bluuebunny/crossref_metadata_2025 huggingface dataset:
Refractory Ulcerated Necrobiosis Lipoidica: Closure of a Difficult Wound with Topical Tacrolimus
Authors: Ginocchio Luke , Draghi Lisa , Darvishian Farbod , Ross Frank L.
Published: September 2017

OBJECTIVE:

To report a case of refractory ulcerated necrobiosis lipoidica (NL) with significant response to treatment with topical tacrolimus.

SUBJECT:

A 55-year-old woman without diabetes and with a previous history of NL presented to the Helen L. and Martin S. Kimmel Hyperbaric and Advanced Wound Healing Center of NYU Langone Medical Center, New York, with bilateral lower-leg ulcerations resistant to wound healing techniques at other institutions.

MATERIALS AND METHODS:

Repeat biopsy performed at the author’s institution confirmed the diagnosis of NL. Initial therapy was based on reports of other successful treatment methods, which included collagen wound grafts and collagen-based dressings coupled with compression. These methods initially showed promising results; however, the wounds reulcerated, and any gains in wound healing were lost. Alternative options were initiated, including topical clobetasol and narrowband ultraviolet B; however, no significant improvement was observed. The patient’s lower-extremity wounds began to deteriorate. The patient also refused systemic therapy. Treatment was changed to topical 0.1% tacrolimus ointment and was applied daily for 10 months with multilayer compression wraps.

RESULTS:

Both lower-extremity ulcerations began to show significant improvement, with the ulcers progressing toward closure except for 1 very small area on the left lower extremity.

CONCLUSIONS:

Topical tacrolimus seems to be an effective treatment option for patients with refractory chronic ulcerated NL who do not want systemic oral therapy. The authors found that successful wound closure may require a multimodal approach, which promotes wound healing, but also concurrently addresses the underlying disease process.
Primum Non Nocere and the 5 Rights
Authors: Popp Gabriele , Clarke Dick , Rothstein Stephen
Published: September 2017

Overutilization of hyperbaric oxygen therapy (HBOT) is commonplace and primarily associated with outpatient wound care. While the number of hospitals providing HBOT is at an all-time high, the number of those willing to treat patients in immediate need is at an all-time low. Huge areas of the country, including major population areas, are now completely devoid of 24/7 HBOT availability and inpatient access. Purchasers of healthcare, including the Centers for Medicare and Medicaid Services, have become increasingly concerned to the point that several strategies have been introduced to constructively deal with this issue. This commentary serves as a counterpoint to concerns that one such approach, prior authorization of elective indications, adversely delays medically necessary care. The historical evolution of HBOT practice will be described to underscore how this problem has become so widespread and, to date, largely unchecked. It will also address the paradoxical national crisis of access for emergencies.
Secondary Traumatic Stress in NICU Nurses
Authors: Beck Cheryl Tatano , Cusson Regina M. , Gable Robert K.
Published: September 2017

Background:

Secondary traumatic stress is an occupational hazard for healthcare providers who care for patients who have been traumatized. This type of stress has been reported in various specialties of nursing, but no study to date had specifically focused on neonatal intensive care unit (NICU) nurses.

Purpose:

(1) To determine the prevalence and severity of secondary traumatic stress in NICU nurses and (2) to explore those quantitative findings in more depth through nurses' qualitative descriptions of their traumatic experiences caring for critically ill infants in the NICU.

Methods:

Members of NANN were sent e-mails with a link to the electronic survey. In this mixed-methods study, a convergent parallel design was used. Neonatal nurses completed the Secondary Traumatic Stress Scale (STSS) and then described their traumatic experiences caring for critically ill infants in the NICU. SPSS version 24 and content analysis were used to analyze the quantitative and qualitative data, respectively.

Results:

In this sample of 175 NICU nurses, 49% of the nurses' scores on the STSS indicated moderate to severe secondary traumatic stress. Analysis of the qualitative data revealed 5 themes that described NICU nurses' traumatic experiences caring for critically ill infants.

Implications for Practice:

NICU nurses need to know the signs of secondary traumatic stress that they may experience caring for their critically ill infants. Avenues for dealing with the stress should be provided.

Implications for Research:

Future research with a higher response rate to increase the external validity of the findings to the population of neonatal nurses is needed.
Notch inhibitors and their role in the treatment of triple negative breast cancer: promises and failures
Authors: Locatelli Marzia , Curigliano Giuseppe
Published: September 2017

Purpose of review

Notch signaling is a highly evolutionarily conserved cell-to-cell communication system that is involved in a number of pivotal cellular processes, such as development, stem cell maintenance, cell fate specification, differentiation, proliferation, and death. Much progress has been made in understanding Notch signaling. This review will focus on the role of canonical Notch signaling pathway in breast cancer cause and progressing.

Recent findings

In this review, we will discuss the results of the studies using drugs, which target the Notch pathway.

