitis [UC]. Micro-RNAs [miRNAs] are small non-coding RNAs detectable in extracellular fluids and can be used as clinical biomarkers. The aim of this study was to determine if faecal miRNA composition is altered in IBD.

Methods

More than 800 different human faecal miRNAs were measured in stool samples from control individuals and patients with active CD by using NanoString technology. Selected miRNAs were quantified by qRT-PCR in faeces, serum and intestinal tissue of controls [n = 23] and patients with inactive or active CD [n = 22, n = 22] or UC [n = 11, n = 24] as well as patients with Clostridium difficile infection [CDI, n = 8].

Results

In total, 150 miRNAs were significantly detected in faeces from controls and patients, and multivariate analyses showed that CD patients with high disease activities had a distinct miRNA profile and that miR-223 and miR-1246 were distinct from other faecal miRNAs. In a larger cohort, active UC patients displayed significantly higher levels of miR-223 and miR-1246 than controls while patients with CDI had higher levels of faecal miR-1246 but not miR-223. No differences were noted in serum samples.

Conclusions

To our knowledge, this is the first comprehensive screen of faecal miRNAs performed in IBD. Further investigation will aim to confirm these findings in a larger cohort and to understand the biological function and cellular sources of faecal miRNAs.
Alexander Grosart, ‘The First True Gentleman That Ever Breathed’, and the Independent Scholar
Authors: Cathcart Charles
Published: June 2019

The Presbyterian clergyman and amateur scholar Alexander Grosart borrowed a line from the Renaissance play, The Honest Whore, Part One, in his sermon for the opening of Blackburn’s new church in 1868. Christ ‒ says Grosart ‒ was ‘the first true gentleman that ever breathed’. Exploring the resonances of this unacknowledged use of secular drama and turning to the editorial work of Grosart himself allows the essay’s underlying concern to emerge. What does it mean to be an independent scholar? This is an issue with implications for all who value scholarly study within the humanities ‒ for the practice of academic research in literary studies is diminished if these studies are the preserve of salaried academics and if the discussions that they comprise rarely extend beyond universities. This subject, so it is argued – the place of scholarship undertaken on an unaffiliated or independent basis in the world of English studies – is a topic worthy of sustained attention. In this essay, I acknowledge the challenges of scope and tact that lie in the path of all who pursue this matter and I propose that one way of doing so is to celebrate the work of the amateur scholars of the past. The essay concludes by returning to Alexander Grosart and reflecting upon his reputation during the years since his death in 1899.
Cardiovascular effect of discontinuing statins for primary prevention at the age of 75 years: a nationwide population-based cohort study in France
Authors: Giral Philippe , Neumann Anke , Weill Alain , Coste Joël
Published: June 2019

Aims

The role of statin therapy in primary prevention of cardiovascular disease in persons older than 75 years remains a subject of debate with little evidence to support or exclude the benefit of this treatment. We assessed the effect of statin discontinuation on cardiovascular outcomes in previously adherent 75-year-olds treated for primary prevention.

Methods and results

A population-based cohort study using French national healthcare databases was performed, studying all subjects who turned 75 in 2012–14, with no history of cardiovascular disease and with a statin medication possession ratio ≥80% in each of the previous 2 years. Statin discontinuation was defined as three consecutive months without exposure. The outcome was hospital admission for cardiovascular event. The hazard ratio comparing statin discontinuation with continuation was estimated using a marginal structural model adjusting for both baseline and time-varying covariates (cardiovascular drug use, comorbidities, and frailty indicators). A total of 120 173 subjects were followed for an average of 2.4 years, of whom 17 204 (14.3%) discontinued statins and 5396 (4.5%) were admitted for a cardiovascular event. The adjusted hazard ratios for statin discontinuation were 1.33 [95% confidence interval (CI) 1.18–1.50] (any cardiovascular event), 1.46 (95% CI 1.21–1.75) (coronary event), 1.26 (95% CI 1.05–1.51) (cerebrovascular event), and 1.02 (95% CI 0.74–1.40) (other vascular event).

