bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonlinear optimal control of bypass transition in a boundary layer flow
Authors: Xiao Dandan , Papadakis George
Published: May 2017

The central aim of the paper is to apply and assess a nonlinear optimal control strategy to suppress bypass transition, due to bimodal interactions [T. A. Zaki and P. A. Durbin, “Mode interaction and the bypass route to transition,” J. Fluid Mech. 531, 85 (2005)] in a zero-pressure-gradient boundary layer. To this end, a Lagrange variational formulation is employed that results in a set of adjoint equations. The optimal wall actuation (blowing and suction from a control slot) is found by solving iteratively the nonlinear Navier-Stokes and the adjoint equations in a forward/backward loop using direct numerical simulation. The optimization is performed in a finite time horizon. Large values of optimization horizon result in the instability of the adjoint equations. The control slot is located exactly in the region of transition. The results show that the control is able to significantly reduce the objective function, which is defined as the spatial and temporal integral of the quadratic deviation from the Blasius profile plus a term that quantifies the control cost. The physical mechanism with which the actuation interacts with the flow field is investigated and analysed in relation to the objective function employed. Examination of the joint probability density function shows that the control velocity is correlated with the streamwise velocity in the near wall region but this correlation is reduced as time elapses. The spanwise averaged velocity is distorted by the control action, resulting in a significant reduction of the skin friction coefficient. Results are presented with and without zero-net mass flow constraint of the actuation velocity. The skin friction coefficient drops below the laminar value if there is no mass constraint; it remains however larger than laminar when this constraint is imposed. Results are also compared with uniform blowing using the same time-average velocity obtained from the nonlinear optimal algorithm.
14N NQR lineshape in nanocrystals: An ab initio investigation of urea
Authors: Gregorovič Alan
Published: May 2017

14N nuclear quadrupole resonance (NQR) lineshapes mostly contain information of low interest, although in nanocrystals they may display some unexpected behaviour. In this work, we present an ab initio computational study of the 14N NQR lineshapes in urea nanocrystals as a function of the nanocrystal size and geometry, focusing on the surface induced broadening of the lineshapes. The lineshapes were obtained through a calculation of the electric field gradient for each nitrogen site in the nanocrystal separately, taking into account the individual crystal field by embedding the molecule of interest in a suitable lattice of point multipoles representing other urea molecules in the nanocrystal. The small influence of distant molecules is found with a series expansion, using the in-crystal Sternheimer shieldings which we also calculated ab initio. We have considered nanocrystals with two geometries: a sphere and a cube, with characteristic sizes between 5 and 100 nm. Our calculations suggest that there is a dramatic difference between the linewidths for the two geometries. For spheres, we find a steep drop in linewidths at ∼10 nm; at 5 nm the linewidth is ∼11 kHz, whereas for sizes above 20 nm the linewidth is practically negligible (<100 Hz). For cubes, on the other hand, we find a steady 1/size decrease, from 12 kHz at 10 nm to 1.2 kHz at 100 nm. This analysis is important for 14N NQR spectroscopy of crystalline pharmaceuticals, where nanoparticles are increasingly more often embedded in some sort of matrix. Although this is only a theoretical analysis, we believe that this work can serve as a guidance for the forthcoming experimental analysis.
Ising computation based combinatorial optimization using spin-Hall effect (SHE) induced stochastic magnetization reversal
Authors: Shim Yong , Jaiswal Akhilesh , Roy Kaushik
Published: May 2017

Ising spin model is considered as an efficient computing method to solve combinatorial optimization problems based on its natural tendency of convergence towards low energy state. The underlying basic functions facilitating the Ising model can be categorized into two parts, “Annealing and Majority vote.” In this paper, we propose an Ising cell based on Spin Hall Effect (SHE) induced magnetization switching in a Magnetic Tunnel Junction (MTJ). The stochasticity of our proposed Ising cell based on SHE induced MTJ switching can implement the natural annealing process by preventing the system from being stuck in solutions with local minima. Further, by controlling the current through the Heavy-Metal (HM) underlying the MTJ, we can mimic the majority vote function which determines the next state of the individual spins. By solving coupled Landau-Lifshitz-Gilbert equations, we demonstrate that our Ising cell can be replicated to map certain combinatorial problems. We present results for two representative problems—Maximum-cut and Graph coloring—to illustrate the feasibility of the proposed device-circuit configuration in solving combinatorial problems. Our proposed solution using a HM based MTJ device can be exploited to implement compact, fast, and energy efficient Ising spin model.
Effects of aspect ratio on the mode couplings of thin-film bulk acoustic wave resonators
Authors: Li Nian , Qian Zhenghua , Yang Jiashi
Published: May 2017