Notch sustains a proliferative signaling and protects from apoptosis, favors the angiogenic switch, the chemoresistance and radioresistance, controls the cancer stemness, and induces a prometastatic phenotype. Therefore, Notch-signaling represented an interesting target in the strategy against cancer growth.
Increasing suicide risk among cancer patients in Lithuania from 1993 to 2012: a cancer registry-based study
Authors: Kaceniene Auguste , Krilaviciute Agne , Kazlauskiene Jurgita , Bulotiene Giedre , Smailyte Giedre
Published: September 2017

Certain groups of individuals seem to have an increased risk of committing suicide, and a number of studies have reported an increased risk of suicide among cancer patients. In this study, we aim to estimate the risk of suicide among cancer patients in Lithuania over the period 1993–2012. The records of patients diagnosed with primary cancer were extracted from the population-based Lithuanian Cancer Registry and 273 511 cases of first cancer were included in the analysis. Sex, age and calendar period-standardized mortality ratios (SMRs) were calculated by dividing the observed numbers of suicides among cancer patients by the expected number using national rates. An increased suicide risk was found for both sexes combined [SMR=1.31, 95% confidence interval (CI): 1.21–1.41] compared with the general population. For all cancer sites except melanoma and skin, and breast and thyroid cancers, the relative suicide risk was elevated. The suicide risk was almost three-fold higher for advanced-stage patients compared with the general population (SMR=2.89, 95% CI: 2.24−3.73). The highest suicide risk observed in our study was during the first 3 months following cancer diagnosis (SMR=2.43, 95% CI: 1.96−3.01), indicating a critical period shortly after diagnosis. Despite ongoing increases in survival among cancer patients and decreases in suicide mortality in the general Lithuanian population during our study period, the increasing risk for suicide indicates that cancer patients’ clinical and psychosocial needs remain unsatisfied. The major clinical implication of these data suggests the importance of multidisciplinary preventive interventions.
Stepwise Guided Photorefractive Keratectomy in Treatment of Irregular Astigmatism After Penetrating Keratoplasty and Deep Anterior Lamellar Keratoplasty
Authors: Sorkin Nir , Einan-Lifshitz Adi , Abelson Sagi , Boutin Tanguy , Showail Mahmood , Borovik Armand , Ashkenazy Zach , Chan Clara C. , Rootman David S.
Published: September 2017

Purpose:

To report the outcome of stepwise ablation using topography-guided photorefractive keratectomy to treat irregular astigmatism after either penetrating keratoplasty (PKP) or deep anterior lamellar keratoplasty (DALK).

Methods:

This is a retrospective, interventional analysis including patients with irregular astigmatism after either PKP or DALK, who underwent topography-guided photorefractive keratectomy. The entire cohort was analyzed, as well as the PKP and DALK groups separately. Analysis of factors associated with a better outcome was also performed.

Results:

Thirty-four eyes of 34 patients (20 PKP patients and 14 DALK patients) aged 47.4 ± 15.9 years were included. Twenty-one patients underwent more than 1 ablation. Refractive stability and a minimal period of 5 months were required before repeat ablation. The average follow-up duration was 17.0 ± 6.0 months. Corrected distance visual acuity (CDVA) improved significantly from 0.22 ± 0.14 logarithm of the minimum angle of resolution (logMAR) to 0.14 ± 0.12 logMAR at final follow-up (P = 0.035). Uncorrected distance visual acuity (UDVA) improved significantly from 0.90 ± 0.54 logMAR to 0.57 ± 0.40 logMAR at final follow-up (P = 0.004). CDVA and UDVA improved by ≥1 Snellen lines in 54.2% and 70.8% of the eyes, respectively, and by ≥3 Snellen lines in 16.7% and 54.2% of the eyes, respectively. Statistically significant improvement was seen in optical aberrometry indices (total root mean square, higher-order aberration root mean square, defocus, coma, trefoil, and spherical aberration). The difference between PKP and DALK in either CDVA (P = 0.562) or UDVA (P = 0.384) improvement was nonsignificant.

Conclusions:

The stepwise topography-guided photorefractive keratectomy approach in cases of irregular astigmatism after PKP or DALK can help improve visual acuity outcomes. Patients should be appropriately counseled that more than 1 treatment will likely be needed.
Management of Type I and Type II laryngeal clefts: controversies and evidence
Authors: Bowe Sarah N. , Hartnick Christopher J.
Published: September 2017

Purpose of review

To summarize the pediatric Type I and Type II laryngeal cleft literature, paying special attention to recent trends, including evolution of surgical techniques, standardization of outcome assessments, and utilization of management algorithms.

Recent findings

There are a variety of options to choose from whenever considering Type I and Type II cleft repair, including endoscopic repair, transoral robotic surgery, and injection laryngoplasty. Conservative management including feeding therapy and treatment of comorbid medical conditions is recommended prior to repair. Validated outcome measures have arisen for swallow study interpretation and timing, as well as caregiver quality-of-life assessment. In addition, a series of medical algorithms have been proposed, which provide specific recommendations for diagnosis, treatment, and follow-up.

