bluuebunny/crossref_metadata_2025 huggingface dataset:
The landscape of SNCA transcripts across synucleinopathies: New insights from long reads sequencing analysis
Authors: Tseng Elizabeth , Rowell William J , Glenn Omolara-Chinue , Hon Ting , Barrera Julio , Kujawa Steve , Chiba-Falek Ornit
Published: January 2019

Dysregulation of alpha-synuclein expression has been implicated in the pathogenesis of synucleinopathies, in particular Parkinson’s Disease (PD) and Dementia with Lewy bodies (DLB). Previous studies have shown that the alternatively spliced isoforms of the SNCA gene are differentially expressed in different parts of the brain for PD and DLB patients. Similarly, SNCA isoforms with skipped exons can have a functional impact on the protein domains. The large intronic region of the SNCA gene was also shown to harbor structural variants that affect transcriptional levels. Here we apply the first study of using long read sequencing with targeted capture of both the gDNA and cDNA of the SNCA gene in brain tissues of PD, DLB, and control samples using the PacBio Sequel system. The targeted full-length cDNA (Iso-Seq) data confirmed complex usage of known alternative start sites and variable 3’ UTR lengths, as well as novel 5’ starts and 3’ ends not previously described. The targeted gDNA data allowed phasing of up to 81% of the ~114kb SNCA region, with the longest phased block excedding 54 kb. We demonstrate that long gDNA and cDNA reads have the potential to reveal long-range information not previously accessible using traditional sequencing methods. This approach has a potential impact in studying disease risk genes such as SNCA, providing new insights into the genetic etiologies, including perturbations to the landscape the gene transcripts, of human complex diseases such as synucleinopathies.
Genetic Nature or Genetic Nurture? Quantifying Bias in Analyses Using Polygenic Scores
Authors: Trejo Sam , Domingue Benjamin W.
Published: January 2019

Summary statistics from a genome-wide association study (GWAS) can be used to generate a polygenic score (PGS). For complex, behavioral traits, the correlation between an individual’s PGS and their phenotype may contain bias alongside the causal effect of the individual’s genes (due to geographic, ancestral, and/or socioeconomic confounding). We formalize the recent introduction of a different source of bias in regression models using PGSs: the effects of parental genes on offspring outcomes, also known as genetic nurture. GWAS do not discriminate between the various pathways through which genes influence outcomes, meaning existing PGSs capture both direct genetic effects and genetic nurture effects. We construct a theoretical model for genetic effects and show that, unlike other sources of bias in PGSs, the presence of genetic nurture biases PGS coefficients from both naïve OLS (between-family) and family fixed effects (within-family) regressions. This bias is in opposite directions; while naïve OLS estimates are biased upwards, family fixed effects estimates are biased downwards. We quantify this bias for a given trait using two novel parameters that we identify and discuss: (1) the genetic correlation between the direct and nurture effects and (2) the ratio of the SNP heritabilities for the direct and nurture effects.
Comparative analyses of chromatin landscape in white adipose tissue suggest humans may have less beigeing potential than other primates
Authors: Swain-Lenz Devjanee , Berrio Alejandro , Safi Alexias , Crawford Gregory E. , Wray Gregory A.
Published: January 2019

Humans carry a much larger percentage of body fat than other primates. Despite the central role of adipose tissue in metabolism, little is known about the evolution of white adipose tissue in primates. Phenotypic divergence is often caused by genetic divergence in cis-regulatory regions. We examined the cis-regulatory landscape of fat during human origins by performing comparative analyses of chromatin accessibility in human and chimpanzee adipose tissue using macaque as an outgroup. We find that many cis-regulatory regions that are specifically closed in humans are under positive selection, located near genes involved with lipid metabolism, and contain a short sequence motif involved in the beigeing of fat, the process in which white adipocytes are transdifferentiated into beige adipocytes. While the primary role of white adipocytes is to store lipids, beige adipocytes are thermogeneic. The collective closing of many putative regulatory regions associated with beiging of fat suggests an adaptive mechanism that increases body fat in humans.
Chaperone-mediated ordered assembly of the SAGA and NuA4 transcription co-activator complexes
Authors: Elías-Villalobos Alberto , Toullec Damien , Faux Céline , Séveno Martial , Helmlinger Dominique
Published: January 2019