Conclusion

Statin discontinuation was associated with a 33% increased risk of admission for cardiovascular event in 75-year-old primary prevention patients. Future studies, including randomized studies, are needed to confirm these findings and support updating and clarification of guidelines on the use of statins for primary prevention in the elderly.
The outer membrane glycolipids of bacteria from cold environments: isolation, characterization, and biological activity
Authors: Casillo Angela , Parrilli Ermenegilda , Tutino Maria Luisa , Corsaro Maria Michela
Published: June 2019

Lipopolysaccharides (LPSs) are the main components of the external leaflet of the outer membrane of Gram-negative bacteria. Microorganisms that colonize permanently or transiently cold habitats have evolved an array of structural adaptations, some of which involve components of bacterial membranes. These adaptations assure the perfect functionality of the membrane even at freezing or sub-freezing growth temperatures. This review summarizes the state-of-the-art information concerning the structural features of the LPSs produced by cold-adapted bacteria. The LPS structure has recently been elucidated from species mainly belonging to Gammaproteobacteria and Flavobacteriaceae. Although the reported structural heterogeneity may arise from the phylogenetic diversity of the analyzed source strains, some generalized trends can be deduced. For instance, it is clear that only a small portion of LPSs displays the O-chain. In addition, the biological activity of the lipid A portion from several cold-adapted strains is reported.
Hausdorff Dimension of Escaping Sets of Nevanlinna Functions
Authors: Cui Weiwei
Published: June 2019

We determine the exact values of Hausdorff dimensions of escaping sets of meromorphic functions with polynomial Schwarzian derivatives. This will follow from the relation between these functions and the second-order differential equations in the complex plane.
Identifying Five Archetypes of Interaction Design Professionals and Their Universal Design Expertise
Authors: Begnum Miriam Eileen Nes , Pettersen Lene , Sørum Hanne
Published: June 2019

Systems and services based on Information and Communications Technology (ICT) are now prevalent in our daily lives. Digital transformations have been, and are still being, initiated across private and public sectors. As such, the consequences of digital exclusion are severe and may block access to key aspects of modern life, such as education, employment, consumerism and health services. In order to combat this, regions and countries such as the USA, Canada, EU and Scandinavia have all legislated universal design (UD) in relation to ICT, in order to ensure as many citizens as possible have the opportunity to access and use digital information and services. However, there has been limited research into how higher educational programs address legislated accessibility responsibilities. This paper looks into the discipline of interaction design (IxD). IxD is the design domain focused on ‘how human beings relate to other human beings through the mediating influence of products’ (Buchanan, R. (2001) Designing research and the new learning. Des. Issues, 17, 3–23). The study presents an analysis of Norwegian higher educational programs within IxD. Based on document analysis, we map the skillsets the study programs state to deliver and investigate to what degree UD expertise is included. Our findings indicate the study programs do not deliver adequate training in UD, in order to fulfill the professional responsibilities related to ICT accessibility. From our findings, we extrapolate five ‘archetypes’ of interaction designers. These personas-like analytical constructs hold slightly different characteristics. For each of the five, we propose UD expertise fitting key skillsets. We hope our contributions are useful both for the higher education sector and the industry and will contribute to raised awareness of UD skills so they can educate interaction designers in their different industry roles with required competences.

RESEARCH HIGHLIGHTS

We indicate the current content of interaction design (IxD) programs in higher education and document the lacking focus on universal design (UD). We identify five different archetypes of interaction designers being educated in such programs. We describe key skillsets and strengths for each archetype. We propose UD expertise for the (IxD) profession and link UD expertise to archetype skillsets to emphasize relevance.
Risk Factors for Multidrug-Resistant Acinetobacter baumannii Infections in a Mass Burn Casualty Incident
Authors: Yeong Eng-Kean , Huang Wei-Lieh
Published: June 2019

They investigated the risk factors of multidrug-resistant Acinetobacter baumannii infections in 33 burn patients in a mass burn casualty. The independent variables included sex, burn size, vancomycin, ampicillin/sulbactam, cefazolin, meropenem, third-/fourth-generation cephalosporin, the number of classes of antibiotic used, and the number of days of antibiotic use. Multidrug-resistant A. baumannii infection was the outcome variable. Logistic regressions and structural equation model were used for statistical analysis. The average age was 21.7 years (range, 17–32 years; M = 11 [33%], F = 22 [67%]; mean burn area, 42% of the total body surface area; study period, June 28, 2015 to July 31, 2015). The incidence of infection was 39% (n = 13/33). For every percent increase in burn size, the odds of developing A. baumannii infections increased by 1.1 (P < .05). Similarly, the odds increased by 2.5 in every number increase in the classes of antibiotic used, by 1.2 in everyday increase in the days of antibiotic used, and by 12 in patients treated with vancomycin (P < .05). The correlations of these risk factors were demonstrated in a hypothetical structural equation model (P-value of chi-squared test > .05 and root mean square error of approximation < 0.05) in which burn size was the fundamental risk factor of multidrug-resistant A. baumannii infections. The model did not predict the emergence of multidrug-resistant A. baumannii infections. Conclusively, the risks of multidrug-resistant A. baumannii infections in burns are correlated with burn size, the number of classes of antibiotic used, the number of days of antibiotic use, and the prior use of vancomycin.
Postglacial Colonization of Northern Coastal Habitat by Bottlenose Dolphins: A Marine Leading-Edge Expansion?
Authors: Nykänen Milaja , Kaschner Kristin , Dabin Willy , Brownlow Andrew , Davison Nicholas J , Deaville Rob , Garilao Cristina , Kesner-Reyes Kathleen , Gilbert M Thomas P , Penrose Rod , Islas-Villanueva Valentina , Wales Nathan , Ingram Simon N , Rogan Emer , Louis Marie , Foote Andrew D
Published: June 2019