For clefts that fail conservative management, endoscopic repair has become the gold standard. In addition, injection laryngoplasty appears to provide both a diagnostic and therapeutic option in the management of these patients. Transoral robotic-assisted endoscopic repair appears well tolerated and feasible, although broader implementation of this technology remains limited. The development and refinement of best practice algorithms can help standardize management and improve decision-making. Furthermore, incorporating validated outcome measures, recorded and followed over time, will improve both patient care and research efforts moving forward.
Relationship Between Alpha Rhythm and the Default Mode Network: An EEG-fMRI Study
Authors: Bowman Anthony D. , Griffis Joseph C. , Visscher Kristina M. , Dobbins Allan C. , Gawne Timothy J. , DiFrancesco Mark W. , Szaflarski Jerzy P.
Published: September 2017

Purpose:

Reports of the relationship between the default mode network (DMN) and alpha power are conflicting. Our goal was to assess this relationship by analyzing concurrently obtained EEG/functional MRI data using hypothesis-independent methods.

Methods:

We collected functional MRI and EEG data during eyes-closed rest in 20 participants aged 19 to 37 (10 females) and performed independent component analysis on the functional MRI data and a Hamming-windowed fast Fourier transform on the EEG data. We correlated functional MRI fluctuations in the DMN with alpha power.

Results:

Of the six independent components found to have significant relationships with alpha, four contained DMN-associated regions: One independent component was positively correlated with alpha power, whereas all others were negatively correlated. Furthermore, two independent components with opposite relationships with alpha had overlapping voxels in the medial prefrontal cortex and posterior cingulate cortex, suggesting that subpopulations of neurons within these classic nodes within the DMN may have different relationships to alpha power.

Conclusions:

Different parts of the DMN exhibit divergent relationships to alpha power. Our results highlight the relationship between DMN activity and alpha power, indicating that networks, such as the DMN, may have subcomponents that exhibit different behaviors.
Phylogenomic analyses of more than 4000 nuclear loci resolve the origin of snakes among lizard families
Authors: Streicher Jeffrey W. , Wiens John J.
Published: September 2017

Squamate reptiles (lizards and snakes) are the most diverse group of terrestrial vertebrates, with more than 10 000 species. Despite considerable effort to resolve relationships among major squamates clades, some branches have remained difficult. Among the most vexing has been the placement of snakes among lizard families, with most studies yielding only weak support for the position of snakes. Furthermore, the placement of iguanian lizards has remained controversial. Here we used targeted sequence capture to obtain data from 4178 nuclear loci from ultraconserved elements from 32 squamate taxa (and five outgroups) including representatives of all major squamate groups. Using both concatenated and species-tree methods, we recover strong support for a sister relationship between iguanian and anguimorph lizards, with snakes strongly supported as the sister group of these two clades. These analyses strongly resolve the difficult placement of snakes within squamates and show overwhelming support for the contentious position of iguanians. More generally, we provide a strongly supported hypothesis of higher-level relationships in the most species-rich tetrapod clade using coalescent-based species-tree methods and approximately 100 times more loci than previous estimates.
Adsorption and movement of water by skin of the Australian thorny devil (Agamidae:Moloch horridus)
Authors: Comanns Philipp , Esser Falk J. , Kappel Peter H. , Baumgartner Werner , Shaw Jeremy , Withers Philip C.
Published: September 2017

Moisture-harvesting lizards, such as the Australian thorny devilMoloch horridus, have remarkable adaptations for inhabiting arid regions. Their microstructured skin surface, with channels in between overlapping scales, enables them to collect water by capillarity and passively transport it to the mouth for ingestion. We characterized this capillary water transport for live thorny devils using high-speed video analyses. Comparison with preserved specimens showed that live lizards are required for detailed studies of skin water transport. For thorny devils, there was no directionality in cutaneous water transport (unlikePhrynosoma) as 7 µl water droplets applied to the skin were transported radially over more than 9.2 mm. We calculated the total capillary volume as 5.76 µl cm−2(dorsal) and 4.45 µl cm−2(ventral), which is reduced to 50% filling by the time transportation ceases. Using micro-computed tomography and scanning electron microscopy of shed skin to investigate capillary morphology, we found that the channels are hierarchically structured as a large channel between the scales that is sub-divided by protrusions into smaller sub-capillaries. The large channel quickly absorbs water whereas the sub-capillary structure extends the transport distance by about 39% and potentially reduces the water volume required for drinking. An adapted dynamics function, which closely reflects the channel morphology, includes that ecological role.
Pedestrian motion modelled by Fokker–Planck Nash games
Authors: Roy S. , Borzì A. , Habbal A.
Published: September 2017

A new approach to modelling pedestrians' avoidance dynamics based on a Fokker–Planck (FP) Nash game framework is presented. In this framework, two interacting pedestrians are considered, whose motion variability is modelled through the corresponding probability density functions (PDFs) governed by FP equations. Based on these equations, a Nash differential game is formulated where the game strategies represent controls aiming at avoidance by minimizing appropriate collision cost functionals. The existence of Nash equilibria solutions is proved and characterized as a solution to an optimal control problem that is solved numerically. Results of numerical experiments are presented that successfully compare the computed Nash equilibria to the output of real experiments (conducted with humans) for four test cases.
Mechanistic insights into molecular evolution of species-specific differential glycosaminoglycan binding surfaces in growth-related oncogene chemokines
Authors: Gulati Khushboo , Jamsandekar Minal , Poluri Krishna Mohan
Published: September 2017