We studied mode couplings in thin film bulk acoustic wave resonators of a piezoelectric film on a dielectric layer operating with the fundamental thickness-extensional mode. A system of plate equations derived in our previous paper was used which includes the couplings to the unwanted in-plane extension, flexure, fundamental and second-order thickness shear modes. It was shown that the couplings depend strongly on the plate length/thickness ratio. For a relatively clean operating mode with weak couplings to unwanted modes, a series of discrete values of the plate length/thickness ratio should be avoided and these values were determined in the present paper. The results can be of great significance to the design and optimization of film bulk acoustic wave resonators.
Prevalence of porA pseudogene deletion among Neisseria gonorrhoeae isolates referred to the UK’s Gonococcal Resistance to Antimicrobials Surveillance Program
Authors: Toby Martina , Saunders Pamela , Cole Michelle , Grigorjev Vlad , Alexander Sarah , Ison Catherine
Published: May 2017

porA pseudogene-negative Neisseria gonorrhoeae isolates produce false-negative results when examined by polymerase chain reaction (PCR) with porA pseudogene targets. In the present study, 533 representative gonococcal isolates received in 2011 via the Gonococcal Resistance to Antimicrobials Surveillance Program were examined to determine the prevalence of porA-negative isolates. Less than 0.4% (2/533) of isolates were found to be reproducibly negative with the porA real-time PCR but were confirmed as N. gonorrhoeae with molecular, biochemical and immunological confirmatory tests. Sequencing revealed both isolates contained the Neisseria meningitidis porA gene. Low prevalence indicates that although these isolates do not present a major public health problem, microbiologists should remain vigilant.
Tobacco smoking and sexual difficulties among Australian adults: a cross-sectional study
Authors: Wen Li Ming , Rissel Chris , Cheng Yan , Richters Juliet , de Visser Richard O.
Published: May 2017

Background
Few studies have examined smoking and female sexual difficulties. The aim of this study was to investigate the association between current tobacco smoking and sexual difficulties in Australian men and women. Methods: Data for this study came from the Second Australian Study of Health and Relationships (2012–13), which includes a representative sample of 18 427 sexually active Australian adults (aged 16–69 years). The main study and outcome measures were tobacco smoking and sexual difficulties. A multiple logistic regression analysis was conducted to adjust for potential confounders. Results: Male heavy smokers (>20 cigarettes per day) were significantly more likely than non-smokers to have trouble keeping an erection [adjusted odds ratio (AOR) 4.14, 95% confidence interval (CI) 1.87–9.20; P < 0.0001], lack interest in having sex (AOR 2.18, 95% CI 1.20–3.97; P = 0.011), have anxiety about performance (AOR 2.46, 95% CI 1.24–4.86; P = 0.010) and be unable to come to orgasm (AOR = 2.81, 95% CI 1.23–6.42; P = 0.015). Female smokers were also significantly more likely than non-smokers to not find sex pleasurable (AOR 1.48, 95% CI 1.05–2.07; P = 0.025); and light female smokers were significantly more likely than non-smokers to be unable to come to orgasm (AOR = 1.44, 95% CI 1.05–1.98; P = 0.025). Conclusions: Current tobacco smoking was associated with sexual difficulties in both men and women. For women, even light smoking was associated with not finding sex pleasurable and being unable to come to orgasm.
Histone chaperone HIRA regulates neural progenitor cell proliferation and neurogenesis via β-catenin
Authors: Li Yanxin , Jiao Jianwei
Published: May 2017

Histone cell cycle regulator (HIRA) is a histone chaperone and has been identified as an epigenetic regulator. Subsequent studies have provided evidence that HIRA plays key roles in embryonic development, but its function during early neurogenesis remains unknown. Here, we demonstrate that HIRA is enriched in neural progenitor cells, and HIRA knockdown reduces neural progenitor cell proliferation, increases terminal mitosis and cell cycle exit, and ultimately results in premature neuronal differentiation. Additionally, we demonstrate that HIRA enhances β-catenin expression by recruiting H3K4 trimethyltransferase Setd1A, which increases H3K4me3 levels and heightens the promoter activity of β-catenin. Significantly, overexpression of HIRA, HIRA N-terminal domain, or β-catenin can override neurogenesis abnormities caused by HIRA defects. Collectively, these data implicate that HIRA, cooperating with Setd1A, modulates β-catenin expression and then regulates neurogenesis. This finding represents a novel epigenetic mechanism underlying the histone code and has profound and lasting implications for diseases and neurobiology.
Invariant holomorphic discs in some non-convex domains
Authors: Bertrand Florian , Gaussier Hervé
Published: May 2017

We give a description of complex geodesics and we study the structure of stationary discs in some non-convex domains for which complex geodesics are not unique.
Identifying reports of randomized controlled trials (RCTs) via a hybrid machine learning and crowdsourcing approach
Authors: Wallace Byron C , Noel-Storr Anna , Marshall Iain J , Cohen Aaron M , Smalheiser Neil R , Thomas James
Published: May 2017

Objectives

Identifying all published reports of randomized controlled trials (RCTs) is an important aim, but it requires extensive manual effort to separate RCTs from non-RCTs, even using current machine learning (ML) approaches. We aimed to make this process more efficient via a hybrid approach using both crowdsourcing and ML.

Methods

We trained a classifier to discriminate between citations that describe RCTs and those that do not. We then adopted a simple strategy of automatically excluding citations deemed very unlikely to be RCTs by the classifier and deferring to crowdworkers otherwise.

Results

Combining ML and crowdsourcing provides a highly sensitive RCT identification strategy (our estimates suggest 95%–99% recall) with substantially less effort (we observed a reduction of around 60%–80%) than relying on manual screening alone.