Transcription initiation involves the coordinated activities of large multimeric complexes that are organized into functional modules. Little is known about the mechanisms and pathways that govern their assembly from individual components. We report here several principles governing the assembly of the highly conserved SAGA and NuA4 co-activator complexes. Using fission yeast, which contain two functionally non-redundant paralogs of the shared Tra1 subunit, we demonstrate that Tra1 contributes to scaffolding the entire NuA4 complex. In contrast, within SAGA, Tra1 specifically promotes the incorporation of the de-ubiquitination module (DUB), defining an ordered assembly pathway. Biochemical and functional analyses elucidated the mechanism by which Tra1 assemble differentially into SAGA or NuA4 and identified a small, conserved region of Spt20 that is both necessary and sufficient to anchor Tra1 within SAGA. Finally, we establish that Hsp90 and its cochaperone TTT are required for Tra1 de novo incorporation into both SAGA and NuA4, indicating that Tra1, a pseudokinase of the PIKK family, shares a dedicated chaperone machinery with its cognate kinases. Overall, our work brings mechanistic insights into the de novo assembly of transcriptional complexes through ordered pathways and reveals the contribution of dedicated chaperones to this process.
In vivo structure of the Legionella type II secretion system by electron cryotomography
Authors: Ghosal Debnath , Kim Ki Woo , Zheng Huaixin , Kaplan Mohammed , Vogel Joseph P. , Cianciotto Nicholas P. , Jensen Grant J.
Published: January 2019

The type II secretion system (T2SS) is a multi-protein envelope-spanning assembly that translocates a wide range of virulence factors, enzymes and effectors through the outer membrane (OM) of many Gram-negative bacteria. Here, using electron cryotomography and subtomogram averaging methods, we present the first in situ structure of an intact T2SS, imaged within the human pathogen Legionella pneumophila. Although the T2SS has only limited sequence and component homology with the evolutionarily-related Type IV pilus (T4P) system, we show that their overall architectures are remarkably similar. Despite similarities, there are also differences, including for instance that the T2SS-ATPase complex is usually present but disengaged from the inner membrane, the T2SS has a much longer periplasmic vestibule, and it has a short-lived flexible pseudopilus. Placing atomic models of the components into our ECT map produced a complete architectural model of the intact T2SS that provides new insights into the structure and function of its components, its position within the cell envelope, and the interactions between its different subcomplexes. Overall, these structural results strongly support the piston model for substrate extrusion.
The genomic architecture of introgression among sibling species of bacteria
Authors: Cavassim Maria Izabel A , Moeskjær Sara , Moslemi Camous , Fields Bryden , Bachmann Asger , Vilhjálmsson Bjarni , Schierup Mikkel H , Young J Peter W , Andersen Stig U
Published: January 2019

Background

Gene transfer between bacterial species is an important mechanism for adaptation. For example, sets of genes that confer the ability to form nitrogen-fixing root nodules on host plants have frequently moved betweenRhizobiumspecies. It is not clear, though, whether such transfer is exceptional, or if frequent inter-species introgression is typical. To address this, we sequenced the genomes of 196 isolates of theRhizobium leguminosarumspecies complex obtained from root nodules of white clover (Trifolium repens).

Results

Core gene phylogeny placed the isolates into five distinct genospecies that show high intra-genospecies recombination rates and remarkably different demographic histories. Most gene phylogenies were largely concordant with the genospecies, indicating that recent gene transfer between genospecies was rare. In contrast, very similar symbiosis gene sequences were found in two or more genospecies, suggesting recent horizontal transfer. The replication and conjugative transfer genes of the plasmids carrying the symbiosis genes showed a similar pattern, implying that introgression occurred by conjugative plasmid transfer. The only other regions that showed strong phylogenetic discordance with the genospecies classification were two small chromosomal clusters, one neighbouring a conjugative transfer system. Phage-related sequences were observed in the genomes, but appeared to have very limited impact on introgression.

