bluuebunny/crossref_metadata_2025 huggingface dataset:
Finding associated variants in genome-wide association studies on multiple traits
Authors: Gai Lisa , Eskin Eleazar
Published: May 2018

Motivation

Many variants identified by genome-wide association studies (GWAS) have been found to affect multiple traits, either directly or through shared pathways. There is currently a wealth of GWAS data collected in numerous phenotypes, and analyzing multiple traits at once can increase power to detect shared variant effects. However, traditional meta-analysis methods are not suitable for combining studies on different traits. When applied to dissimilar studies, these meta-analysis methods can be underpowered compared to univariate analysis. The degree to which traits share variant effects is often not known, and the vast majority of GWAS meta-analysis only consider one trait at a time.

Results

Here, we present a flexible method for finding associated variants from GWAS summary statistics for multiple traits. Our method estimates the degree of shared effects between traits from the data. Using simulations, we show that our method properly controls the false positive rate and increases power when an effect is present in a subset of traits. We then apply our method to the North Finland Birth Cohort and UK Biobank datasets using a variety of metabolic traits and discover novel loci.

Availability and implementation

Our source code is available at https://github.com/lgai/CONFIT.

Supplementary information

Supplementary data are available at Bioinformatics online.
dbCRSR: a manually curated database for regulation of cancer radiosensitivity
Authors: Wen Pengbo , Xia Junfeng , Cao Xianbin , Chen Bin , Tao Yinping , Wu Lijun , Xu An , Zhao Guoping
Published: May 2018

Radiotherapy is used to treat approximately 50% of all cancer patients, with varying prognoses. Intrinsic radiosensitivity is an important factor underlying the radiotherapeutic efficacy of this precise treatment. During the past decades, great efforts have been made to improve radiotherapy treatment through multiple strategies. However, invaluable data remains buried in the extensive radiotherapy literature, making it difficult to obtain an overall view of the detailed mechanisms leading to radiosensitivity, thus limiting advances in radiotherapy. To address this issue, we collected data from the relevant literature contained in the PubMed database and developed a literature-based database that we term the cancer radiosensitivity regulation factors database (dbCRSR). dbCRSR is a manually curated catalogue of radiosensitivity, containing multiple radiosensitivity regulation factors (395 coding genes, 119 non-coding RNAs and 306 chemical compounds) with appropriate annotation. To illustrate the value of the data we collected, data mining was performed including functional annotation and network analysis. In summary, dbCRSR is the first literature-based database to focus on radiosensitivity and provides a resource to better understand the detailed mechanisms of radiosensitivity. We anticipate dbCRSR will be a useful resource to enrich our knowledge and to promote further study of radiosensitivity.

Database URL: http://bioinfo.ahu.edu.cn:8080/dbCRSR/
Growing health in UK prison settings
Authors: Baybutt Michelle , Dooris Mark , Farrier Alan
Published: May 2018

Globally, prisoners tend to come from marginalized and socially disadvantaged sections of the society and exhibit a high incidence of ill health, linked to social exclusion and multiple complex needs. Prisons therefore offer an important opportunity to tackle inequality and injustice, through promoting health, reducing reoffending and facilitating community reintegration.This paper reports on and critically discusses findings from an evaluative research study, which aimed to identify and explore impacts of prisoners’ participation in an innovative social and therapeutic horticultural programme, ‘Greener on the Outside for Prisons’ (GOOP), delivered in prisons in North West England. Focus groups with 16 prisoners and semi-structured interviews with six prison staff were conducted at five sites. Presented under three overarching themes (health and well-being; skills development, employability, and work preparedness; and relationships), findings suggest that engagement with and participation in GOOP were important in improving positive mental well-being, increasing physical activity and knowledge about healthier eating; developing skills and work readiness; and building relationships and catalysing and strengthening prosocial behaviours, important for good citizenship and effective resettlement. The paper concludes that – in the context of the current UK prison reform agenda and concern about the high incidence of violence, substance misuse, self-harm and suicide – prison-based horticulture can offer multiple benefits and make a significant contribution to the creation of safe, secure, supportive and health-enhancing environments. Furthermore, it contends that by joining up health and justice agendas, programmes such as GOOP have the potential to serve as powerful catalysts for wider systemic change, thereby helping tackle inequalities and social exclusion within societies across the globe.
Dimension Formulae in Genus Zero and Uniqueness of Vertex Operator Algebras
Authors: van Ekeren Jethro , Möller Sven , Scheithauer Nils R
Published: May 2018

We prove a dimension formula for orbifold vertex operator algebras of central charge 24 by automorphisms of order n such that $\Gamma _{0}(n)$ is a genus zero group. We then use this formula together with the inverse orbifold construction for automorphisms of orders 2, 4, 5, 6, and 8 to establish that each of the following fifteen Lie algebras is the weight-one space $V_{1}$ of exactly one holomorphic, $C_{2}$-cofinite vertex operator algebra V of CFT type and central charge 24: $A_{5}C_{5}E_{6,2}$, $A_{3}A_{7,2}{C_{3}^{2}}$, $A_{8,2}F_{4,2}$, $B_{8}E_{8,2}$, ${A_{2}^{2}}A_{5,2}^{2}B_{2}$, $C_{8}{F_{4}^{2}}$, $A_{4,2}^{2}C_{4,2}$, $A_{2,2}^{4}D_{4,4}$, $B_{5}E_{7,2}F_{4}$, $B_{4}{C_{6}^{2}}$, $A_{4,5}^{2}$, $A_{4}A_{9,2}B_{3}$, $B_{6}C_{10}$, $A_{1}C_{5,3}G_{2,2}$, and $A_{1,2}A_{3,4}^{3}$.
A Generalized Turán Problem and its Applications
Authors: Gishboliner Lior , Shapira Asaf
Published: May 2018