Conclusions

Hybrid crowd-ML strategies warrant further exploration for biomedical curation/annotation tasks.
A Review of Clinical Influenza A and B Infections With Reduced Susceptibility to Both Oseltamivir and Zanamivir
Authors: Abed Yacine , Boivin Guy
Published: May 2017

Anti-influenza drugs play major roles in the management of severe influenza infections. Neuraminidase inhibitors (NAIs), which are active against all influenza A subtypes and the 2 major influenza B lineages, constitute the only class of antivirals recommended for the control of influenza epidemics and eventual pandemics. Thus, the emergence of NAI resistance could be a major clinical concern. Although most currently circulating influenza A and B strains are susceptible to NAIs, clinical cases of influenza viruses harboring single or multiple NA substitutions or deletions conferring a cross-resistance phenotype to the 2 main NAIs (oseltamivir and zanamivir) have been reported, mostly in immunocompromised individuals. Moreover, such events seem to be more frequent in A(H1N1)pdm09 viruses containing the H274Y substitution together with other NA changes (I222R, E119D/G). This review summarizes the therapeutic regimens leading to the emergence of NAI cross-resistant influenza A and B viruses as well as the virologic properties of such variants.
Exposure of the External Carotid Artery Through the Posterior Triangle of the Neck: A Novel Approach to Facilitate Bypass Procedures to the Posterior Cerebral Circulation
Authors: Meybodi Ali Tayebi , Lawton Michael T. , Mokhtari Pooneh , Kola Olivia , El-Sayed Ivan H. , Benet Arnau
Published: May 2017

BACKGROUND: The external carotid artery (ECA) is the main high-flow donor for extracranial–intracranial revascularization procedures. However, anatomic restraints limit the availability of ECA in posterior exposures of the craniocervical junction aimed for bypass to distal vertebral artery segments.

OBJECTIVE: To examine the feasibility and safety of exposure of the ECA through the posterior triangle of the neck.

METHODS: A preliminary feasibility study on the posterior neck exposure of the ECA was performed in 1 cadaveric head (2 sides) followed by a morphometric study on 9 cadaveric heads (18 sides). Through an extension of the muscular stage of the far-lateral approach, the fascial plane between the posterior belly of the digastric muscle and the capsule of the parotid gland was dissected inferior to the C1. Topographic anatomy of the exposed distal segment of the ECA was defined in detail, including bony landmarks and the facial nerve.

RESULTS: ECA was found successfully using the proposed technique in all specimens. In 90% of the specimens, ECA was exposed without transgression of the capsule of the parotid gland. The facial nerve was not encountered during the surgical exposures.

CONCLUSION: ECA can be safely and effectively exposed through the posterior triangle of the neck using the proposed approach. This method can facilitate extracranial–intracranial bypass procedures to V3/V4 vertebral artery. Advantages of this novel approach are shortening the graft length and surgical timing, less invasiveness, and optimizing surgical trajectories for completion of both donor and recipient bypass anastomosis.
Does Negative-Pressure Wound Therapy for the Open Abdomen Benefit the Patient? A Retrospective Cohort Study
Authors: Krebs Bojan , Jagrič Tomaž
Published: May 2017

OBJECTIVE:

Negative-pressure wound therapy (NPWT) is the most modern and sophisticated method of temporary abdominal closure. The aim of the study was to determine the significant predictors for mortality in patients with NPWT.

SETTING:

University Clinical Centre Maribor, Slovenia

MATERIALS AND METHODS:

The authors performed a retrospective cohort study of all patients treated with NPWT between January 1, 2011, and December 31, 2014.

RESULTS:

In the univariate analysis, the type of wound closure, more than 7 NPWT changes, the total days with NPWT, and time to wound closure were significantly associated with death of the patient. In the multivariate analysis, only the number of more than 7 NPWT changes was found as a significant predictor for death (P = .038).

CONCLUSIONS:

Negative-pressure wound therapy is a method of choice for the treatment of open abdomen if there is a clear indication. However, clinicians should try all measures to remove the NPWT system and close the abdomen as soon as possible because prolonged use is associated with significantly higher mortality.
Subcrestal Iliac-Screw
Authors: Liu Gabriel , Hasan Muhammed Y. , Wong Hee-Kit
Published: May 2017

Study Design.

Case-series.

Objective.

To report our modified iliac-screw insertion technique and its clinical outcomes.

Summary of Background Data.

Iliac-screws are one of the preferred methods for modern spinopelvic-fixation. However, the technique is not without complications, predominantly because of iliac-screw head prominence, leading to pain and revisions. Conventional iliac-screw entry point is sited superficially at the posterior-superior-iliac-spine (PSIS) contributing to screw-head prominence. We propose a more low-profile, subcrestal entry point that is more medial and inferior to the PSIS at the medial wall of the iliac crest, lying underneath the crest but above the sacroiliac joint. This position keeps the screw-head low profile and in-line with proximal instrumentation to ease rod engagement.

Methods.

Ten consecutive patients who underwent spinal deformity correction surgery using the modified iliac-screw entry point fixations were enrolled. Clinical, radiological, and surgical parameters were reviewed.

Results.

Five males and five females with average age of 66 years and average follow up of 29 months were reviewed. Mean preoperative Cobb angle and C7-SVA were 32.1° and 10.3 cm, respectively. Surgical indication was progressive deformity and neurogenic claudication in eight cases and fracture in two cases. Twenty noncannulated, polyaxial iliac-screws with median dimension of 7.5 x 75 mm were inserted free hand. Bilateral S1 screws were used in all except two cases. Only five out of 16 iliac-screws with concomitant S1 screws needed side-connectors. At the last follow up only one iliac-screw head was felt to be prominent but without pain in a Parkinson's patient. None of the 10 patients had cases of revision, breakages, or sacroiliac pain.