Oscillations in the Earth’s temperature and the subsequent retreating and advancing of ice-sheets around the polar regions are thought to have played an important role in shaping the distribution and genetic structuring of contemporary high-latitude populations. After the Last Glacial Maximum (LGM), retreating of the ice-sheets would have enabled early colonizers to rapidly occupy suitable niches to the exclusion of other conspecifics, thereby reducing genetic diversity at the leading-edge. Bottlenose dolphins (genus Tursiops) form distinct coastal and pelagic ecotypes, with finer-scale genetic structuring observed within each ecotype. We reconstruct the postglacial colonization of the Northeast Atlantic (NEA) by bottlenose dolphins using habitat modeling and phylogenetics. The AquaMaps model hindcasted suitable habitat for the LGM in the Atlantic lower latitude waters and parts of the Mediterranean Sea. The time-calibrated phylogeny, constructed with 86 complete mitochondrial genomes including 30 generated for this study and created using a multispecies coalescent model, suggests that the expansion to the available coastal habitat in the NEA happened via founder events starting ~15 000 years ago (95% highest posterior density interval: 4 900–26 400). The founders of the 2 distinct coastal NEA populations comprised as few as 2 maternal lineages that originated from the pelagic population. The low effective population size and genetic diversity estimated for the shared ancestral coastal population subsequent to divergence from the pelagic source population are consistent with leading-edge expansion. These findings highlight the legacy of the Late Pleistocene glacial cycles on the genetic structuring and diversity of contemporary populations.
Overdiagnosis and Lives Saved by Reflex Testing Men With Intermediate Prostate-Specific Antigen Levels
Authors: Gulati Roman , Morgan Todd M , A'mar Teresa , Psutka Sarah P , Tosoian Jeffrey J , Etzioni Ruth
Published: June 2019

Background

Several prostate cancer (PCa) early-detection biomarkers are available for reflex testing in men with intermediate prostate-specific antigen (PSA) levels. Studies of these biomarkers typically provide information about diagnostic performance but not about overdiagnosis and lives saved, the primary drivers of associated harm and benefit.

Methods

We projected overdiagnoses and lives saved using an established microsimulation model of PCa incidence and mortality with screening and treatment efficacy based on randomized trials. We used this framework to evaluate four urinary reflex biomarkers (measured in 1112 men presenting for prostate biopsy at 10 US academic or community clinics) and two hypothetical ideal biomarkers (with 100% sensitivity or specificity for any or for high-grade PCa) at one-time screening tests at ages 55 and 65 years.

Results

Compared with biopsying all men with elevated PSA, reflex testing reduced overdiagnoses (range across ages and biomarkers = 8.8–60.6%) but also reduced lives saved (by 7.3–64.9%), producing similar overdiagnoses per life saved. The ideal biomarker for high-grade disease improved this ratio (by 35.2% at age 55 years and 42.0% at age 65 years). Results were similar under continued screening for men not diagnosed at age 55 years, but the ideal biomarker for high-grade disease produced smaller incremental improvement.

Conclusions

Modeling is a useful tool for projecting the implications of using reflex biomarkers for long-term PCa outcomes. Under simplified conditions, reflex testing with urinary biomarkers is expected to reduce overdiagnoses but also produce commensurate reductions in lives saved. Reflex testing that accurately identifies high-grade PCa could improve the net benefit of screening.
Hiatal hernia and morbid obesity—‘Roux-en-Y gastric bypass’ the one step solution
Authors: Khan Mohsin , Mukherjee Aloy J
Published: June 2019