The investigation of conditions guaranteeing the appearance of cycles of certain lengths is one of the most well-studied topics in graph theory. In this paper we consider a problem of this type that asks, for fixed integers ℓ and k, how many copies of the k-cycle guarantee the appearance of an ℓ-cycle? Extending previous results of Bollobás–Gy̋ri–Li and Alon–Shikhelman, we fully resolve this problem by giving tight (or nearly tight) bounds for all values of ℓ and k. We also present a somewhat surprising application of the above mentioned estimates to the study of the graph removal lemma. Prior to this work, all bounds for removal lemmas were either polynomial or there was a tower-type gap between the best-known upper and lower bounds. We fill this gap by showing that for every super-polynomial function $f(\varepsilon )$, there is a family of graphs ${\mathcal F}$, such that the bounds for the ${\mathcal F}$ removal lemma are precisely given by $f(\varepsilon )$. We thus obtain the 1st examples of removal lemmas with tight super-polynomial bounds. A special case of this result resolves a problem of Alon and the 2nd author, while another special case partially resolves a problem of Goldreich.
Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma
Authors: Gupta Nalin , Goumnerova Liliana C , Manley Peter , Chi Susan N , Neuberg Donna , Puligandla Maneka , Fangusaro Jason , Goldman Stewart , Tomita Tadanori , Alden Tord , DiPatri Arthur , Rubin Joshua B , Gauvain Karen , Limbrick David , Leonard Jeffrey , Geyer J Russel , Leary Sarah , Browd Samuel , Wang Zhihong , Sood Sandeep , Bendel Anne , Nagib Mahmoud , Gardner Sharon , Karajannis Matthias A , Harter David , Ayyanar Kanyalakshmi , Gump William , Bowers Daniel C , Weprin Bradley , MacDonald Tobey J , Aguilera Dolly , Brahma Barunashish , Robison Nathan J , Kiehna Erin , Krieger Mark , Sandler Eric , Aldana Philipp , Khatib Ziad , Ragheb John , Bhatia Sanjiv , Mueller Sabine , Banerjee Anu , Bredlau Amy-Lee , Gururangan Sri , Fuchs Herbert , Cohen Kenneth J , Jallo George , Dorris Kathleen , Handler Michael , Comito Melanie , Dias Mark , Nazemi Kellie , Baird Lissa , Murray Jeff , Lindeman Neal , Hornick Jason L , Malkin Hayley , Sinai Claire , Greenspan Lianne , Wright Karen D , Prados Michael , Bandopadhayay Pratiti , Ligon Keith L , Kieran Mark W
Published: May 2018

Background

Diagnosis of diffuse intrinsic pontine glioma (DIPG) has relied on imaging studies, since the appearance is pathognomonic, and surgical risk was felt to be high and unlikely to affect therapy. The DIPG Biology and Treatment Study (DIPG-BATS) reported here incorporated a surgical biopsy at presentation and stratified subjects to receive FDA-approved agents chosen on the basis of specific biologic targets.

Methods

Subjects were eligible for the trial if the clinical features and imaging appearance of a newly diagnosed tumor were consistent with a DIPG. Surgical biopsies were performed after enrollment and prior to definitive treatment. All subjects were treated with conventional external beam radiotherapy with bevacizumab, and then stratified to receive bevacizumab with erlotinib or temozolomide, both agents, or neither agent, based on O6-methylguanine-DNA methyltransferase status and epidermal growth factor receptor expression. Whole-genome sequencing and RNA sequencing were performed but not used for treatment assignment.

Results

Fifty-three patients were enrolled at 23 institutions, and 50 underwent biopsy. The median age was 6.4 years, with 24 male and 29 female subjects. Surgical biopsies were performed with a specified technique and no deaths were attributed to the procedure. Two subjects experienced grade 3 toxicities during the procedure (apnea, n = 1; hypertension, n = 1). One subject experienced a neurologic deficit (left hemiparesis) that did not fully recover. Of the 50 tumors biopsied, 46 provided sufficient tissue to perform the study assays (92%, two-stage exact binomial 90% CI: 83%–97%).

Conclusions

Surgical biopsy of DIPGs is technically feasible, associated with acceptable risks, and can provide biologic data that can inform treatment decisions.
Flavescence Dorée and Bois Noir Diseases of Grapevine Are Evolving Pathosystems
Authors: Tessitori Matilde , La Rosa Rosa , Marzachì Cristina
Published: May 2018

Grapevine yellows (GYs) are mainly spread in European viticultural areas. Phytosanitary measures worldwide are based on data obtained on classical pathosystems, but the latest findings suggest that the epidemiological pattern of these diseases is evolving and adapting to different ecological conditions. Risk assessment of introduction in GY-free areas has to be reconsidered in view of the broadening of the range of pathways of entry and means of diffusion in the field. The purpose of this review is to make available an update on findings of recent years to provide useful tools to prevent further spread of these serious diseases of grapevine.
Disruptive Technology
Authors: McPherson Penne , Talbot Elizabeth
Published: May 2018