Conclusions

Introgression among these closely-related species has been very limited, confined to the symbiosis plasmids and a few chromosomal islands. Both introgress through conjugative transfer, but have been subject to different types of selective forces.
Buffer Therapy in Acute Metabolic Acidosis: Effects on Acid-Base Status and Glomerular Permeability
Authors: Schnapauff Jan , Piros David , Rippe Anna , Bentzer Peter , Clyne Naomi , Öberg Carl M.
Published: January 2019

Background:

Correction of acute metabolic acidosis using sodium bicarbonate is effective, but has been hypothesized to exacerbate intra-cellular acidosis causing cellular dysfunction. The effects of acidemia and bicarbonate therapy on the cellular components of the glomerular filtration barrier, crucial for the integrity of the renal filter, are as yet unknown. Controversy persists regarding the most appropriate method to assess acid-base status: the “Stewart approach” or the “Siggaard-Andersen approach” using the standard base excess (SBE).

Methods:

Here we performed physiological studies in anesthetized Sprague-Dawley rats during severe metabolic acidosis (HCl iv 6 mmol kg-1) and following bicarbonate (2.5 mmol kg-1) administration. We assessed glomerular permeability using sieving coefficients of polydisperse fluorescein isothiocyanate (FITC)-Ficoll 70/400. Acid-base status was evaluated using SBE, standard bicarbonate, total CO2, the Stewart-Fencl strong ion difference (ΔSID = Na – Cl – 38) and a theoretical model of plasma and erythrocyte strong ion difference.

Results:

Our data show that neither acidosis nor its correction with NaHCO3altered glomerular permeability. We identified ΔSID as a strong estimator of plasma base excess (as assessed using the Van Slyke equation).In silicomodeling indicates that changes in the strong ion difference in erythrocytes would explain their buffering effect by means of a shift of anions from the extracellular fluid.

Conclusion:

These data demonstrate a remarkable tolerance of the glomerular filter to severe acute acidosis and bicarbonate therapy. Our results also cast light on the buffer mechanism in erythrocytes and the ability of different acid-base parameters to evaluate the extent of an acid-base disorder.

IMPORTANCE STATEMENT

Metabolic acidosis is a frequent complication of acute kidney injury in critically ill patients and is associated with a high risk of mortality. Correction of acidosis using sodium bicarbonate is simple and effective, but could possibly induce intracellular acidosis causing cellular dysfunction. The effects of acidemia and subsequent bicarbonate treatment on the cellular components of the glomerular filtration barrier, crucial for the integrity of the renal filter, are unknown. We show that neither severe acidemia nor bicarbonate therapy appear to have negative effects on glomerular permeability. Our analysis also highlights the buffering effects of erythrocytes, which appear to be mediated by a shift of strong anions into the red cells, increasing the strong ion difference in the extracellular fluid.
Spread of pathological α-synuclein from urogenital nerves initiates multiple system atrophy-like symptoms
Authors: Wang Xuejing , Ma Mingming , Wu Erxi , Teng Dongyang , Yuan Xin , Zhou Lebo , Zhang Rui , Yao Jing , Chen Yongkang , Xia Danhao , Teng Robert K.F. , Wang Fengfei , Huang Jason H. , Yue Zhenyu , Zhang Zhuohua , Teng Junfang , Tang Beisha , Ding Xuebing
Published: January 2019

Multiple system atrophy (MSA) is a fatal adult-onset movement disorder with autonomic failures, especially urogenital dysfunction. The neuropathological feature of MSA is the accumulation of misfolded α-synuclein (α-Syn) in the nervous system. Here, we show that misfolded α-Syn exist in nerve terminals in detrusor (DET) and external urethral sphincter (EUS) of patients with MSA. Moreover, α-Syn preformed fibrils inoculated into the EUS or DET in TgM83+/− mice initiated the transmission of misfolded α-Syn from the lower urinary tract to brain, and these mice developed α-Syn inclusion pathology through micturition reflex pathways along with urinary dysfunction and motor impairments. These findings indicate that spreading of misfolded α-Syn from the autonomic control of the lower urinary tract to the brain via micturition reflex pathways induces autonomic failure and motor impairments. These results provide important new insights into the pathogenesis of MSA as well as highlight potential targets for early detection and therapeutics.
Chemogenetic inhibition of a monosynaptic projection from the basolateral amygdala to the ventral hippocampus selectively reduces appetitive, but not consummatory, alcohol drinking-related behaviors
Authors: Bach Eva C. , Ewin Sarah E. , Heaney Chelcie F. , Carlson Hannah N. , Almonte Antoine G. , Chappell Ann M. , Raab-Graham Kimberly F. , Weiner Jeffrey L.
Published: January 2019