Obesity and hiatal hernia go hand in hand as siblings. Morbidly obese patients commonly have gastroesophageal reflux (GERD) and associated hiatal hernias (HH). The gold standard for all symptomatic reflux patients is still surgical correction of the paraesophageal hernia, hiatal closure and fundoplication. Laparoscopic Roux-en-Y gastric bypass (LRYGB) is an effective surgical treatment for morbid obesity and is known to effectively control symptoms of gastroesophageal reflux (GERD). It appears to be safe and feasible and becoming more common. Moreover, LRYGB plus Hiatus hernia repair (HHR) appears to be a good alternative for HH patients suffering from morbid obesity as well than antireflux surgery alone because of the additional benefit of significant weight loss and improvement of obesity related co-morbidity. One patient suffering from giant hiatal hernia and morbid obesity where a combined LRYGB and HHR without mesh was performed is presented in this paper.
Linear analysis of the non-axisymmetric secular gravitational instability
Authors: Shadmehri Mohsen , Oudi Razieh , Rastegarzadeh Gohar
Published: June 2019

In protoplanetary discs (PPDs) consisting of gas and dust particles, fluid instabilities induced by the drag force, including secular gravitational instability (SGI), can facilitate planet formation. Although SGI subject to the axisymmetric perturbations was originally studied in the absence of gas feedback and it then generalized using a two-fluid approach, the fate of the non-axisymmetric SGI, in either case, is an unexplored problem. We present a linear perturbation analysis of the non-axisymmetric SGI in a PPD by implementing a two-fluid model. We explore the growth of the local, non-axisymmetric perturbations using a set of linearized perturbation equations in a sheared frame. The non-axisymmetric perturbations display a significant growth during a finite time interval even when the system is stable against the axisymmetric perturbations. Furthermore, the surface density perturbations do not show the continuous growth but are temporally amplified. We also study cases where the dust component undergoes amplification whereas the gas component remains stable. The amplitude amplification, however, strongly depends on the model parameters. In the minimum mass solar nebula (MMSN), for instance, the dust fluid amplification at the radial distance 100 au occurs when the Stokes number is about unity. But the amplification factor reduces as the dust and gas coupling becomes weaker. Furthermore, perturbations with a larger azimuthal wavelength exhibit a larger amplification factor.
The Magellanic System: the puzzle of the leading gas stream
Authors: Tepper-García Thor , Bland-Hawthorn Joss , Pawlowski Marcel S , Fritz Tobias K
Published: June 2019

The Magellanic Clouds (MCs) are the most massive gas-bearing systems falling into the Galaxy at the present epoch. They show clear signs of interaction, manifested in particular by the Magellanic Stream, a spectacular gaseous wake that trails from the MCs extending more than 150° across the sky. Ahead of the MCs is the ‘Leading Arm’ usually interpreted as the tidal counterpart of the Magellanic Stream, an assumption we now call into question. We revisit the formation of these gaseous structures in a first-infall scenario, including for the first time a Galactic model with a weakly magnetized, spinning hot corona. In agreement with previous studies, we recover the location and the extension of the Stream on the sky. In contrast, we find that the formation of the Leading Arm – that is otherwise present in models without a corona – is inhibited by the hydrodynamic interaction with the hot component. These results hold with or without coronal rotation or a weak, ambient magnetic field. Since the existence of the hot corona is well established, we are led to two possible interpretations: (i) the Leading Arm survives because the coronal density beyond 20 kpc is a factor ≳10 lower than required by conventional spheroidal coronal X-ray models, in line with recent claims of rapid coronal rotation; or (ii) the ‘Leading Arm’ is cool gas trailing from a frontrunner, a satellite moving ahead of the MCs, consistent with its higher metallicity compared to the trailing stream. Both scenarios raise issues that we discuss.
The escape fraction of ionizing photons during the Epoch of Reionization: observability with the Square Kilometre Array
Authors: Seiler Jacob , Hutter Anne , Sinha Manodeep , Croton Darren
Published: June 2019

One of the most important parameters in characterizing the Epoch of Reionization, the escape fraction of ionizing photons, fesc, remains unconstrained both observationally and theoretically. With recent work highlighting the impact of galaxy-scale feedback on the instantaneous value of fesc, it is important to develop a model in which reionization is self-consistently coupled to galaxy evolution. In this work, we present such a model and explore how physically motivated functional forms of fesc affect the evolution of ionized hydrogen within the intergalactic medium. Using the 21 cm power spectrum evolution, we investigate the likelihood of observationally distinguishing between a constant fesc and other models that depend upon different forms of galaxy feedback. We find that changing the underlying connection between fesc and galaxy feedback drastically alters the large-scale 21 cm power. The upcoming Square Kilometre Array Low Frequency instrument possesses the sensitivity to differentiate between our models at a fixed optical depth, requiring only 200 h of integration time focused on redshifts z = 7.5–8.5. Generalizing these results to account for a varying optical depth will require multiple 800 h observations spanning redshifts z = 7–10. This presents an exciting opportunity to observationally constrain one of the most elusive parameters during the Epoch of Reionization.
Structural basis of specific DNA binding by the transcription factor ZBTB24
Authors: Ren Ren , Hardikar Swanand , Horton John R , Lu Yue , Zeng Yang , Singh Anup K , Lin Kevin , Coletta Luis Della , Shen Jianjun , Lin Kong Celine Shuet , Hashimoto Hideharu , Zhang Xing , Chen Taiping , Cheng Xiaodong
Published: June 2019