Competent, efficient, and cost-effective delivery of professional development is a challenge in health care. Collaboration of teaching methodologies with academia and acute care offers fresh perspectives and delivery methods that can facilitate optimal outcomes. One multihospital system introduced the academic “flipped classroom” model to its acute care setting and integrated it into professional development requirements. The concept of the flipped classroom requires independent student engagement prior to classroom activities versus the traditional classroom lecture model. Results realized a cost savings in 2 years of $28,737 in addition to positive employee engagement.
Transforming Orientation Through a Tiered Skills Acquisition Model
Authors: Joswiak M. Ellen
Published: May 2018

The tiered skills acquisition model (TSAM) is an effective method for structuring the clinical unit orientation. The orientee gradually assumes increased responsibilities based on advancing through tiers of skills from simple to complex. This article focuses on TSAM implemented at a teaching hospital with 188 newly licensed registered nurses. TSAM has increased nurses’ confidence, role satisfaction, retention, reduced overall length of orientation by 18%, and increased the number of patient experiences by 45%.
Use of a Contralateral Nasoseptal Flap for Sino-Orbital Fistula Closure
Authors: Hararah Mohammad K. , Mattingly Jameson K. , Ramakrishnan Vijay R.
Published: May 2018

Sino-orbital fistulas can occur after orbital exenteration. Chronic nonhealing fistulas lead to bothersome symptoms including malodorous discharge, hypernasal speech, crusting, wound breakdown, or inability to wear an ocular prosthesis. Reconstruction can be difficult due to the complexity of the defects and the multitude of treatments patients often undergo for the management of the primary disease. Prior radiation, lack of available local tissue, or compromised blood supply are some of the issues that make successful fistula closure problematic. This report describes a method for autologous vascularized tissue coverage using a contralateral nasoseptal flap to successfully close a sino-orbital fistula.
Ocular Chemical Burns Secondary to Accidental Administration of e-Cigarette Liquid
Authors: McCague Yvonne
Published: May 2018

Chemical burns to the eye represent a true ocular emergency, requiring immediate and proficient attention to preserve visual function. Although there have been very few reports of serious ocular burns secondary to the accidental administration of electronic cigarette liquid, this case report discusses the risk of same because of product confusion between electronic cigarette liquid and ocular preparations. This article presents a patient's case including patient history and management in the emergency department. The significance of chemical burns to the eye and its management is discussed in relation to significance to clinical practice for all nurses, nurse practitioners, and physicians working in the emergency department.
Time Spent in the Emergency Department and Outcomes in Patients With Severe Sepsis and Septic Shock
Authors: Hirschy RaeAnn , Sterk Ethan , Dobersztyn Rachel , Rech Megan A.
Published: May 2018

A majority of patients with severe sepsis and septic shock are first evaluated in the emergency department (ED). Methods such as screening tools have proven advantageous in earlier identification, allowing for timely initiation of treatment. Delay in symptom presentation and ED overcrowding contribute to deferment of sepsis bundle components and admission. To examine the impact of time from ED arrival to inpatient admission on mortality and length of stay (LOS) in patients with severe sepsis or septic shock. A retrospective analysis of adult patients with severe sepsis or septic shock was completed for those presenting between January 2013 and December 2014. Patients were dichotomized on the basis of the length of time from completed triage in the ED to intensive care unit (ICU) admission (at less than 6 hr and at 6 hr or more). Of the 294 patients screened, 172 patients (58.5%) met inclusion criteria (n= 70 cases at less than 6 hr;n= 102 at 6 hr or more). Mean wait time from ED arrival to ICU admission was 470.7 ± 333.9 min (range = 84–2,390 min). Groups were similar in baseline, disease severity, and bundle characteristics. There were no differences in the less than 6-hr group compared with the 6-hr-or-more group in rates of 30-day mortality (37.1% vs. 32.4%;p= 0.52), as well as in-hospital (27.1% vs. 23.5%;p= 0.59) or 90-day mortality (42.9% vs. 34.3%;p= 0.26). There were also no differences in hospital or ICU LOS. Timing of transfer from the ED to the ICU was not found to impact mortality or LOS. These results suggest that the ED can provide similar sepsis care to that in the ICU when transfer is delayed in patients with sepsis.
Acute Headache in the Emergency Department
Authors: Steffens Sarah , Tucker Paula , Evans Dian Dowling
Published: May 2018

The purpose of the Research to Practice column is to review current primary journal articles that directly affect the practice of the advanced practice nurse (APN) in the emergency department. This review examines the findings of Carpenter et al. (2016) from their article, “Spontaneous Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis Describing the Diagnostic Accuracy of History, Physical Exam, Imaging, and Lumbar Puncture With an Exploration of Test Thresholds.” The authors concluded that although no history or physical examination finding can be used to rule in or rule out spontaneous subarachnoid hemorrhage (SAH), the complaint of neck stiffness can increase the likelihood of SAH. In addition, the authors concluded that noncontrast head computed tomography (CT) is accurate in ruling out/in SAH when performed within 6 hr of symptom onset in adults with symptoms consistent with SAH and that the traditional gold standard of confirmatory lumbar puncture after a negative head CT scan is only helpful in patients with a very high pretest probability of SAH. By applying the evidence-based criteria presented in this study, the emergency department APN can confidently rule out SAH and reduce patient risks from unnecessary invasive and costly testing.
Illuminating the microbiome’s dark matter: a functional genomic toolkit for the study of human gut Actinobacteria
Authors: Bisanz Jordan E , Soto-Perez Paola , Lam Kathy N , Bess Elizabeth N , Haiser Henry J , Allen-Vercoe Emma , Rekdal Vayu M , Balskus Emily P , Turnbaugh Peter J
Published: May 2018