Conclusion.

Subcrestal iliac-screw insertion is feasible, safe, and has the potential to reduce screw-head complications and avoid the use of side-connectors, lowering construct complexity and cost. The technique has the advantage of both the low-profile S2 alar iliac screw and the ease of free-hand insertion of the traditional iliac-screw.

Level of Evidence: 4
Anatomic Fixation of Posterior Malleolus Fractures as an Alternative to Transsyndesmotic Fixation
Authors: Kahn Mani D. , Fox Rabun , Stang Thomas , Marrero Christopher E. , Zura Robert D.
Published: May 2017

The treatment of posterior malleolus fractures has traditionally been based on the size of the fracture fragment. Biomechanical evidence does suggest that larger posterior malleolar fragments can alter the load transmission through the tibiotalar joint. In trimalleolar fractures with smaller posterior malleolus fractures, fixation of the posterior malleolar fragment has been suggested as an alternative to the gold standard practice of fixing the fibular fracture first, then stressing the syndesmosis and adding transsyndesmotic fixation if necessary. This paper reviews the rationale for posterior malleolus fracture fixation based on fragment size and based on syndesmotic instability. The technique of posterior malleolar fixation is also reviewed.
Practical Syndesmosis Anatomy in the Setting of Ankle Fractures
Authors: Ford Amy , Pinzur Michael , Schiff Adam
Published: May 2017

The syndesmosis is the distal articulation of the tibia and fibula. Its stability is determined by its bone architecture and ligamentous contributions. The syndesmosis has an important role for normal function of the ankle, and disruption of the syndesmosis from ankle fractures can have functional implications. In this article, the anatomy and biomechanics of the syndesmosis are reviewed.
Medial Clear Space: When to Address the Deltoid Ligament in the Setting of Suspected Syndesmotic Injury?
Authors: Hamid Kamran S. , Barnwell Jonathan C.
Published: May 2017

The primary objective of ankle fracture fixation is to recreate a tibiotalar articulation with physiological contact stresses. Although fixation of fracture fragments is conceptually straightforward, diagnosis and treatment of soft tissue constraints has proven difficult. The authors discuss historical diagnostic and treatment algorithms as well as empirical treatment strategies.
Contributions to Executive Dysfunction in Operation Enduring Freedom/Operation Iraqi Freedom Veterans With Posttraumatic Stress Disorder and History of Mild Traumatic Brain Injury
Authors: Jurick Sarah M. , Crocker Laura D. , Sanderson-Cimino Mark , Keller Amber V. , Trenova Liljana S. , Boyd Briana L. , Twamley Elizabeth W. , Rodgers Carie S. , Schiehser Dawn M. , Aupperle Robin L. , Jak Amy J.
Published: May 2017

Objective:

Posttraumatic stress disorder (PTSD), history of mild traumatic brain injury (mTBI), and executive function (EF) difficulties are prevalent in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans. We evaluated the contributions of injury variables, lower-order cognitive component processes (processing speed/attention), and psychological symptoms to EF.

Participants:

OEF/OIF Veterans (N= 65) with PTSD and history of mTBI were administered neuropsychological tests of EF and self-report assessments of PTSD and depression.

Results:

Those impaired on one or more EF measures had higher PTSD and depression symptoms and lower processing speed/attention performance than those with intact performance on all EF measures. Across participants, poorer attention/processing speed performance and higher psychological symptoms were associated with worse performance on specific aspects of EF (eg, inhibition and switching) even after accounting for injury variables. Although direct relationships between EF and injury variables were equivocal, there was an interaction between measures of injury burden and processing speed/attention such that those with greater injury burden exhibited significant and positive relationships between processing speed/attention and inhibition/switching, whereas those with lower injury burden did not.

Conclusion:

Psychological symptoms as well as lower-order component processes of EF (attention and processing speed) contribute significantly to executive dysfunction in OEF/OIF Veterans with PTSD and history of mTBI. However, there may be equivocal relationships between injury variables and EF that warrant further study. Results provide groundwork for more fully understanding cognitive symptoms in OEF/OIF Veterans with PTSD and history of mTBI that can inform psychological and cognitive interventions in this population.
Follow-Up Care Adherence After Hospital Discharge in Children With Traumatic Brain Injury
Authors: Spaw Alexandra J. , Lundine Jennifer P. , Johnson Sarah A. , Peng Jin , Wheeler Krista K. , Shi Junxin , Yang Ginger , Haley Kathy J. , Groner Jonathan I. , Xiang Henry
Published: May 2017

Objective:

To investigate factors associated with follow-up care adherence in children hospitalized because of traumatic brain injury (TBI).

Design:

An urban level 1 children's hospital trauma registry was queried to identify patients (2-18 years) hospitalized with a TBI in 2013 to 2014. Chart reviewers assessed discharge summaries and follow-up instructions in 4 departments.

Main Measures:

Three levels of adherence—nonadherence, partial adherence, and full adherence—and their associations with care delivery, patient, and injury factors.

Results:

In our population, 80% were instructed to follow up within the hospital network. These children were older and had more severe TBIs than those without follow-up instructions and those referred to outside providers. Of the 352 eligible patients, 19.9% were nonadherent, 27.3% were partially adherent, and 52.8% were fully adherent. Those recommended to follow up with more than 1 department had higher odds of partial adherence over nonadherence (adjusted odds ratio [AOR] = 5.8, 95% CI: 1.9-17.9); however, these patients were less likely to be fully adherent (AOR = 0.1; 95% CI: 0.1-0.3). Privately insured patients had a higher AOR of full adherence.