ZBTB24, encoding a protein of the ZBTB family of transcriptional regulators, is one of four known genes—the other three being DNMT3B, CDCA7 and HELLS—that are mutated in immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome, a genetic disorder characterized by DNA hypomethylation and antibody deficiency. The molecular mechanisms by which ZBTB24 regulates gene expression and the biological functions of ZBTB24 are poorly understood. Here, we identified a 12-bp consensus sequence [CT(G/T)CCAGGACCT] occupied by ZBTB24 in the mouse genome. The sequence is present at multiple loci, including the Cdca7 promoter region, and ZBTB24 binding is mostly associated with gene activation. Crystallography and DNA-binding data revealed that the last four of the eight zinc fingers (ZFs) (i.e. ZF5-8) in ZBTB24 confer specificity of DNA binding. Two ICF missense mutations have been identified in the ZBTB24 ZF domain, which alter zinc-binding cysteine residues. We demonstrated that the corresponding C382Y and C407G mutations in mouse ZBTB24 abolish specific DNA binding and fail to induce Cdca7 expression. Our analyses indicate and suggest a structural basis for the sequence specific recognition by a transcription factor centrally important for the pathogenesis of ICF syndrome.
Anticipated Effects of Nicotine Reduction on Youth Smoking Initiation and Maintenance
Authors: Colby Suzanne M , Cassidy Rachel N , Denlinger-Apte Rachel , Smith Tracy T , Pacek Lauren R , McClernon F Joseph , Tidey Jennifer W
Published: June 2019

This commentary summarizes emerging findings on the potential impact of a nicotine reduction policy on youth and young adults. We conclude that: (1) adolescent smokers and nonsmokers alike are likely to be less sensitive to reinforcement from very low nicotine content (VLNC) cigarettes compared with adults; (2) reducing nicotine in cigarettes to 0.4 mg/g would reduce the abuse potential of cigarettes in adolescents and young adults; (3) findings to date do not support concerns that nicotine reduction leads to compensatory smoking in young smokers; and (4) if the scope of a reduced nicotine product standard were applied to all combusted tobacco products, that would likely maximize public health benefit of this policy.
Temporal and spectral X-ray properties of magnetar SGR 1900+14 derived from observations with NuSTAR and XMM-Newton
Authors: Tamba Tsubasa , Bamba Aya , Odaka Hirokazu , Enoto Teruaki
Published: June 2019

X-ray observations play a crucial role in understanding the emission mechanism and relevant physical phenomena of magnetars. We report on X-ray observations made in 2016 of a young magnetar, SGR 1900+14, which is famous for a giant flare in 1998 August. Simultaneous observations were conducted with XMM-Newton and NuSTAR on 2016 October 20 with 23 and 123 ks exposures, respectively. The NuSTAR hard X-ray coverage enabled us to detect the source up to 70 keV. The 1–10 keV and 15–60 keV fluxes were $3.11(3)\times 10^{-12} \, {\rm erg \, s^{-1} \, cm^{-2}}$ and $6.8(3)\times 10^{-12} \, {\rm erg \, s^{-1} \, cm^{-2}}$, respectively. The 1–70 keV spectra were fitted well by a blackbody plus power-law model with a surface temperature of $kT=0.52(2) \, {\rm keV}$, a photon index of the hard power-law of Γ = 1.21(6), and a column density of $N_{\,\rm H}=1.96(11)\times 10^{22} \, {\rm cm^{-2}}$. Compared with previous observations with Suzaku in 2006 and 2009, the 1–10 keV flux showed a decrease by 25%–40%, while the spectral shape did not show any significant change with differences of kT and NH being within 10% of each other. Through timing analysis, we found that the rotation period of SGR 1900+14 on 2016 October 20 was $5.22669(3) \, {\rm s}$. The long-term evolution of the rotation period shows a monotonic decrease in the spin-down rate $\dot{P}$ lasting for more than 15 yr. We also found characteristic behavior of the hard-tail power-law component of SGR 1900+14. The energy-dependent pulse profiles vary in morphology with a boundary of 10 keV. The phase-resolved spectra show the differences between photon indices (Γ = 1.02–1.44) as a function of the pulse phase. Furthermore, the photon index is positively correlated with the X-ray flux of the hard power-law component, which could not be resolved by the previous hard X-ray observations.
Hydroxychloroquine was associated with reduced risk of new-onset diabetes mellitus in patients with Sjögren syndrome
Authors: Chen T -H , Lai T -Y , Wang Y -H , Chiou J -Y , Hung Y -M , Wei J C -C
Published: June 2019

Objectives

To determine whether taking hydroxychloroquine (HCQ) could prevent the development of new-onset diabetes mellitus (DM) among patients with Sjögren syndrome (SS).