Alcohol use disorder (AUD) and anxiety/stressor disorders frequently co-occur and this dual diagnosis represents a major health and economic problem worldwide. The basolateral amygdala (BLA) is a key brain region that is known to contribute to the etiology of both disorders. Although many studies have implicated BLA hyperexcitability in the pathogenesis of AUD and comorbid conditions, relatively little is known about the specific efferent projections from this brain region that contribute to these disorders. Recent optogenetic studies have shown that the BLA sends a strong monosynaptic excitatory projection to the ventral hippocampus (vHC) and that this circuit modulates anxiety- and fear-related behaviors. However, it is not known if this pathway influences alcohol drinking-related behaviors. Here, we employed a rodent operant drinking regimen that procedurally separates appetitive (e.g. seeking) and consummatory (e.g. intake) behaviors, chemogenetics, and brain region-specific microinjections, to determine if BLA-vHC circuitry influences alcohol drinking-related measures. We first confirmed prior optogenetic findings that silencing this circuit reduced anxiety-like behaviors on the elevated plus-maze. We then demonstrated that inhibiting the BLA-vHC pathway significantly reduced appetitive alcohol drinking-related behaviors while having no effect on consummatory measures. Sucrose seeking measures were also reduced following chemogenetic inhibition of this circuit. Taken together, these findings provide the first indication that the BLA-vHC circuit may regulate appetitive alcohol drinking-related behaviors and add to a growing body of evidence suggesting that dysregulation of this pathway may contribute to the pathophysiology of AUD and anxiety/stressor-related disorders.

HIGHLIGHTS

The basolateral amygdala sends a monosynaptic glutamatergic projection to the ventral hippocampus

Inhibiting this circuit reduces anxiety-like behaviors in male Long Evans rats

Inhibition of this pathway also decreases operant alcohol seeking-related behaviors
Chemsex: origins of the word, a history of the phenomenon and a respect to the culture
Authors: Stuart David
Published: January 2019

Purpose

The purpose of this paper is to clarify the origins, use and meaning of the term “chemsex”.

Design/methodology/approach

The approach used here is one born of personal experiences and reflection.

Findings

The term chemsex has a definition and a purpose that promotes culturally competent care for a marginalized group of vulnerable people.

Research limitations/implications

This is a qualitative, personal, point-of-view piece which may be of value in broadening understandings and responses amongst public health and academic activities.

Practical implications

The findings can be used to develop a sense of community and support amongst men who have sex with men in a chemsex setting, and to provide some background and context for professionals working in this field.

Originality/value

This paper is amongst the first, if not the first, of its nature to be published in an academic journal.
Two-phase investigation of water-Al2O3 nanofluid in a micro concentric annulus under non-uniform heat flux boundary conditions
Authors: Toghraie Davood , Mashayekhi Ramin , Arasteh Hossein , Sheykhi Salman , Niknejadi Mohammadreza , Chamkha Ali J.
Published: January 2019

Purpose

This is a 3D numerical study of convective heat transfer through a micro concentric annulus governing non-uniform heat flux boundary conditions employing water-Al2O3 nanofluid. The nanofluid is modeled using two-phase mixture model, as it has a good agreement to experimental results.

Design/methodology/approach

Half of the inner pipe surface area of the annulus section of a double pipe heat exchanger is exposed to a constant heat flux which two models are considered to divide the exposing surface area to smaller ones considering the fact that in all cases half of the inner pipe surface area has to be exposed to the heat flux: in model (A), the exposing surface area is divided radially to two parts (A1), four parts (A2) and eight parts (A3) by covering the whole length of the annulus and in model (B) the exposing surface area is divided axially to two parts (B1), four parts (B2) and eight parts (B3) by covering half of the annulus radially.

Findings

The results reveal that model (B) leads to higher Nusselt numbers compared to model (A); however, at Reynolds number 10, model (A3) exceeds model (B3). The average Nusselt number is increased up to 142 and 83 per cent at models (A3) with Reynolds number 10 and model (B3) with Reynolds number 1000, respectively.