Chemokines are chemotactic cytokines involved in leucocyte trafficking to infected tissue. Growth-related oncogene (GRO) chemokines namely CXCL1, CXCL2 and CXCL3 are neutrophil activating chemokines sharing a conserved three-dimensional structure, but encompassing functional diversity due to gene duplication and evolutionary events. However, the evolutionary mechanisms including selection pressures involved in diversification of GRO genes have not yet been characterized. Here, we performed comprehensive evolutionary analysis of GRO genes among different mammalian species. Phylogenetic analysis illustrated a species-specific evolution pattern. Selection analysis evidenced that these genes have undergone concerted evolution. Seventeen positively selected sites were obtained, although the majority of the protein is under purifying selection. Interestingly, these positively selected sites are more concentrated on the C-terminal/glycosaminoglycan (GAG) binding and dimerization segment compared to receptor binding domain. Substitution rate analysis confirmed the C-terminal domain of GRO genes as the highest substituted segment. Further, structural analysis established that the nucleotide alterations in the GAG binding domain are the source of surface charge modulation, thus generating the differential GAG binding surfaces and multiple binding sites as per evolutionary pressure, although the helical surface is primordial for GAG binding. Indeed, such variable electrostatic surfaces are crucial to regulate chemokine gradient formation during a host's defence against pathogens and also explain the significance of chemokine promiscuity.
Fully localized post-buckling states of cylindrical shells under axial compression
Authors: Kreilos Tobias , Schneider Tobias M.
Published: September 2017

We compute nonlinear force equilibrium solutions for a clamped thin cylindrical shell under axial compression. The equilibrium solutions are dynamically unstable and located on the stability boundary of the unbuckled state. A fully localized single dimple deformation is identified as the
edge state
—the attractor for the dynamics restricted to the stability boundary. Under variation of the axial load, the single dimple undergoes homoclinic snaking in the azimuthal direction, creating states with multiple dimples arranged around the central circumference. Once the circumference is completely filled with a ring of dimples, snaking in the axial direction leads to further growth of the dimple pattern. These fully nonlinear solutions embedded in the stability boundary of the unbuckled state constitute critical shape deformations. The solutions may thus be a step towards explaining when the buckling and subsequent collapse of an axially loaded cylinder shell is triggered.
Rate-based structural health monitoring using permanently installed sensors
Authors: Corcoran Joseph
Published: September 2017

Permanently installed sensors are becoming increasingly ubiquitous, facilitating very frequentin situmeasurements and consequently improved monitoring of ‘trends’ in the observed system behaviour. It is proposed that this newly available data may be used to provide prior warning and forecasting of critical events, particularly system failure. Numerous damage mechanisms are examples of positive feedback; they are ‘self-accelerating’ with an increasing rate of damage towards failure. The positive feedback leads to a common time-response behaviour which may be described by an empirical relation allowing prediction of the time to criticality. This study focuses on Structural Health Monitoring of engineering components; failure times are projected well in advance of failure for fatigue, creep crack growth and volumetric creep damage experiments. The proposed methodology provides a widely applicable framework for using newly available near-continuous data from permanently installed sensors to predict time until failure in a range of application areas including engineering, geophysics and medicine.
On the differing growth mechanisms of black-smoker and Lost City-type hydrothermal vents
Authors: Cardoso Silvana S. S. , Cartwright Julyan H. E.
Published: September 2017

Black smokers and Lost City-type springs are varieties of hydrothermal vents on the ocean floors that emit hot, acidic water and cool, alkaline water, respectively. While both produce precipitation structures as the issuing fluid encounters oceanic water, Lost City-type hydrothermal vents in particular have been implicated in the origin of life on the Earth. We present a parallel-velocity flow model for the radius and flow rate of a cylindrical jet of fluid that forms the template for the growth of a tube precipitated about itself and we compare the solution with previous laboratory experimental results from growth of silicate chemical gardens. We show that when the growth of the solid structure is determined by thermal diffusion, fluid flow is slow at the solid–liquid contact. However, in the case of chemical diffusive transport, the fluid jet effectively drags the liquid in the pores of the solid precipitate. These findings suggest a continuum in the diffusive growth rate of hydrothermal vent structures, where Lost City-type hydrothermal vents favour contact between the vent fluid and the external seawater. We explore the implications for the road to life.
Bird and bat species' global vulnerability to collision mortality at wind farms revealed through a trait-based assessment
Authors: Thaxter Chris B. , Buchanan Graeme M. , Carr Jamie , Butchart Stuart H. M. , Newbold Tim , Green Rhys E. , Tobias Joseph A. , Foden Wendy B. , O'Brien Sue , Pearce-Higgins James W.
Published: September 2017