Methods

This is a nationwide, population-based, retrospective cohort study utilizing the Taiwan National Health Insurance Research Database (NHIRD). Data were collected from 1 January 1999, through 31 December 2013, using the International Classification of Diseases, Ninth Revision, Clinical Modification codes. In total, 7774 patients newly diagnosed with SS by at least three outpatient visits or one inpatient admission were selected from the NHIRD as participants. Patients who had previously been diagnosed with DM and whose follow-up durations shorter than 90 days were excluded. HCQ exposure group includes patients who had been diagnosed with SS no longer than 180 days previously, and had been prescribed HCQ for the first time for at least 90 days. The diagnosis of DM was defined as at least two outpatient visits or one inpatient admission with anti-diabetic medication prescription.

Results

Patients with SS treated with HCQ had a significantly lower cumulative incidence of new-onset DM than those not treated with HCQ (adjusted hazard ratio: 0.51, 95% confidence interval: 0.28–0.96, P < 0.05). HCQ use for 3 years or more had favorable protective effects (adjusted hazard ratio: 0.22, CI: 0.05–0.92).

Conclusions

HCQ reduced the incidence of DM in a time and dose-dependent manner. Patients with SS who had taken HCQ for 3 years or more exhibited significant protective effects against developing new-onset DM.
Genotyping-by-Sequencing Reveals Fine-Scale Differentiation in Populations of Pseudoperonospora humuli
Authors: Gent David H. , Adair Nanci , Knaus Brian J. , Grünwald Niklaus J.
Published: June 2019

Pseudoperonospora humuli is the causal agent of downy mildew of hop, one of the most important diseases of this plant and a limiting factor for production of susceptible cultivars in certain environments. The degree of genetic diversity and population differentiation within and among P. humuli populations at multiple spatial scales was quantified using genotyping-by-sequencing to test the hypothesis that populations of P. humuli have limited genetic diversity but are differentiated at the scale of individual hop yards. Hierarchical sampling was conducted to collect isolates from three hop yards in Oregon, plants within these yards, and infected shoots within heavily diseased plants. Additional isolates also were collected broadly from other geographic regions and from the two previously described clades of the sister species, P. cubensis. Genotyping of these 240 isolates produced a final quality-filtered data set of 216 isolates possessing 25,227 variants. Plots of G’ST values indicated that the majority of variants had G’ST values near 0 and were scattered randomly across contig positions. However, there was a subset of variants that were highly differentiated (G’ST > 0.3) and reproducible when genotyped independently. Within P. humuli, there was evidence of genetic differentiation at the level of hop yards and plants within yards; 19.8% of the genetic variance was associated with differences among yards and 20.3% of the variance was associated with plants within the yard. Isolates of P. humuli were well differentiated from two isolates of P. cubensis representative of the two clades of this organism. There was strong evidence of linkage disequilibrium in variant loci, consistent with nonrandom assortment of alleles expected from inbreeding and/or asexual recombination. Mantel tests found evidence that the genetic distance between isolates collected from heavily diseased plants within a hop yard was associated with the physical distance of the plants from which the isolates were collected. The sum of the data presented here indicates that populations of P. humuli are consistent with a clonal or highly inbred genetic structure with a small, yet significant differentiation of populations among yards and plants within yards. Fine-scale genetic differentiation at the yard and plant scales may point to persistence of founder genotypes associated with planting material, and chronic, systemic infection of hop plants by P. humuli. More broadly, genotyping-by-sequencing appears to have sufficient resolution to identify rare variants that differentiate subpopulations within organisms with limited genetic variability.
Sandaracinomonas limnophila gen. nov., sp. nov., a new member of the family Cytophagaceae isolated from a freshwater mesocosm
Authors: Chen Wen-Ming , Cai Cheng-Ye , Sheu Shih-Yi
Published: June 2019

A bacterial strain designated FSY-15T was isolated from a freshwater mesocosm in Taiwan and characterised using a polyphasic taxonomic approach. Cells of strain FSY-15T were Gram-negative, aerobic, non-spore forming, non-motile rods and formed orange coloured colonies. Growth occurred at 20–30 °C (optimum, 25 °C), at pH 6–7.5 (optimum, pH 7) and with 0–0.5 % NaCl (optimum, 0 %). Phylogenetic analyses based on 16S rRNA gene sequences and coding sequences of 92 protein clusters indicated that strain FSY-15T formed a phylogenetic lineage in the the family