Originality/value

This paper is a two-phase investigation of water-Al2O3 nanofluid in a micro concentric annulus under non-uniform heat flux boundary conditions.
Review of tribological behavior of graphene coatings on piston rings in engines
Authors: Acunaş Karagöz Zeynep Burcu , Demirtaş Selman , Kaleli Hakan , Yüksek Levent , Çıtak Emre
Published: January 2019

Purpose

This study aims to find out friction and wear characteristics of graphene and graphene coating deposited by the Chemical Vapor Deposition (CVD) process on Honda GX270 engine (nodular cast iron) piston rings experimentally investigated under boundary lubricated conditions.

Design/methodology/approach

This study consists of two stages: tribotest and engine tests. First test was conducted through a reciprocating tribotest machine and second test was conducted through an engine bench with a duration of 75h. Engine piston ring was coated with graphene by two different methods: transfer method and direct CVD method.

Findings

Graphene has been demonstrated to be a potential and promising candidate for wear- and scratch-resistant coating because it is the thinnest, lightest and strongest known nanomaterial. In this case, the ability of a mono-layer graphene film to withstand high pressure differences (6 atm) indicates its mechanical robustness. It can effectively prevent or reduce mechanical failure by strengthening and toughening the loaded surface as well as by transferring the stress throughout the structure. The positive tribological outcomes of the graphene reinforced material under various dynamic loads revealed the potential of graphene-based coatings in macro - and micro-tribology.

Originality/value

This study fulfils an identified need to study for automotive industry a coating which is wear and scratch resistant.
Exploring the use of standardised design in addressing the shortage of primary school places in the UK
Authors: Opoku Alex , Mills Sarah A.
Published: January 2019

Purpose

As part of the UK Government’s strategy to address the current shortage of primary school places is the construction of standardised designed schools. The UK Government has been facing an uphill battle to meet the demand for the ever-increasing number of school places it requires. This paper aims to explore the use of standardised school design in addressing the problem of primary school places in the UK.

Design/methodology/approach

Due to the exploratory nature of this investigation, a pragmatic research philosophy is utilised and mixed-method data collection techniques are used. Quantitative data collection is in the form of a survey involving 306 construction professionals and stakeholders; this has been consolidated using qualitative data collection in the form of nine purposefully selected semi-structured interviews.

Findings

The research highlighted the influence that people and their perceptions have on the successful implementation of standardisation. The results show that a high level of misunderstanding exists around the concept of standardisation and its definition. Standardised design has shown to have a remarkable influence in reducing the cost and time required for delivering the construction of new schools.

Research limitations/implications

Due to the exploratory nature of this research, the results obtained have not been wholly conclusive but have instead provided a contribution to the area of standardisation in construction.

Originality/value

The research has uncovered that, to truly promote and drive standardisation in the delivery of schools, a joint approach is required with designers, contractors, clients and manufacturers, working in partnership to develop successful solutions. The paper will, therefore, help the key stakeholders delivering standardised schools in UK to fully understand the concept and turn the challenges into opportunities.
An uncertainty management theory on the effects of abusive supervision
Authors: Yang Jih-Hua , Lin Cheng-Chen , Fang Shih-Chieh , Huang Ching-Ying
Published: January 2019

Purpose

The vast majority of research on traditional leadership focuses on effective and positive leadership behavior. However, scholars have begun to pay attention to the impact of negative leadership behavior on employees and the organization. Hence, the main purpose is to examine the effects of abusive supervision. While the literature does not examine the time future orientation of the effects of abusive supervision, the purpose of this paper is to fill up this gap and examine the moderating role of future orientation.

Design/methodology/approach

A total of 584 valid questionnaires were collected from respondents aged between 21 and 30 years old and analyzed using the hierarchical regression and structural equation modeling method.

Findings

The main results show that abusive supervision positively affects counterproductive work behavior and future orientation positively moderates both the relationship between abusive supervision and originality behavior and the relationship between abusive supervision and organizational citizenship behavior (OCB).