Mitigation of anthropogenic climate change involves deployments of renewable energy worldwide, including wind farms, which can pose a significant collision risk to volant animals. Most studies into the collision risk between species and wind turbines, however, have taken place in industrialized countries. Potential effects for many locations and species therefore remain unclear. To redress this gap, we conducted a systematic literature review of recorded collisions between birds and bats and wind turbines within developed countries. We related collision rate to species-level traits and turbine characteristics to quantify the potential vulnerability of 9538 bird and 888 bat species globally. Avian collision rate was affected by migratory strategy, dispersal distance and habitat associations, and bat collision rates were influenced by dispersal distance. For birds and bats, larger turbine capacity (megawatts) increased collision rates; however, deploying a smaller number of large turbines with greater energy output reduced total collision risk per unit energy output, although bat mortality increased again with the largest turbines. Areas with high concentrations of vulnerable species were also identified, including migration corridors. Our results can therefore guide wind farm design and location to reduce the risk of large-scale animal mortality. This is the first quantitative global assessment of the relative collision vulnerability of species groups with wind turbines, providing valuable guidance for minimizing potentially serious negative impacts on biodiversity.
An edrioasteroid from the Silurian Herefordshire Lagerstätte of England reveals the nature of the water vascular system in an extinct echinoderm
Authors: Briggs Derek E. G. , Siveter Derek J. , Siveter David J. , Sutton Mark D. , Rahman Imran A.
Published: September 2017

Echinoderms are unique in having a water vascular system with tube feet, which perform a variety of functions in living forms. Here, we report the first example of preserved tube feet in an extinct group of echinoderms. The material, from the Silurian Herefordshire Lagerstätte, UK, is assigned to a new genus and species of rhenopyrgid edrioasteroid,Heropyrgus disterminus. The tube feet attach to the inner surface of compound interradial plates and form two sets, an upper and a lower, an arrangement never reported previously in an extant or extinct echinoderm. Cover plates are absent and floor plates are separated creating a large permanent entrance to the interior of the oral area. The tube feet may have captured food particles that entered the oral area and/or enhanced respiration. The pentameral symmetry of the oral surface transitions to eight columns in which the plates are vertically offset resulting in a spiral appearance. This change in symmetry may reflect flexibility in the evolutionary development of the axial and extraxial zones in early echinoderm evolution.
Quantitative study of developmental biology confirms
Dickinsonia
as a metazoan
Authors: Hoekzema Renee S. , Brasier Martin D. , Dunn Frances S. , Liu Alexander G.
Published: September 2017

The late Ediacaran soft-bodied macroorganism
Dickinsonia
(age range approx. 560–550 Ma) has often been interpreted as an early animal, and is increasingly invoked in debate on the evolutionary assembly of eumetazoan body plans. However, conclusive positive evidence in support of such a phylogenetic affinity has not been forthcoming. Here we subject a collection of
Dickinsonia
specimens interpreted to represent multiple ontogenetic stages to a novel, quantitative method for studying growth and development in organisms with an iterative body plan. Our study demonstrates that
Dickinsonia
grew via pre-terminal ‘deltoidal’ insertion and inflation of constructional units, followed by a later inflation-dominated phase of growth. This growth model is contrary to the widely held assumption that
Dickinsonia
grew via terminal addition of units at the end of the organism bearing the smallest units. When considered alongside morphological and behavioural attributes, our developmental data phylogenetically constrain
Dickinsonia
to the Metazoa, specifically the Eumetazoa plus Placozoa total group. Our findings have implications for the use of
Dickinsonia
in developmental debates surrounding the metazoan acquisition of axis specification and metamerism.
Extreme diel dissolved oxygen and carbon cycles in shallow vegetated lakes
Authors: Andersen Mikkel R. , Kragh Theis , Sand-Jensen Kaj
Published: September 2017

A common perception in limnology is that shallow lakes are homogeneously mixed owing to their small water volume. However, this perception is largely gained by downscaling knowledge from large lakes to their smaller counterparts. Here we show that shallow vegetated lakes (less than 0.6 m), in fact, undergo recurring daytime stratification and nocturnal mixing accompanied by extreme chemical variations during summer. Dense submerged vegetation effectively attenuates light and turbulence generating separation between warm surface waters and much colder bottom waters. Photosynthesis in surface waters produces oxygen accumulation and CO
2
depletion, whereas respiration in dark bottom waters causes anoxia and CO
2
accumulation. High daytime pH in surface waters promotes precipitation of CaCO
3
which is re-dissolved in bottom waters. Nocturnal convective mixing re-introduces oxygen into bottom waters for aerobic respiration and regenerated inorganic carbon into surface waters, which supports intense photosynthesis. Our results reconfigure the basic understanding of local environmental gradients in shallow lakes, one of the most abundant freshwater habitats globally.
Genetic markers of ADHD-related variations in intracranial volume
Authors: Klein Marieke , Walters Raymond K. , Demontis Ditte , Stein Jason L. , Hibar Derrek P. , Adams Hieab H. , Bralten Janita , Mota Nina Roth , Schachar Russell , Sonuga-Barke Edmund , Mattheisen Manuel , Neale Benjamin M. , Thompson Paul M. , Medland Sarah E. , Børglum Anders D. , Faraone Stephen V. , Arias-Vasquez Alejandro , Franke Barbara
Published: September 2017