Cytophagaceae

. Strain FSY-15T was most closely related to the genera

Pseudarcicella

and Arcicella, and the levels of 16S rRNA gene sequence identity with respect to members of related genera are less than 94.1 %. Strain FSY-15T showed less than 68.8 % average nucleotide identity and less than 24.7 % digital DNA–DNA hybridisation identity compared to the type strains of related genera within the family

Cytophagaceae

. The predominant fatty acids were iso-C15 : 0, C16 : 1ω5c and the major hydroxyl fatty acid was iso-C15 : 0 3-OH. The major isoprenoid quinone was MK-7 and the DNA G+C content was 35.8 mol%. The major polar lipids were phosphatidylethanolamine and several uncharacterised aminophospholipid, aminolipid, phospholipid and lipid. The major polyamine was spermidine. On the basis of the genotypic and phenotypic data, strain FSY-15T represents a novel species of a new genus in the family

Cytophagaceae

, for which the name Sandaracinomonas limnophila gen. nov., sp. nov. is proposed. The type strain is FSY-15T (=BCRC 81011T =LMG 29732T =KCTC 52445T).
Early Stem Cell Aging in the Mature Brain
Authors: Ibrayeva Albina , Bay Maxwell , Pu Elbert , Jörg David , Peng Lei , Jun Heechul , Zhang Naibo , Aaron Daniel , Lin Congrui , Resler Galen , Hidalgo Axel , Jang Mi-Hyeon , Simons Benjamin D. , Bonaguidi Michael A.
Published: June 2019

Stem cell dysfunction drives many age-related disorders. Identifying mechanisms that initially compromise stem cell function represent early targets to enhance stem cell behavior later in life. Here, we pinpoint multiple factors that disrupt neural stem cells (NSC) in the adult hippocampus. We find that NSCs exhibit asynchronous maintenance by identifying short-term (ST-NSC) and intermediate-term NSCs (IT-NSCs). ST-NSC divide rapidly to generate neurons and deplete in the young brain. Meanwhile, multipotent IT-NSCs persist for months, but are pushed out of homeostasis by lengthening quiescence. Single cell transcriptome analysis of deep NSC quiescence revealed several hallmarks of biological aging in the mature brain and identified tyrosine-protein kinase Abl1 as an NSC pro-aging factor. Treatment with the Abl-inhibitor Imatinib increased NSC proliferation without impairing NSC maintenance in the middle-aged brain. Further intersectional analysis of mature NSC with old epidermal, hematopoietic and muscle stem cell transcriptomes identified consensus changes in stem cell aging. Our study elucidates multiple origins of adult neurogenesis decline and reveals that hippocampal NSCs are particularly vulnerable to a shared stem cell aging signature.
Microbial Nitrogen Metabolism in Chloraminated Drinking Water Reservoirs
Authors: Potgieter Sarah C , Dai Zihan , Venter Stefanus N , Sigudu Makhosazana , Pinto Ameet J
Published: June 2019

Nitrification is a common concern in chloraminated drinking water distribution systems. The addition of ammonia promotes the growth of nitrifying organisms, causing the depletion of chloramine residuals and resulting in operational problems for many drinking water utilities. Therefore, a comprehensive understanding of the microbially mediated processes behind nitrogen metabolism together with chemical water quality data, may allow water utilities to better address the undesirable effects caused by nitrification. In this study, a metagenomic approach was applied to characterise the microbial nitrogen metabolism within chloraminated drinking water reservoirs. Samples from two geographically separated but connected chloraminated reservoirs within the same drinking water distribution system (DWDS) were collected within a 2-year sampling campaign. Spatial changes in the nitrogen compounds (ammonium (NH4+), nitrites (NO2−) and nitrates (NO3−)) across the DWDS were observed, where nitrate concentrations increased as the distance from the site of chloramination increased. The observed dominance ofNitrosomonasandNitrospira-like bacteria, together with the changes in the concentration of nitrogen species, suggests that these bacteria play a significant role in contributing to varying stages of nitrification in both reservoirs. Functionally annotated protein sequences were mined for the genes associated with nitrogen metabolism and the community gene catalogue contained mostly genes involved in nitrification, nitrate and nitrite reduction and nitric oxide reduction. Furthermore, based on the construction of Metagenome Assembled Genomes (MAGs), a highly diverse assemblage of bacteria (i.e., predominatelyAlpha- andBetaproteobacteriain this study) was observed among the draft genomes. Specifically, 5 MAGs showed high coverage across all samples including twoNitrosomonas, Nitrospira, Sphingomonasand aRhizobiales-like MAGs. The role of these MAGs in nitrogen metabolism revealed that the fate nitrate may be linked to changes in ammonia concentrations, that is, when ammonia concentrations are low, nitrate may be assimilated back to ammonia for growth. Alternatively, nitrate may be reduced to nitric oxide and potentially used in the regulation of biofilm formation. Therefore, this study provides insight into the genetic network behind microbially mediated nitrogen metabolism and together with the water chemistry data improves our understanding nitrification in chloraminated DWDSs.
Nationwide prediction of type 2 diabetes comorbidities
Authors: Dworzynski Piotr , Aasbrenn Martin , Rostgaard Klaus , Melbye Mads , Gerds Thomas Alexander , Hjalgrim Henrik , Pers Tune H
Published: June 2019