Despite the remarkable evolutionary and metabolic diversity found within the human microbiome, the vast majority of mechanistic studies focus on two phyla: the Bacteroidetes and the Proteobacteria. Generalizable tools for studying the other phyla are urgently needed in order to transition microbiome research from a descriptive to a mechanistic discipline. Here, we focus on the Coriobacteriia class within the Actinobacteria phylum, detected in the distal gut of 90% of adult individuals around the world, which have been associated with both chronic and infectious disease, and play a key role in the metabolism of pharmaceutical, dietary, and endogenous compounds. We established, sequenced, and annotated a strain collection spanning 14 genera, 8 decades, and 3 continents, with a focus onEggerthella lenta. Genome-wide alignments revealed inconsistencies in the taxonomy of the Coriobacteriia for which amendments have been proposed. Re-sequencing of theE. lentatype strain from multiple culture collections and our laboratory stock allowed us to identify errors in the finished genome and to identify point mutations associated with antibiotic resistance. Analysis of 24E. lentagenomes revealed an “open” pan-genome suggesting we still have not fully sampled the genetic and metabolic diversity within this bacterial species. Consistent with the requirement for arginine duringin vitrogrowth, the coreE. lentagenome included the arginine dihydrolase pathway. Surprisingly, glycolysis and the citric acid cycle was also conserved inE. lentadespite the lack of evidence for carbohydrate utilization. We identified a species-specific marker gene and validated a multiplexed quantitative PCR assay for simultaneous detection ofE. lentaand specific genes of interest from stool samples. Finally, we demonstrated the utility of comparative genomics for linking variable genes to strain-specific phenotypes, including antibiotic resistance and drug metabolism. To facilitate the continued functional genomic analysis of the Coriobacteriia, we have deposited the full collection of strains in DSMZ and have written a general software tool (ElenMatchR) that can be readily applied to novel phenotypic traits of interest. Together, these tools provide a first step towards a molecular understanding of the many neglected but clinically-relevant members of the human gut microbiome.
Cas9/CRISPR genome editing to demonstrate the contribution of Cyp51A Gly138Ser to azole resistance in Aspergillus fumigatus
Authors: Umeyama Takashi , Hayashi Yuta , Shimosaka Hisaki , Inukai Tatsuya , Yamagoe Satoshi , Takatsuka Shogo , Hoshino Yasutaka , Nagi Minoru , Nakamura Shigeki , Kamei Katsuhiko , Ogawa Kenji , Miyazaki Yoshitsugu
Published: May 2018

Azole resistance in Aspergillus fumigatus is predominantly associated with increased expression of Cyp51A (lanosterol 14α-demethylase), the target enzyme of azole antifungal agents, or with single-nucleotide polymorphisms (SNPs) in cyp51A. Although several SNPs that may be linked to low susceptibility in azole-resistant isolates have previously been reported, few studies have been conducted to conclusively demonstrate the contribution of SNPs to decreased azole susceptibility. An A. fumigatus strain was isolated from the sputum of a 74-year-old male receiving long-term voriconazole treatment for chronic progressive pulmonary aspergillosis. Etest antifungal susceptibility testing showed low susceptibility to voriconazole, itraconazole, and posaconazole. Nucleotide sequencing of cyp51A from this isolate revealed the mutations Gly138Ser (GGC→AGC) and Asn248Lys (AAT→AAA) compared with the cyp51A of azole-susceptible isolates. PCR-amplified DNA fragments containing cyp51A with or without the mutations of interest and a hygromycin marker were simultaneously introduced along with the Cas9 protein and in vitro-synthesized single-guide RNA into protoplasts of the azole-resistant/susceptible strains. Etest azole susceptibility testing of recombinant strains showed an increased susceptibility via the replacement of Ser138 by glycine. In contrast, azole susceptibility was slightly decreased when a Ser138 mutation was introduced into the azole-susceptible strain AfS35, indicating that the serine at position 138 of Cyp51A contributes to low susceptibility in the azole-resistant isolate. Genetic recombination, which has been hampered thus far in clinical isolates, can now be achieved using Cas9/CRISPR genome editing. This technique could be useful to investigate the contribution of other SNPs of cyp51A to azole resistance.
Clear, extended field-of-view single-molecule imaging by highly inclined swept illumination
Authors: Tang Jialei , Han Kyu Young
Published: May 2018

Highly inclined and laminated optical sheet (HILO) illumination facilitates high-contrast single-molecule imaging inside cells with a single objective lens. However, the beam thickness is strongly coupled to the illumination area, limiting its usage. Here, we present highly inclined swept tile illumination microscopy (HIST). By sweeping a thin HILO beam with confocal slit detection, HIST provides a 2-fold thinner illumination and >40-fold larger imaging area than conventional HILO microscopy, enabling 3D single-molecule imaging with high signal-to-background ratio. We demonstrate single-molecule mRNA imaging with a few probes or a single probe in cultured cells and mouse brain tissues.
Spatiotemporally controlled Myosin relocalization and internal pressure cause biased cortical extension to generate sibling cell size asymmetry
Authors: Pham Tri Thanh , Monnard Arnaud , Helenius Jonne , Lund Erik , Lee Nicole , Müller Daniel J. , Cabernard Clemens
Published: May 2018