Originality/value

This study demonstrates the moderating roles of future orientation in the effects of abusive supervision, and thus deepens the understanding of the moderating effect. It departs from the prior works and presents a more detailed examination examines the distinct dimensions of personality traits. It makes three main theoretical contributions. First, it introduces uncertainty management theory as a means to interpret the effects of abusive supervision. Second, it contributes to the literature on abusive supervision. Third, it does not lead to discovery as an OCB and originality, conclusions which differ from the results suggested in past literature.
Long‐term recovery of multifunctionality in Mediterranean forests depends on restoration strategy and forest type
Authors: Cruz‐Alonso Verónica , Ruiz‐Benito Paloma , Villar‐Salvador Pedro , Rey‐Benayas José María
Published: January 2019

Forest area is increasing in temperate biomes through active and passive restoration of old fields. Despite the large extension of restored forests, the success of contrasting restoration strategies (active – planted forests ‐ vs. passive – secondary forests ‐) over time has never been evaluated in Mediterranean forests.

We studied how restoration strategy determined forest restoration success. We evaluated which restoration strategy resulted in forests more like references (i.e. forests with continuous canopy cover since at least the 1940s) in terms of structure, diversity, functional composition, and dynamics. We then assessed whether active restoration accelerated forest recovery compared to passive restoration.

We studied a chronosequence of recovery in four forest types (mountain and Mediterranean pine forests and mesic and Mediterranean oak forests) using the data of the Spanish Forest Inventory in central Spain. Each plot was classified as planted, secondary or reference forest. We modelled the response ratios of 11 forest attributes and a multifunctionality index as a function of restoration strategy, forest age, and abiotic and biotic constraints.

Secondary forests showed a greater likeness to references than planted forests in oak forests while minor differences between secondary and planted forests were found in pine forests. The recovery speed of most forest attributes in secondary and planted forests was similar. Multifunctionality was higher, and increased more rapidly, in planted than in secondary forests in Mediterranean oak forests. However, multifunctionality was similar for both restoration strategies in the other forest types.

Synthesis and applications. The long‐term assessment of forest recovery in Mediterranean abandoned fields indicated that both planted forests and natural forest succession are successful restoration strategies, depending on the aim and the forest type. In our research, restoration strategy did not influence the magnitude and speed of forest recovery in pine forests. However, in oak forests, natural forest succession led to forests more alike to references, but planted forests can maximize and accelerate recovery of forest multifunctionality.
Weighting effective number of species measures by abundance weakens detection of diversity responses
Authors: Cao Yong , Hawkins Charles P.
Published: January 2019

The effective number of species (ENS) has been proposed as a robust measure of species diversity that overcomes several limitations in terms of both diversity indices and species richness (SR). However, it is not yet clear if ENS improves interpretation and comparison of biodiversity monitoring data, and ultimately resource management decisions.

We used simulations of five stream macroinvertebrate assemblages and spatially extensive field data of stream fishes and mussels to show (a) how different ENS formulations respond to stress and (b) how diversity–environment relationships change with values of q, which weight ENS measures by species abundances.

Values of ENS derived from whole simulated assemblages with all species weighted equally (true SR) steadily decreased as stress increased, and ENS‐stress relationships became weaker and more different among assemblages with increased weighting.

The amount of variation in ENS across the fish and mussel assemblages that was associated with environmental gradients decreased with increasing q.

Synthesis and applications. Species diversity is valued by many human societies, which often have policies designed to protect and restore it. Natural resources managers and policy makers may use species richness and diversity indices to describe the status of ecological communities. However, these traditional diversity measures are known subject to limitations that hinder their interpretation and comparability. The effective number of species (ENS) was proposed to overcome the limitations. Unfortunately, our analyses show that ENS does not improve interpretability of how species diversity responds to either stress or natural environmental gradients. Moreover, incorporating the relative abundance of individuals in different species (evenness) into diversity measures as implemented in ENS can actually weaken detection of diversity responses. Natural resources managers and policy makers therefore need to be cautious when interpreting diversity measures, including ENS, whose values are jointly influenced by richness and evenness. We suggest that both researchers and practitioners measure and report three aspects of diversity (species richness, evenness, and composition) separately when assessing and monitoring the diversity of ecological communities.
Dissection of patulin biosynthesis, spatial control and regulation mechanism in Penicillium expansum
Authors: Li Boqiang , Chen Yong , Zong Yuanyuan , Shang Yanjiao , Zhang Zhanquan , Xu Xiaodi , Wang Xiao , Long Manyuan , Tian Shiping
Published: January 2019