Conclusions:

Nearly 20% of children hospitalized for TBI never returned for outpatient follow-up and 27% missed appointments. Care providers need to educate families, coordinate service provision, and promote long-term monitoring.
Structural Connectivity Related to Persistent Symptoms After Mild TBI in Adolescents and Response to Aerobic Training: Preliminary Investigation
Authors: Yuan Weihong , Wade Shari L. , Quatman-Yates Catherine , Hugentobler Jason A. , Gubanich Paul J. , Kurowski Brad G.
Published: May 2017

Objective:

To quantify structural connectivity abnormalities in adolescents with mild traumatic brain injury (mTBI) and to investigate connectivity changes following aerobic training using graph theory and diffusion tensor imaging tractography.

Setting:

Outpatient research setting.

Participants:

Twenty-two children (age: 15.83 ± 1.77 years, 10 females) with 4 to 16 weeks of persistent symptoms after mTBI and a matched healthy comparison group.

Design:

Randomized clinical trial of aerobic training and stretching comparison combined with case-control comparison.

Main Measures:

(1) Five global network measures: global efficiency (Eglob), mean local efficiency, modularity, normalized clustering coefficient (γ), normalized characteristic path length (λ), and small-worldness (σ). (2) The self-reported Post-Concussion Symptom Inventory score.

Results:

At initial enrollment, adolescents with mTBI had significantly lower Eglob and higher γ, λ, and σ (all P < .05) than healthy peers. After the intervention, significantly increased Eglob and decreased λ (both P < .05) were found in the aerobic training group. Improvement in Post-Concussion Symptom Inventory scores was significantly correlated with the Eglob increase and λ decrease in the aerobic training and λ decrease in the stretching comparison group (all P < .05).

Conclusion:

This pilot study showed initial evidence that structural connectivity analysis was sensitive to brain network abnormalities and may serve as an imaging biomarker in children with persistent symptoms after mTBI.
The Role of Cognitive Reserve in Recovery From Traumatic Brain Injury
Authors: Steward Kayla A. , Kennedy Richard , Novack Thomas A. , Crowe Michael , Marson Daniel C. , Triebel Kristen L.
Published: May 2017

Objective:

To examine whether cognitive reserve (CR) attenuates the initial impact of traumatic brain injury (TBI) on cognitive performance (neural reserve) and results in faster cognitive recovery rates in the first year postinjury (neural compensation), and whether the advantage of CR differs on the basis of the severity of TBI.

Setting:

Inpatient/outpatient clinics at an academic medical center.

Participants:

Adults with mild TBI (mTBI; n = 28), complicated mild TBI (cmTBI; n = 24), and moderate to severe TBI (msevTBI; n = 57), and demographically matched controls (n = 66).

Design:

Retrospective, longitudinal cohort assessed at 1, 6, and 12 months postinjury.

Main Measures:

Outcomes were 3 cognitive domains: processing speed/executive function, verbal fluency, and memory. Premorbid IQ, estimated with the Wechsler Test of Adult Reading, served as CR proxy.

Results:

Higher premorbid IQ was associated with better performance on cognitive domains at 1 month postinjury, and the effect of IQ was similarly beneficial for all groups. Cognitive recovery rate was moderated only by TBI severity; those with more severe TBI had faster recovery in the first year.

Conclusion:

Results support only the neural reserve theory of CR within a TBI population and indicate that CR is neuroprotective, regardless of the degree of TBI. Higher premorbid CR does not allow for more rapid adaptation and recovery from injury.
Genetic diseases associated with an increased risk of skin cancer development in childhood
Authors: Fogel Alexander L. , Sarin Kavita Y. , Teng Joyce M.C.
Published: May 2017

Purpose of review

Childhood skin cancers are relatively rare and may indicate an underlying genetic disorder. The increasing elucidation of genetic pathways is changing the diagnosis and management of genetic skin cancer susceptibility syndromes. In this review, we provide an overview of genetic conditions that predispose to skin cancer development in childhood and signs that providers should assess when evaluating affected individuals.

Recent findings

In basal cell nevus syndrome (BCNS), the patched2 (PTCH2) and suppressor of fused (SUFU) genes have been implicated in disease pathogenesis. The sonic hedgehog (SHH) pathway inhibitor vismodegib was shown in a placebo-controlled phase III randomized trial to reduce the tumor burden in patients with BCNS. Epidermolysis bullosa (EB) has been classified into four major types and more than 30 subtypes based partly on specific mutations, and best clinical practice guidelines for the management of cutaneous squamous cell carcinoma in EB have been developed. Oculocutaneous albinism (OCA) has been associated with new mutations in genes named OCA5, OCA6, and OCA7, bringing to the total number of culprit genes to seven (OCA1–OCA7).