Metazoan cells can generate unequal sized sibling cells during cell division. This form of asymmetric cell division depends on spindle geometry and Myosin distribution but the underlying mechanics are unclear. Here, we use atomic force microscopy and live cell imaging to elucidate the biophysical forces involved in the establishment of physical asymmetry in Drosophila neural stem cells. We show that the force driving initial apical membrane expansion is provided by hydrostatic pressure, peaking shortly after anaphase onset, and enabled by a relieve of actomyosin contractile tension on the apical cell cortex. The subsequent increase in contractile forces at the cleavage furrow, combined with the relocalization of basally located Myosin results in basal membrane extension and sustained apical expansion. We propose that spatiotemporally controlled actomyosin contractile tension and hydrostatic pressure enables stereotypic biased membrane expansion to generate sibling cell size asymmetry.
Dissecting the herpesvirus architecture by targeted proteolysis
Authors: Daniel Gina R. , Pegg Caitlin E. , Smith Gregory A.
Published: May 2018

Herpesvirus particles have a complex architecture consisting of an icosahedral capsid that is surrounded by a lipid envelope. Connecting these two components is a layer of tegument that consists of varying amounts of twenty or more proteins. The arrangement of proteins within the tegument cannot easily be assessed and instead is inferred from tegument interactions identified in reductionist models. To better understand the tegument architecture, we have developed an approach to probe capsid-tegument interactions within extracellular viral particles by encoding tobacco etch virus (TEV) protease sites in viral structural proteins, along with distinct fluorescent tags in capsid and tegument components. In this study, TEV sites were engineered within the pUL36 large tegument protein: a critical structural element that is anchored directly on the capsid surface. Purified pseudorabies virus extracellular particles were permeabilized and TEV protease was added to selectively cleave the exposed pUL36 backbone. Interactions with the capsid were assessed in situ by monitoring the fate of the fluorescent signals following cleavage. Although several regions of pUL36 are proposed to bind capsids, pUL36 was found stably anchored to the capsid exclusively at its carboxyl terminus. Two additional tegument proteins, pUL37 and pUS3, were tethered to the capsid via pUL36 whereas the pUL16, pUL47, pUL48, and pUL49 tegument proteins were not stably bound to the capsid.

IMPORTANCE

Neuroinvasive alphaherpesviruses produce diseases of clinical and economic significance in humans and veterinary animals, but are predominantly associated with less serious recurrent disease. Like all viruses, herpesviruses assemble a metastable particle that selectively dismantles during initial infection. This process is made more complex by the presence of a tegument layer that resides between the capsid surface and envelope. Components of the tegument are essential for particle assembly and also serve as critical effectors that promote infection upon entry into cells. How this dynamic network of protein interactions is arranged within virions is largely unknown. We present a molecular approach to dissect the tegument and with it, begin to tease apart the protein interactions that underlie this complex layer of the virion architecture.
Intestinal bacteria modulate the foraging behavior of the Oriental fruit flyBactrocera dorsalis(Diptera: Tephritidae)
Authors: Akami Mazarin , Andongma Awawing A. , Zhengzhong Chen , Nan Jiang , Khaeso Kanjana , Jurkevitch Edouard , Niu Chang-Ying , Yuval Boaz
Published: May 2018

The gut microbiome of insects directly or indirectly affects the metabolism, immune status, sensory perception and feeding behavior of its host. Here, we examine the hypothesis that in the Oriental fruit fly(Bactrocera dorsalis, Diptera: Tephritidae), the presence or absence of gut symbionts affects foraging behavior and nutrient ingestion. We offered protein starved flies, symbiotic or aposymbiotic, a choice between diets containing all amino acids or only the non-essential ones. The different diets were presented in a foraging arena as drops that varied in their size and density, creating an imbalanced foraging environment. Suppressing the microbiome resulted in significant changes of the foraging behavior of both male and female flies. Aposymbiotic flies responded faster to the diets offered in experimental arenas, spent more time feeding, ingested more drops of food, and were constrained to feed on time consuming patches (containing small drops of food), when these offered the full complement of amino acids. We discuss these results in the context of previous studies on the effect of the gut microbiome on host behavior, and suggest that these be extended to the life history dimension.

Importance and significance of the study

The gut bacteria of tephritid fruit flies provide nutritional benefits to their hosts, by making essential amino-acids readily available. Foraging for food is risky, as active flies are exposed to predators and incur a considerable investment of time and energy. Therefore, making beneficial compromises between the feeding time and nutrient ingestion is a question of survival for the flies. Our study demonstrates how gut bacteria drive this behavior by allowing symbiotic flies to forage optimally while acquiring essential nutrients. This finding adds a novel step to the nexus connecting the insect gut, its microbiome, the nervous system, chemoreception to individual patterns of foraging.
Skyhawk: An Artificial Neural Network-based discriminator for reviewing clinically significant genomic variants
Authors: Luo Ruibang , Lam Tak-Wah , Schatz Michael C.
Published: May 2018

Motivation

Many rare diseases and cancers are fundamentally diseases of the genome. In the past several years, genome sequencing has become one of the most important tools in clinical practice for rare disease diagnosis and targeted cancer therapy. However, variant interpretation remains the bottleneck as is not yet automated and may take a specialist several hours of work per patient. On average, one-fifth of this time is spent on visually confirming the authenticity of the candidate variants.