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology, where genetic risk is hypothesized to be mediated by alterations in structure and function of diverse brain networks. We tested one aspect of this hypothesis by investigating the genetic overlap between ADHD (n=55,374) and (mainly subcortical) brain volumes (n=11,221-24,704), using the largest publicly available studies. At the level of common variant genetic architecture, we discovered a significant negative genetic correlation between ADHD and intracranial volume (ICV). Meta-analysis of individual variants found significant loci associated with both ADHD risk and ICV; additional loci were identified for ADHD and amygdala, caudate nucleus, and putamen volumes. Gene-set analysis in the ADHD-ICV meta-analytic data showed significant association with variation in neurite outgrowth-related genes. In summary, our results suggest new hypotheses about biological mechanisms involved in ADHD etiology and highlight the need to study additional brain parameters.
Gene neighbourhood integrity disrupted by CTCF lossin vivo
Authors: Paul Lee Dominic , Wen Tan Wilson Lek , Anene-Nzelu Chukwuemeka George , Yiqing Li Peter , Luu Danh Tuan Anh , Tiang Zenia , Ng Shi Ling , Efthymios Motakis , Autio Matias I. , Jiang Jianming , Fullwood Melissa , Prabhakar Shyam , Sik-Yin Foo Roger
Published: September 2017

The mammalian genome is coiled, compacted and compartmentalized into complex non-random three-dimensional chromatin loops in the nucleus1–3. At the core of chromatin loop formation is CCCTC-binding factor (CTCF), also described as a “weaver of the genome”45. Anchored by CTCF, chromatin loops are proposed to form through a loop extrusion process6, organising themselves into gene neighbourhoods2that harbour insulated enhancer-promoter domains, restricting enhancer activities to genes within loops, and insulating genes from promiscuous interactions outside of loops2,7–9. Studies targeting CTCF binding site deletions at gene neighbourhood boundaries result in localised gene expression dysregulation8,10–12, and global CTCF depletion recently showed CTCF to be crucial for higher hierarchical chromatin organisation of topologically associating domains (TADs)13. However, the role for CTCF in maintaining sub-TAD CTCF gene neighbourhoods and how gene transcription is affected by CTCF loss remains unclear. In particular, how CTCF gene neighbourhoods govern genome-wide enhancer-promoter interactions require clarification. Here, we took anin vivoapproach to assess the global dissolution of CTCF anchored structures in mouse cardiomyocyte-specificCtcf-knockout (Ctcf-KO), and uncovered large-scale ectopicde novoEnhancer-Promoter (E-P) interactions.In vivocardiomyocyte-specific Ctcf-KO leads to a heart failure phenotype14, but our analysis integrates genome-wide transcription dysregulation with aberrant E-P interactions in context of CTCF-loop structures, identifying how genes engage their E-P interactions, requiring CTCF looping for their maintenance. Our study points to a mammalian genome that possesses a strong propensity towards spontaneous E-P interactionsin vivo, resulting in a diseased transcriptional state, manifest as organ failure. This work solidifies the role of CTCF as the central player for specifying global E-P connections.
Spreading pre-saccadic attentional resources without trade-off
Authors: Puntiroli Michael , Deubel Heiner , Szinte Martin
Published: September 2017

When preparing a saccade, attentional resources are focused at the saccade target and its immediate vicinity. Here we show that this does not hold true when saccades are prepared towards a recently extinguished target. We obtained detailed maps of orientation sensitivity when participants prepared a saccade toward a target that either remained on the screen or disappeared before the eyes moved. We found that attention was mainly focused at the immediate surround of the visible target and increasingly spread to more peripheral locations as a function of the delay between the target’s disappearance and the saccade. Interestingly, this spread was accompanied by an overall increase in sensitivity, speaking against a dilution of limited resources over a larger spatial area. We hypothesize that these results reflect the behavioral consequences of the spatio-temporal dynamics of visual receptive fields in the presence and in the absence a structured visual cue.
“Theory, practice, and conservation in the age of genomics: the Galápagos giant tortoise as a case study”
Authors: Gaughran Stephen J , Quinzin Maud C , Miller Joshua M , Garrick Ryan C , Edwards Danielle L , Russello Michael A , Poulakakis Nikos , Ciofi Claudio , Beheregaray Luciano B , Caccone Adalgisa
Published: September 2017

High-throughput DNA sequencing allows efficient discovery of thousands of single nucleotide polymorphisms (SNPs) in non-model species. Population genetic theory predicts that this large number of independent markers should provide detailed insights into population structure, even when only a few individuals are sampled. Still, sampling design can have a strong impact on such inferences. Here, we use simulations and empirical SNP data to investigate the impacts of sampling design on estimating genetic differentiation among populations that represent three species of Galápagos giant tortoises (Chelonoidisspp.). Though microsatellite and mitochondrial DNA analyses have supported the distinctiveness of these species, a recent study called into question how well these markers matched with data from genomic SNPs, thereby questioning decades of studies in non-model organisms. Using >20,000 genome-wide SNPs from 30 individuals from three Galápagos giant tortoise species, we find distinct structure that matches the relationships described by the traditional genetic markers. Furthermore, we confirm that accurate estimates of genetic differentiation in highly structured natural populations can be obtained using thousands of SNPs and 2-5 individuals, or hundreds of SNPs and 10 individuals, but only if the units of analysis are delineated in a way that is consistent with evolutionary history. We show that the lack of structure in the recent SNP-based study was likely due to unnatural grouping of individuals and erroneous genotype filtering. Our study demonstrates that genomic data enable patterns of genetic differentiation among populations to be elucidated even with few samples per population, and underscores the importance of sampling design. These results have specific implications for studies of population structure in endangered species and subsequent management decisions.