Identification of individuals at risk of developing disease comorbidities represents an important task in tackling the growing personal and societal burdens associated with chronic diseases. We employed machine learning techniques to investigate to what extent data from longitudinal, nationwide Danish health registers can be used to predict individuals at high risk of developing type 2 diabetes (T2D) comorbidities. Based on register data spanning hospitalizations, drug prescriptions and contacts with primary care contractors from >200,000 individuals newly diagnosed with T2D, we used logistic regression-, random forest- and gradient boosting models to predict five-year risk of heart failure (HF), myocardial infarction (MI), stroke (ST), cardiovascular disease (CVD) and chronic kidney disease (CKD). For HF, MI, CVD, and CKD, register-based models outperformed a reference model leveraging canonical individual characteristics by achieving area under the receiver operating characteristic curve improvements of 0.06, 0.03, 0.06, and 0.07, respectively. The top 1,000 patients predicted to be at highest risk exhibited observed incidence ratios exceeding 4.99, 3.52, 2.92 and 4.71 respectively. In summary, prediction of T2D comorbidities utilizing Danish registers led to consistent albeit modest performance improvements over reference models, suggesting that register data could be leveraged to systematically identify individuals at risk of developing disease comorbidities.
Two distinct feedback codes in V1 for ‘real’ and ‘imaginary’ internal experiences
Authors: Bergmann Johanna , Morgan Andrew T. , Muckli Lars
Published: June 2019

Visual illusions and visual imagery are conscious sensory events that lack a corresponding physical input. But while everyday mental imagery feels distinct from incoming stimulus input, visual illusions, like hallucinations, are under limited volitional control and appear indistinguishable from physical reality. Illusions are thought to arise from lower-level processes within sensory cortices. In contrast, imagery involves a wide network of brain areas that recruit early visual cortices for the sensory representation of the imagined stimulus. Here, we combine laminar fMRI brain imaging with psychophysical methods and multivariate pattern analysis to investigate in human participants how seemingly ‘real’ and imaginary non-physical experiences are processed in primary visual cortex (V1). We find that the content of mental imagery is only decodable in deep layers, whereas illusory content is only decodable at superficial depths. This suggests that feedback to the different layers may serve distinct functions: low-level feedback to superficial layers might be responsible for shaping perception-like experiences, while deep-layer feedback might serve the formation of a more malleable ‘inner’ world, separate from ongoing perception.
Deamidation disrupts native and transient contacts to weaken the interaction between UBC13 and RING-finger E3 ligases
Authors: Mohanty Priyesh , Rashmi  , Habibullah Batul Ismail , G S Arun , Das Ranabir
Published: June 2019

The deamidase OspI from enteric bacteriaShigella flexnerideamidates a glutamine residue in the host ubiquitin-conjugating enzyme UBC13 and converts it to glutamate (Q100E). Consequently, its polyubiquitination activity in complex with the RING-finger ubiquitin ligase TRAF6 and the downstream NF-κB inflammatory response is inactivated. The precise role of deamidation in inactivating the UBC13/TRAF6 complex is unknown. We report that deamidation inhibits the interaction between UBC13 and TRAF6 RING-domain (TRAF6RING) by perturbing both the native and transient interactions. Deamidation creates a new intramolecular salt-bridge in UBC13 that competes with a critical intermolecular salt-bridge at the native UBC13/TRAF6RINGinterface. Moreover, the salt-bridge competition prevents transient interactions necessary to form a typical UBC13/RING complex. Repulsion between E100 and the negatively charged surface of RING also prevents transient interactions in the UBC13/RING complex. Our findings highlight a mechanism where a post-translational modification perturbs the conformation and stability of transient complexes to inhibit protein-protein association.