Results

We developed Skyhawk, an artificial neural network-based discriminator that mimics the process of expert review on clinically significant genomics variants. Skyhawk runs in less than one minute to review ten thousand variants, and about 30 minutes to review all variants in a typical whole-genome sequencing sample. Among the false positive singletons identified by GATK HaplotypeCaller, UnifiedGenotyper and 16GT in the HG005 GIAB sample, 79.7% were rejected by Skyhawk. Worked on the Variants with Unknown Significance (VUS), Skyhawk marked most of the false positive variants for manual review and most of the true positive variants no need for review.

Availability

Skyhawk is easy to use and freely available at https://github.com/aquaskyline/Skyhawk
Molecular architecture of theLegionellaDot/Icm type IV secretion system
Authors: Ghosal Debnath , Chang Yi-Wei , Jeong Kwang Cheol , Vogel Joseph P. , Jensen Grant J.
Published: May 2018

Legionella pneumophilasurvives and replicates inside host cells by secreting ~300 effectors through the Dot/Icm type IVB secretion system (T4BSS). Understanding this machine’s structure is challenging because of its large number of components (27) and integration into all layers of the cell envelope. Previously we overcame this obstacle by imaging the Dot/Icm T4BSS in its native state within intact cells through electron cryotomography. Here we extend our observations by imaging a stabilized mutant that yielded a higher resolution map. We describe for the first time the presence of a well-ordered central channel that opens up into a windowed large (~32 nm wide) secretion chamber with an unusual 13-fold symmetry. We then dissect the complex by matching proteins to densities for many components, including all those with periplasmic domains. The placement of known and predicted structures of individual proteins into the map reveals the architecture of the T4BSS and provides a roadmap for further investigation of this amazing specialized secretion system.
Melissa: Bayesian clustering and imputation of single cell methylomes
Authors: Kapourani Chantriolnt-Andreas , Sanguinetti Guido
Published: May 2018

Measurements of DNA methylation at the single cell level are promising to revolutionise our understanding of epigenetic control of gene expression. Yet, intrinsic limitations of the technology result in very sparse coverage of CpG sites (around 5% to 20% coverage), effectively limiting the analysis repertoire to a semi-quantitative level. Here we introduce Melissa (MEthyLation Inference for Single cell Analysis), a Bayesian hierarchical method to quantify spatially-varying methylation profiles across genomic regions from single-cell bisulfite sequencing data (scBS-seq). Melissa clusters individual cells based on local methylation patterns, enabling the discovery of epigenetic differences and similarities among individual cells. The clustering also acts as an effective regularisation method for imputation of methylation on unassayed CpG sites, enabling transfer of information between individual cells. We show both on simulated and real data sets that Melissa provides accurate and biologically meaningful clusterings, and state-of-the-art imputation performance. An R implementation of Melissa is publicly available at https://github.com/andreaskapou/Melissa.
A non-canonical lysosome biogenesis pathway generates Golgi-associated lysosomes during epidermal differentiation
Authors: Mahanty Sarmistha , Dakappa Shruthi Shirur , Shariff Rezwan , Patel Saloni , Swamy Mruthyunjaya Mathapathi , Majumdar Amitabha , Setty Subba Rao Gangi
Published: May 2018

Keratinocytes maintain epidermis integrity and function including physical and antimicrobial barrier through cellular differentiation. This process is predicted to be controlled by calcium ion gradient and nutritional stress. Keratinocytes undergo proteome changes during differentiation, which enhances the intracellular organelle digestion to sustain the stress conditions. However, the molecular mechanism between epidermal differentiation and organelle homeostasis is poorly understood. Here, we used primary neonatal human epidermal keratinocytes to study the link between cellular differentiation, signaling pathways and organelle turnover. Upon addition of calcium chloride (2 mM) to the culture medium, keratinocytes increased their cell size and the expression of differentiation markers. Moreover, differentiated keratinocytes showed enhanced lysosome biogenesis that was dependent on ATF6-arm of UPR signaling but independent of mTOR-MiT/TFE transcription factors. Furthermore, chemical inhibition of mTOR has increased keratinocyte differentiation and relocalized the MiT/TFE TFs to the lysosome membranes, indicating that autophagy activation promotes the epidermal differentiation. Interestingly, differentiation of keratinocytes resulted in dispersal of fragmented Golgi and lysosomes, and the later organelles showed colocalization with Golgi-tethering proteins, suggesting that these lysosomes possibly originated from Golgi, hence named as Golgi-associated lysosomes (GALs). Consistent to this prediction, inhibition of Golgi function using brefeldin A completely abolished the formation of GALs and the keratinocyte differentiation. Thus, ER stress regulates the biogenesis of GALs, which maintains keratinocyte differentiation and epidermal homeostasis.
Sensory neuron lineage mapping and manipulation in theDrosophila olfactorysystem
Authors: Chai Phing Chian , Cruchet Steeve , Wigger Leonore , Benton Richard
Published: May 2018