“Modern molecular techniques provide unprecedented power to understand genetic variation in natural populations. Nevertheless, application of this information requires sound understanding of population genetics theory.”

- Fred Allendorf (2017, p. 420)
Statistical machine learning of sleep and physical activity phenotypes from sensor data in 96,220 UK Biobank participants
Authors: Willetts Matthew , Hollowell Sven , Aslett Louis , Holmes Chris , Doherty Aiden
Published: September 2017

Current public health guidelines on physical activity and sleep duration are limited by a reliance on subjective self-reported evidence. Using data from simple wrist-worn activity monitors, we developed a tailored machine learning model, using balanced random forests with Hidden Markov Models, to reliably detect a number of activity modes. We show that physical activity and sleep behaviours can be classified with 87% accuracy in 159,504 minutes of recorded free-living behaviours from 132 adults. These trained models can be used to infer fine resolution activity patterns at the population scale in 96,220 participants. For example, we find that men spend more time in both low- and high-intensity behaviours, while women spend more time in mixed behaviours. Walking time is highest in spring and sleep time lowest during the summer. This work opens the possibility of future public health guidelines informed by the health consequences associated with specific, objectively measured, physical activity and sleep behaviours.
Exome chip meta-analysis elucidates the genetic architecture of rare coding variants in smoking and drinking behavior
Authors: Liu Dajiang J. , Brazel David M. , Turcot Valérie , Zhan Xiaowei , Gong Jian , Barnes Daniel R. , Bertelsen Sarah , Chou Yi-Ling , Erzurumluoglu A. Mesut , Faul Jessica D. , Haessler Jeff , Hammerschlag Anke R. , Hsu Chris , Kapoor Manav , Lai Dongbing , Le Nhung , de Leeuw Christiaan A , Loukola Ana , Mangino Massimo , Melbourne Carl A. , Pistis Giorgio , Qaiser Beenish , Rohde Rebecca , Shao Yaming , Stringham Heather , Wetherill Leah , Zhao Wei , Agrawal Arpana , Beirut Laura , Chen Chu , Eaton Charles B. , Goate Alison , Haiman Christopher , Heath Andrew , Iacono William G. , Martin Nicholas G. , Polderman Tinca J. ,   CHD Exome+ Consortium,   Consortium for Genetics of Smoking Behavior, Reiner Alex , Rice John , Schlessinger David , Scholte H. Steven , Smith Jennifer A. , Tardif Jean-Claude , Tindle Hilary A. , van der Leij Andreis R , Boehnke Michael , Chang-Claude Jenny , Cucca Francesco , David Sean P. , Foroud Tatiana , Kardia Sharon L.R. , Kooperberg Charles , Laakso Markku , Lettre Guillaume , Madden Pamela , McGue Matt , North Kari , Posthuma Danielle , Spector Timothy , Stram Daniel , Weir David R. , Kaprio Jaakko , Abecasis Gonçalo R. , Vrieze Scott
Published: September 2017

Background

Smoking and alcohol use behaviors in humans have been associated with common genetic variants within multiple genomic loci. Investigation of rare variation within these loci holds promise for identifying causal variants impacting biological mechanisms in the etiology of disordered behavior. Microarrays have been designed to genotype rare nonsynonymous and putative loss of function variants. Such variants are expected to have greater deleterious consequences on gene function than other variants, and significantly contribute to disease risk.

Methods

In the present study, we analyzed ∼250,000 rare variants from 17 independent studies. Each variant was tested for association with five addiction-related phenotypes: cigarettes per day, pack years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted single variant tests of all variants, and gene-based burden tests of nonsynonymous or putative loss of function variants with minor allele frequency less than 1%.

Results

Meta-analytic sample sizes ranged from 70,847 to 164,142 individuals, depending on the phenotype. Known loci tagged by common variants replicated, but there was no robust evidence for individually associated rare variants, either in gene based or single variant tests. Using a modified method-of-moment approach, we found that all low frequency coding variants, in aggregate, contributed 1.7% to 3.6% of the phenotypic variation for the five traits (p<.05).

Conclusions

The findings indicate that rare coding variants contribute to phenotypic variation, but that much larger samples and/or denser genotyping of rare variants will be required to successfully identify associations with these phenotypes, whether individual variants or gene‐ based associations.
The FACT complex is required for DNA demethylation at heterochromatin during reproduction in Arabidopsis
Authors: Frost Jennifer M. , Kim M. Yvonne , Park Guen-Tae , Hsieh Ping-Hung , Nakamura Miyuki , Lin Samuel , Yoo Hyunjin , Choi Jaemyung , Ikeda Yoko , Kinoshita Tetsu , Choi Yeonhee , Zilberman Daniel , Fischer Robert L.
Published: September 2017