Advances in our understanding of genetic conditions that predispose to childhood skin cancer include new disease classification systems, management guidelines, and treatment options.
Increased Risk of Myocardial Infarction in HIV-Infected Individuals in North America Compared With the General Population
Authors: Drozd Daniel R. , Kitahata Mari M. , Althoff Keri N. , Zhang Jinbing , Gange Stephen J. , Napravnik Sonia , Burkholder Greer A. , Mathews William C. , Silverberg Michael J. , Sterling Timothy R. , Heckbert Susan R. , Budoff Matthew J. , Van Rompaey Stephen , Delaney Joseph A.C. , Wong Cherise , Tong Weiqun , Palella Frank J. , Elion Richard A. , Martin Jeffrey N. , Brooks John T. , Jacobson Lisa P. , Eron Joseph J. , Justice Amy C. , Freiberg Matthew S. , Klein Daniel B. , Post Wendy S. , Saag Michael S. , Moore Richard D. , Crane Heidi M.
Published: May 2017

Background:

Previous studies of cardiovascular disease (CVD) among HIV-infected individuals have been limited by the inability to validate and differentiate atherosclerotic type 1 myocardial infarctions (T1MIs) from other events. We sought to define the incidence of T1MIs and risk attributable to traditional and HIV-specific factors among participants in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) and compare adjusted incidence rates (IRs) to the general population Atherosclerosis Risk in Communities (ARIC) cohort.

Methods:

We ascertained and adjudicated incident MIs among individuals enrolled in 7 NA-ACCORD cohorts between 1995 and 2014. We calculated IRs, adjusted incidence rate ratios (aIRRs), and 95% confidence intervals of risk factors for T1MI using Poisson regression. We compared aIRRs of T1MIs in NA-ACCORD with those from ARIC.

Results:

Among 29,169 HIV-infected individuals, the IR for T1MIs was 2.57 (2.30 to 2.86) per 1000 person-years, and the aIRR was significantly higher compared with participants in ARIC [1.30 (1.09 to 1.56)]. In multivariable analysis restricted to HIV-infected individuals and including traditional CVD risk factors, the rate of T1MI increased with decreasing CD4 count [≥500 cells/μL: ref; 350–499 cells/μL: aIRR = 1.32 (0.98 to 1.77); 200–349 cells/μL: aIRR = 1.37 (1.01 to 1.86); 100–199 cells/μL: aIRR = 1.60 (1.09 to 2.34); <100 cells/μL: aIRR = 2.19 (1.44 to 3.33)]. Risk associated with detectable HIV RNA [<400 copies/mL: ref; ≥400 copies/mL: aIRR = 1.36 (1.06 to 1.75)] was significantly increased only when CD4 was excluded.

Conclusions:

The higher incidence of T1MI in HIV-infected individuals and increased risk associated with lower CD4 count and detectable HIV RNA suggest that early suppressive antiretroviral treatment and aggressive management of traditional CVD risk factors are necessary to maximally reduce MI risk.
Hydrogen isotope composition ofThermoanaerobacterium saccharolyticumlipids: comparing wild type to anfn-transhydrogenase mutant
Authors: Leavitt William D. , Murphy Sean Jean-Loup , Lynd Lee R. , Bradley Alexander S.
Published: May 2017

Abstract

The2H/1H ratio in microbial fatty acids can record information about the energy metabolism of microbes and about the isotopic composition of environmental water. However, the mechanisms involved in the fractionation of hydrogen isotopes between water and lipid are not fully resolved. We provide data aimed at understanding this fractionation in the Gram-positive obligately thermophilic anaerobe,Thermoanaerobacterium saccharolyticum, by comparing a wild-type strain to a deletion mutant in which thenfnABgenes encoding electron-bifurcating transhydrogenase have been removed. The wild-type strain showed faster growth rates and larger overall fractionationthan the mutant strain. The overall trend in growth rate and fractionation, along with the isotopic ordering of individual lipids, is consistent with results reported for the Gram-negative sulfate reducer,Desulfovibrio alaskensisG20.
scNMT-seq enables joint profiling of chromatin accessibility DNA methylation and transcription in single cells
Authors: Clark Stephen J. , Argelaguet Ricard , Kapourani Chantriolnt-Andreas , Stubbs Thomas M. , Lee Heather J. , Alda-Catalinas Celia , Krueger Felix , Sanguinetti Guido , Kelsey Gavin , Marioni John C. , Stegle Oliver , Reik Wolf
Published: May 2017

Parallel single-cell sequencing protocols represent powerful methods for investigating regulatory relationships, including epigenome-transcriptome interactions. Here, we report a novel single-cell method for parallel chromatin accessibility, DNA methylation and transcriptome profiling. scNMT-seq (single-cell nucleosome, methylation and transcription sequencing) uses a GpC methyltransferase to label open chromatin followed by bisulfite and RNA sequencing. We validate scNMT-seq by applying it to differentiating mouse embryonic stem cells, finding links between all three molecular layers and revealing dynamic coupling between epigenomic layers during differentiation.
An FGF-driven feed-forward circuit patterns the cardiopharyngeal mesoderm in space and time
Authors: Razy-Krajka Florian , Gravez Basile , Kaplan Nicole , Racioppi Claudia , Wang Wei , Christiaen Lionel
Published: May 2017