Nervous systems exhibit myriad cell types, but understanding how this diversity arises is hampered by the difficulty to visualize and genetically-interrogate specific lineages, especially at early developmental stages prior to expression of unique molecular markers. Here, we use a genetic immortalization method to analyze the development of sensory neuron lineages in theDrosophilaolfactory system, from their origin to terminal differentiation. We apply this approach to first define a fate map of all olfactory lineages and refine the model of temporal patterns of lineage divisions. Taking advantage of a selective marker for the lineage that gives rise to Or67d pheromone-sensing neurons and a genome-wide transcription factor RNAi screen, we identify the spatial and temporal requirements for Pointed, an ETS family member, in this developmental pathway. Transcriptomic analysis of wild-type and Pointed-depleted olfactory tissue reveals a universal requirement for this factor as a switch-like determinant of fates in these sensory lineages.
Redox fluctuations control the coupled cycling of iron and carbon in tropical forest soils
Authors: Bhattacharyya Amrita , Campbell Ashley N. , Tfaily Malak M. , Lin Yang , Silver Whendee L. , Nico Peter S. , Pett-Ridge Jennifer
Published: May 2018

Oscillating redox conditions are the norm in tropical soils; driven by an ample supply of reductants, high moisture, microbial oxygen consumption, and finely textured clays that limit diffusion. Yet the net result of variable soil redox regimes on iron-organic matter (Fe-OM) associations in tropical soils owing to changing climate is poorly understood. Using a 44-day redox incubation experiment with humid tropical soils from Puerto Rico, we examined patterns of Fe and C transformation under four redox regimes: static anoxic, flux 4-day (4d oxic, 4d anoxic), flux 8-day (8d oxic, 4d anoxic) and static anoxic. Prolonged anoxia promoted reductive dissolution of Fe-oxides and an increase in short-range ordered (SRO) Fe oxides. Preferential dissolution of this less-crystalline Fe pool was evident immediately following a shift in bulk redox status (oxic to anoxic), and coincided with increased dissolved organic carbon, presumably due to acidification or direct release of OM from dissolving Fe(III) mineral phases. Average nominal oxidation state of water-soluble carbon was lowest under persistent anoxic conditions, suggesting more reduced OC is microbially preserved under reducing conditions. Anoxic soil compounds had high H/C values (similar to lignin-like metabolites) whereas oxic soil compounds had higher O/C values, akin to tannin- and cellulose-like components. Cumulative respiration derived from native soil organic carbon was highest in static oxic soils. These results highlight the volatility of mineral-OM interactions in tropical soils, and suggest that short-term impacts of shifting soil O2 availability control exchanges of C between mineral-sorbed and aqueous pools, implying that the periodicity of low-redox moments may control the fate of C in wet tropical soils.

Toc Art
ChIP-seq
Authors: Kim Tae Hoon , Dekker Job
Published: May 2018

Owing to its digital nature, ChIP-seq has become the standard method for genome-wide ChIP analysis. Using next-generation sequencing platforms (notably the Illumina Genome Analyzer), millions of short sequence reads can be obtained. The densities of recovered ChIP sequence reads along the genome are used to determine the binding sites of the protein. Although a relatively small amount of ChIP DNA is required for ChIP-seq, the current sequencing platforms still require amplification of the ChIP DNA by ligation-mediated PCR (LM-PCR). This protocol, which involves linker ligation followed by size selection, is the standard ChIP-seq protocol using an Illumina Genome Analyzer. The size-selected ChIP DNA is amplified by LM-PCR and size-selected for the second time. The purified ChIP DNA is then loaded into the Genome Analyzer. The ChIP DNA can also be processed in parallel for ChIP-chip results.
Mouse Embryo Cryopreservation by Rapid Cooling
Authors: Shaw Jillian
Published: May 2018

Embryo cryopreservation has been used to archive mouse strains. Protocols have evolved over this time and now vary considerably in terms of cryoprotectant solution, cooling and warming rates, methods to add and remove cryoprotectant, container or carrier type, volume of cryoprotectant, the stage of preimplantation development, and the use of additional treatments such as blastocyst puncture and microinjection. The rapid cooling methods use concentrated solutions of cryoprotectants to reduce the water content of the cell before cooling commences, thus preventing the formation of ice crystals. Embryos are equilibrated with the cryoprotectants, loaded into a carrier, and then rapidly cooled (e.g., by being plunged directly into LN2 or onto a surface cooled in LN2). The rapid cooling methods eliminate the need for controlled-rate freezers and seeding procedures. However, they are much more sensitive to minor variations when performing the steps. The rapid-cooling protocol described here is suitable for use with plastic insemination straws. Because it uses relatively large volumes, it is less technically demanding than some other methods that use minivolume devices.
Making Weak Antigens Strong: Modifying Antigens by Dinitrophenol or Arsynyl Coupling
Authors: Greenfield Edward A. , DeCaprio James , Brahmandam Mohan
Published: May 2018

Many compounds on their own do not have all of the properties needed to induce a strong antibody response. However, small changes in the structure of an antigen can often greatly alter the immunogenicity of a compound. Common methods for doing so include the addition of small modifying groups such as dinitrophenol or arsenate to the molecules. These techniques either alter regions of the immunogen to provide better sites for T-cell binding or expose new epitopes for B-cell binding. The techniques are rapid and easy, and have been used extensively as a general procedure to increase the chances of raising antisera, particularly against well-conserved antigens.
Making Weak Antigens Strong: Modifying Protein Antigens by Denaturation
Authors: Greenfield Edward A. , DeCaprio James , Brahmandam Mohan
Published: May 2018