The DEMETER (DME) DNA glycosylase catalyzes genome-wide DNA demethylation and is required for endosperm genomic imprinting and embryo viability. Targets of DME-mediated DNA demethylation reside in small, euchromatic, AT-rich transposons and at the boundaries of large transposons, but how DME interacts with these diverse chromatin states is unknown. The STRUCTURE SPECIFIC RECOGNITION PROTEIN 1 (SSRP1), subunit of the chromatin remodeler FAcilitates Chromatin Transactions (FACT), was previously shown to be involved in the DME-dependent regulation of genomic imprinting in Arabidopsis endosperm. Therefore, to investigate the interaction between DME and chromatin, we focused on the activity of the two FACT subunits, SSRP1 and SUPPRESSOR of TY16 (SPT16), during reproduction in Arabidopsis. We find that FACT co-localizes with nuclear DME in vivo, and that DME has two classes of target sites, the first being euchromatic and accessible to DME, but the second, representing over half of DME targets, requiring the action of FACT for DME-mediated DNA demethylation genome-wide. Our results show that the FACT-dependent DME targets are GC-rich heterochromatin domains with high nucleosome occupancy enriched with H3K9me2 and H3K27me1. Further, we demonstrate that heterochromatin-associated linker histone H1 specifically mediates the requirement for FACT at a subset of DME-target loci. Overall, our results demonstrate that FACT is required for DME targeting by facilitating its access to heterochromatin.
Computational complexity as an ultimate constraint on evolution
Authors: Kaznatcheev Artem
Published: September 2017

Experiments show that evolutionary fitness landscapes can have a rich combinatorial structure due to epistasis. For some landscapes, this structure can produce a computational constraint that prevents evolution from finding local fitness optima – thus overturning the traditional assumption that local fitness peaks can always be reached quickly if no other evolutionary forces challenge natural selection. Here, I introduce a distinction between easy landscapes of traditional theory where local fitness peaks can be found in a moderate number of steps and hard landscapes where finding local optima requires an infeasible amount of time. Hard examples exist even among landscapes with no reciprocal sign epistasis; on these semi-smooth fitness landscapes, strong selection weak mutation dynamics cannot find the unique peak in polynomial time. More generally, on hard rugged fitness landscapes that include reciprocal sign epistasis, no evolutionary dynamics – even ones that do not follow adaptive paths – can find a local fitness optimum quickly. Moreover, on hard landscapes, the fitness advantage of nearby mutants cannot drop off exponentially fast but has to follow a power-law that long term evolution experiments have associated with unbounded growth in fitness. Thus, the constraint of computational complexity enables open-ended evolution on finite landscapes. Knowing this constraint allows us to use the tools of theoretical computer science and combinatorial optimization to characterize the fitness landscapes that we expect to see in nature. I present candidates for hard landscapes at scales from single genes, to microbes, to complex organisms with costly learning (Baldwin effect) or maintained cooperation (Hankshaw effect). Just how ubiquitous hard landscapes (and the corresponding ultimate constraint on evolution) are in nature becomes an open empirical question.
Mitochondrial Dual-coding Genes inTrypanosomabrucei
Authors: Kirby Laura E. , Koslowsky Donna
Published: September 2017

Trypanosoma bruceiis transmitted between mammalian hosts by the tsetse fly. In the mammal, they are exclusively extracellular, continuously replicating within the bloodstream. During this stage, the mitochondrion lacks a functional electron transport chain (ETC). Successful transition to the fly, requires activation of the ETC and ATP synthesis via oxidative phosphorylation. This life cycle leads to a major problem: in the bloodstream, the mitochondrial genes are not under selection and are subject to genetic drift that endangers their integrity. Exacerbating this,T. bruceiundergoes repeated population bottlenecks as they evade the host immune system that would create additional forces of genetic drift. These parasites possess several unique genetic features, including RNA editing of mitochondrial transcripts. RNA editing creates open reading frames by the guided insertion and deletion of U-residues within the mRNA. A major question in the field has been why this metabolically expensive system of RNA editing would evolve and persist. Here, we show that many of the edited mRNAs can alter the choice of start codon and the open reading frame by alternative editing of the 5’ end. Analyses of mutational bias indicate that six of the mitochondrial genes may be dual-coding and that RNA editing allows access to both reading frames. We hypothesize that dual-coding genes can protect genetic information by essentially hiding a non-selected gene within one that remains under selection. Thus, the complex RNA editing system found in the mitochondria of trypanosomes provides a unique molecular strategy to combat genetic drift in non-selective conditions.

Author Summary

In African trypanosomes, many of the mitochondrial mRNAs require extensive RNA editing before they can be translated. During this process, each edited transcript can undergo hundreds of cleavage/ligation events as U-residues are inserted or deleted to generate a translatable open reading frame. A major paradox has been why this incredibly metabolically expensive process would evolve and persist. In this work, we show that many of the mitochondrial genes in trypanosomes are dual-coding, utilizing different reading frames to potentially produce two very different proteins. Access to both reading frames is made possible by alternative editing of the 5’ end of the transcript. We hypothesize that dual-coding genes may work to protect the mitochondrial genes from mutations during growth in the mammalian host, when many of the mitochondrial genes are not being used. Thus, the complex RNA editing system may be maintained because it provides a unique molecular strategy to combat genetic drift.