In embryos, multipotent progenitors divide to produce distinct progeny and express their full potential. In vertebrates, multipotent cardiopharyngeal progenitors produce second-heart-field-derived cardiomyocytes, and branchiomeric skeletal head muscles. However, the mechanisms underlying these early fate choices remain largely elusive. The tunicateCionaemerged as an attractive model to study early cardiopharyngeal development at high resolution: through two asymmetric and oriented divisions, defined cardiopharyngeal progenitors produce distinct first and second heart precursors, and pharyngeal muscle (aka atrial siphon muscle, ASM) precursors. Here, we demonstrate that differential FGF-MAPK signaling distinguishes between heart and ASM precursors. We characterize a feed-forward circuit that promotes the successive activations of essential ASM determinants,Hand-related, Tbx1/10andEbf. Finally, we show that coupling FGF-MAPK restriction and cardiopharyngeal network deployment with cell divisions defines the timing of gene expression and permits the emergence of diverse cell types from multipotent progenitors.
Evaluating the accuracy of DNA stable isotope probing
Authors: Youngblut Nicholas D. , Buckley Daniel H.
Published: May 2017

Originality-Significance Statement

By combining DNA Stable Isotope Probing (DNA-SIP) with multiplexed high throughput DNA sequencing (HTS-DNA-SIP), it is now possible to identify patterns of isotope incorporation for thousands of microbial taxa. HTS-DNA-SIP has enormous potential to reveal patterns of carbon and nitrogen exchange within microbial food webs. A current limitation is that, due to the expense of these experiments, it has been impossible to evaluate the accuracy of DNA-SIP methods. We have developed a model that simulates DNA-SIP data, and we use the model to systematically evaluate and validate the accuracy of DNA-SIP analyses. This model can determine the analytical accuracy of DNA-SIP experiments in a range of contexts. Furthermore, the ability to predict experimental outcomes, as a function of experimental design and community characteristics, should be of great use in the design and interpretation DNA-SIP experiments.

DNA Stable isotope probing (DNA-SIP) is a powerful method that identifiesin situisotope assimilation by microbial taxa. Combining DNA-SIP with multiplexed high throughput DNA sequencing (HTS-DNA-SIP) creates the potential to mapin situassimilation dynamics for thousands of microbial taxonomic units. However, the accuracy of methods for analyzing DNA-SIP data has never been evaluated. We have developed a toolset (SIPSim) for simulating HTS-DNA-SIP datasets and evaluating the accuracy of methods for analyzing HTS-DNA-SIP data. We evaluated two different approaches to analyzing HTS-DNA-SIP data: “high resolution stable isotope probing” (HR-SIP) and “quantitative stable isotope probing” (q-SIP). HR-SIP was highly specific and moderately sensitive, with very few false positives but potential for false negatives. In contrast, q-SIP had fewer false negatives but many false positives. We also found HR-SIP more robust than q-SIP with respect to experimental variance. Furthermore, we found that the detection sensitivity of HTS-DNA-SIP can be increased without compromising specificity by evaluating evidence of isotope incorporation over multiple windows of buoyant density (MW-HR-SIP). SIPSim provides a platform for determining the accuracy of HTS-DNA-SIP methods across a range of experimental parameters, which will be useful in the design, analysis, and validation of DNA-SIP experiments.
Graph-guided assembly for novel HLA allele discovery
Authors: Lee Heewook , Kingsford Carl
Published: May 2017

Accurate typing of human leukocyte antigen (HLA), a histocompatibility test, is important because HLA genes play various roles in immune responses, and have also been shown to be associated with many diseases such as cancer. The current gold standard for HLA typing uses DNA sequencing technology combined with sequence enrichment techniques using specially designed primers or probes, causing it to be slow and labor-intensive. Although there exist enrichment-free computational methods that use various types of sequencing data, hyper-polymorphism found in HLA region of the human genome makes it challenging to type HLA genes with high accuracy from whole genome sequencing data. Furthermore, these methods are database-matching approaches where their output is inherently limited by the completeness of already known types, forcing them to find the best matching known alleles from a database, thereby causing them to be unsuitable for discovery of rare or novel alleles. In order to ensure both high accuracy as well as the ability to type novel alleles, we have developed a graph-guided assembly technique for classical HLA genes, which is capable of assembling phased, full-length haplotype sequences of typing exons given high-coverage (>30-fold) whole genome sequencing data. Our method delivers highly accurate HLA typing, comparable to the current state-of-the-art database-matching methods. We also demonstrate that our method can type novel alleles by experimenting on various data including simulated, Illumina Platinum Genomes, and 1000 Genomes data.
Removal of inhibition uncovers latent movement potential during preparation
Authors: Jagadisan Uday K. , Gandhi Neeraj J.
Published: May 2017

The motor system prepares for movements well in advance of their execution. In the gaze control system, premotor neurons that produce a burst of activity for the movement are also active leading up to the saccade. The dynamics of preparatory neural activity have been well described by stochastic accumulator models, and variability in the accumulation dynamics has been shown to be correlated with reaction times of the eventual saccade, but it is unclear whether this activity is purely preparatory in nature or has features indicative of a hidden movement command. We explicitly tested whether preparatory neural activity in premotor neurons of the primate superior colliculus has “motor potential”. We removed inhibition on the saccadic system using reflex blinks, which turn off downstream gating, and found that saccades can be initiated before underlying activity reaches levels seen under normal conditions. Accumulating low-frequency activity was predictive of eye movement dynamics tens of milliseconds in advance of the actual saccade, indicating the presence of a latent movement command. We also show that reaching threshold is not a necessary condition for movement initiation, contrary to the postulates of accumulation-to-threshold models. The results bring into question extant models of saccade generation and support the possibility of a concurrent representation for movement preparation and generation.