Many molecules can be made more immunogenic by denaturation. This treatment will change the structure of many compounds, particularly proteins, and expose new epitopes. In addition, heating will often cause protein antigens to aggregate, and, because aggregated antigens are often more immunogenic, this can increase the antibody response. Either heating alone or heating with sodium dodecyl sulfate (SDS) is the usual treatment. Injecting denatured antigens will be more likely to produce an antibody response against epitopes that are not found on the native antigen. If antibodies against totally denatured proteins are desired, the SDS–heat treatment is normally best. These treatments will generate antibodies that should be particularly good for immunoblots, for screening bacterial expression libraries, and for immunoprecipitation of proteins synthesized during in vitro translations.
Crystal structure of a new polymorph of (2S,3S)-2-amino-3-methylpentanoic acid
Authors: Curland Sofia , Meirzadeh Elena , Diskin-Posner Yael
Published: May 2018

A new polymorph of (2S,3S)-2-amino-3-methylpentanoic acid, L-isoleucine C6H13NO2, crystallizes in the monoclinic space group P21 with four independent molecules in the asymmetric unit. The molecules are zwitterions. In the crystal, N—H...O hydrogen bonds link two pairs of independent molecules and their symmetry-related counterparts to form two types of layers stacked in an anti-parallel manner parallel to (001). The hydrophobic aliphatic isopropyl groups protrude from these layers.
RbFe(HAsO4)2 and TlFe(HAsO4)2, two new hydrogenarsenates adopting two closely related structure types
Authors: Schwendtner Karolina , Kolitsch Uwe
Published: May 2018

Rubidium iron bis[hydrogen arsenate(V)], RbFe(HAsO4)2, and thallium iron bis[hydrogen arsenate(V)], TlFe(HAsO4)2, were grown under mild hydrothermal conditions (T = 493 K, 7 d). RbFe(HAsO4)2 adopts the RbFe(HPO4)2 structure type (space group R-3c), while TlFe(HAsO4)2 crystallizes in the (NH4)Fe(HPO4)2 structure type (space group P-1. Both compounds have tetrahedral–octahedral framework topologies. The M
+ cations are located in channels of the respective framework and are disordered in TlFe(HAsO4)2, which may suggest that the M
+ cations can move in the channels.
Redetermination of the crystal structure of K[BrF4] from single-crystal X-ray diffraction data
Authors: Ivlev Sergei I. , Kraus Florian
Published: May 2018

Single crystals of K[BrF4], potassium tetrafluoridobromate(III), were grown from a solution of KHF2 in bromine trifluoride. The current report is the first refinement of the crystal structure of K[BrF4] using single-crystal X-ray diffraction data. In comparison with previous refinements from powder data, the fractional coordinates of the F atom were determined with higher precision, and anisotropic displacement parameters were refined for all atoms. The structure contains square-planar [BrF4]− anions. The coordination polyhedron of the potassium cation is a square antiprism.
Counter-Landnahme? Labour disputes in the care-work field
Authors: Becker Karina , Dörre Klaus , Kutlu Yalcin
Published: May 2018

Purpose

The thesis of our paper is that the industrial dispute articulates a counter-movement against the progressive capitalist Landnahme of care work. What is ostensibly a standard wage conflict proves, on closer scrutiny, to be a dispute that contains a transformative social dynamic. It cannot be conceived either as a traditional class struggle or as a movement against the market’s unreasonable demands. The paper aims to discuss these issues.

Design/methodology/approach

The authors draw on a qualitative survey in the social and childcare services (expert interviews, groups discussions, expert hearings) and two partial-studies on the renewal of trade unions in East and West Germany (54 expert and 46 employee interviews).

Findings

Professional pride along with confidence in their own professional skills collides with the market- and competition-driven devaluation of the work of entire groups of employees. Used correctly, a putative professional consciousness can transform into a source of resilience, protest and collective engagement, which the authors interpret as counter-Landnahme. A consciousness rooted in professionality develops into a subjective power resource, the activation of which simultaneously strengthens trade unions’ power to effectuate change.

Originality/value

In the case of the childcare workers, this movement is rooted in a newly awakened consciousness as skilled labourers. What at first appears as a wage conflict is in fact, upon closer inspection, a conflict loaded with transformative potential. After all, any greater social recognition of this occupational group will naturally, at least by tendency, prompt a discussion concerning the modes of financing public reproductive activities.
Women in rural South Africa: a post-wage existence and the role of the state
Authors: Williams Michelle
Published: May 2018

Purpose

The purpose of this paper is to consider women in rural villages of Keiskammahoek in the Eastern Cape province of South Africa. What the author discovered is that some women are carving out a space through a complex, triple relation to the state. The state is distributor of social grants, a midwife of economic activity, and a technocratic system of governance and “service delivery.” The paper asks whether post-wage livelihoods are simply survivalists or have emancipatory potential.

Design/methodology/approach

The paper is based on research conducted in 2013-2015 in the rural villages of Keiskammahoek. The author spent time in the villages informally speaking to women and conducted 39 in-depth interviews.

Findings

The author found that the women are finding ways to engender non-capitalist relations in new and creative ways within their rural communities. The three sources of state activity (and power) – grants, economic projects, and governance – are engaged and used in different ways, but together create an interesting nexus of livelihoods and survival. What is interesting is the survivalist livelihoods – even if not representing an alternative mode of production – are allowing women a degree of independence, dignity, and self-determination.

Originality/value

The research has not been published and this argument has not been made before. The manuscript is a new approach to understanding post-wage livelihoods.