Significance Statement

How the brain plans for upcoming actions before deciding to initiate them is a central question in neuroscience. Popular theories suggest that movement planning and execution occur in serial stages, separated by a decision boundary in neural activity space (e.g., “threshold”), which needs to be crossed before the movement is executed. By removing inhibitory gating on the motor system, we show here that the activity required to initiate a saccade can be flexibly modulated. We also show that evolving activity during movement planning is a hidden motor command. The results have important implications for our understanding of how movements are generated, in addition to providing useful information for decoding movement intention based on planning-related activity.

Impact Statement

Non-invasive disinhibition of the oculomotor system shows that ongoing preparatory activity in the superior colliculus has movement-generating potential and need not rise to threshold in order to produce a saccade.
Evolutionary genetic analysis uncovers multiple species with distinct habitat preferences and antibiotic resistance phenotypes in theStenotrophomonas maltophiliacomplex
Authors: Ochoa-Sánchez Luz Edith , Vinuesa Pablo
Published: May 2017

The genusStenotrophomonas(Gammaproteobacteria) has a broad environmental distribution.S. maltophiliais its best known species because it is a globally emerging, multidrug-resistant (MDR), opportunistic pathogen. Members of this species are known to display high genetic, ecological and phenotypic diversity, forming the so-calledS. maltophiliacomplex (Smc). Heterogeneous resistance and virulence phenotypes have been reported for environmental Smc isolates of diverse ecological origin. We hypothesized that this heterogeneity could be in part due to the potential lumping of several cryptic species in the Smc. Here we used state-of-the-art phylogenetic and population genetics methods to test this hypothesis based on the multilocus dataset available for the genus at pubmlst.org. It was extended with sequences from complete and draft genome sequences to assemble a comprehensive set of reference sequences. This framework was used to analyze 108 environmental isolates obtained in this study from the sediment and water column of four rivers and streams in Central Mexico, affected by contrasting levels of anthropogenic pollution. The aim of the study was to identify species in this collection, defined as genetically cohesive sequence clusters, and to determine the extent of their genetic, ecological and phenotypic differentiation. The multispecies coalescent, coupled with Bayes factor analysis was used to delimit species borders, together with population genetic structure analyses, recombination and gene flow estimates between sequence clusters.

These analyses consistently revealed that the Smc contains at least 5 significantly differentiated lineages:S. maltophiliaand Smc1 to Smc4. OnlyS. maltophiliawas found to be intrinsically MDR, all its members expressing metallo-β-lactamases (MBLs). The other Smc lineages were not MDR and did not express MBLs. We also obtained isolates related toS. acidaminiphila,S. humiandS. terrae. They were significantly more susceptible to antibiotics thanS. maltophilia. We demonstrate that the sympatric lineages recovered display significantly differentiated habitat preferences, antibiotic resistance profiles and beta-lactamase expression phenotypes, as shown by diverse multivariate analyses and robust univariate statistical tests. We discuss our data in light of current models of bacterial speciation, which fit these data well, stressing the implications of species delimitation in ecological, evolutionary and clinical research.
Clusternomics: Integrative Context-Dependent Clustering for Heterogeneous Datasets
Authors: Gabasova Evelina , Reid John , Wernisch Lorenz
Published: May 2017

Integrative clustering is used to identify groups of samples by jointly analysing multiple datasets describing the same set of biological samples, such as gene expression, copy number, methylation etc. Most existing algorithms for integrative clustering assume that there is a shared consistent set of clusters across all datasets, and most of the data samples follow this structure. However in practice, the structure across heterogeneous datasets can be more varied, with clusters being joined in some datasets and separated in others.

In this paper, we present a probabilistic clustering method to identify groups across datasets that do not share the same cluster structure. The proposed algorithm, Clusternomics, identifies groups of samples that share their global behaviour across heterogeneous datasets. The algorithm models clusters on the level of individual datasets, while also extracting global structure that arises from the local cluster assignments. Clusters on both the local and the global level are modelled using a hierarchical Dirichlet mixture model to identify structure on both levels.

We evaluated the model both on simulated and on real-world datasets. The simulated data exemplifies datasets with varying degrees of common structure. In such a setting Clusternomics outperforms existing algorithms for integrative and consensus clustering. In a real-world application, we used the algorithm for cancer subtyping, identifying subtypes of cancer from heterogeneous datasets. We applied the algorithm to TCGA breast cancer dataset, integrating gene expression, miRNA expression, DNA methylation and proteomics. The algorithm extracted clinically meaningful clusters with significantly different survival probabilities. We also evaluated the algorithm on lung and kidney cancer TCGA datasets with high dimensionality, again showing clinically significant results and scalability of the algorithm.

Author Summary

Integrative clustering is the task of identifying groups of samples by combining information from several datasets. An example of this task is cancer subtyping, where we cluster tumour samples based on several datasets, such as gene expression, proteomics and others. Most existing algorithms assume that all such datasets share a similar cluster structure, with samples outside these clusters treated as noise. The structure can, however, be much more heterogeneous: some meaningful clusters may appear only in some datasets.

In the paper, we introduce the Clusternomics algorithm that identifies groups of samples across heterogeneous datasets. It models both cluster structure of individual datasets, and the global structure that appears as a combination of local structures. The algorithm uses probabilistic modelling to identify the groups and share information across the local and global levels. We evaluated the algorithm on both simulated and real world datasets, where the algorithm found clinically significant clusters with different survival outcomes.