The patulin biosynthesis is one of model pathways in an understanding of secondary metabolite biology and network novelties in fungi. However, molecular regulation mechanism of patulin biosynthesis and contribution of each gene related to the different catalytic enzymes in the biochemical steps of the pathway remain largely unknown in fungi. In this study, the genetic components of patulin biosynthetic pathway were systematically dissected in Penicillium expansum, which is an important fungal pathogen and patulin producer in harvested fruits and vegetables. Our results revealed that all the 15 genes in the cluster are involved in patulin biosynthesis. Proteins encoded by those genes are compartmentalized in various subcellular locations, including cytosol, nucleus, vacuole, endoplasmic reticulum, plasma membrane and cell wall. The subcellular localizations of some proteins, such as PatE and PatH, are required for the patulin production. Further, the functions of eight enzymes in the 10‐step patulin biosynthetic pathway were verified in P. expansum. Moreover, velvet family proteins, VeA, VelB and VelC, were proved to be involved in the regulation of patulin biosynthesis, but not VosA. These findings provide a thorough understanding of the biosynthesis pathway, spatial control and regulation mechanism of patulin in fungi.
Social Media and Medicolegal Death Investigation: Logged in…To the Morgue
Authors: Gitto Lorenzo , Arunkumar Ponni , Cina Stephen J.
Published: January 2019

Social media (SM) represent a global consumer phenomenon with an exponential rise in usage within the last few years. The various applications and websites are relatively easy and fast to access, and the number of users increases continuously. SM are an incredible source of freely available, public information about their users. The purpose of this study is to provide information about the usefulness of SM in forensic practice. The electronic database of the Cook County of Medical Examiner's Office (“CCMEO”) in Illinois was searched for investigative narratives that included specific SM keywords, in the period from August 2014 to January 2018. A total of 48 cases met the study's criteria. Among these, “Facebook” has been found to be the most helpful SM for medicolegal investigation purposes. Information obtained by SM can play an important role in forensic practice since it can be used to clarify certain aspects of the medicolegal death investigation, with particular regard to time and manner of death.
Feasibility of Emergency Department–initiated, Mobile Health Blood Pressure Intervention: An Exploratory, Randomized Clinical Trial
Authors: Meurer William J. , Dome Mackenzie , Brown Devin , Delemos Destinee , Oska Sandra , Gorom Victoria , Skolarus Lesli
Published: January 2019

Objectives

We aimed to assess the feasibility of a text messaging intervention by determining the proportion of emergency department (ED) patients who responded to prompted home blood pressure (BP) self‐monitoring and had persistent hypertension. We also explored the effect of the intervention on systolic blood pressure (sBP) over time.

Methods

We conducted a randomized, controlled trial of ED patients with expected discharge to home with elevated BP. Participants were identified by automated alerts from the electronic health record. Those who consented received a BP cuff to take home and enrolled in the 3‐week screening phase. Text responders with persistent hypertension were randomized to control or weekly prompted BP self‐monitoring and healthy behavior text messages.

Results

Among the 104 patients enrolled in the ED, 73 reported at least one home BP over the 3‐week run‐in (screening) period. A total of 55 of 73 reported a home BP of ≥140/90 and were randomized to SMS intervention (n = 28) or control (n = 27). The intervention group had significant sBP reduction over time with a mean drop of 9.1 mm Hg (95% confidence interval = 1.1 to 17.6).

Conclusions

The identification of ED patients with persistent hypertension using home BP self‐monitoring and text messaging was feasible. The intervention was associated with a decrease in sBP likely to be clinically meaningful. Future studies are needed to further refine this approach and determine its efficacy.
Low‐risk drinking guidelines: a pragmatic approach to health promotion?
Authors: Ferri Marica , Mouteney Jane , Griffiths Paul
Published: January 2019

Commentary to: How should we set consumption thresholds for low risk drinking guidelines? Achieving objectivity and transparency using evidence, expert judgement and pragmatism.
E2F1 copy number variations contribute to spermatogenic impairment and cryptorchidism by increasing susceptibility to heat stress
Authors: Rocca M. S. , Di Nisio A. , Sabovic I. , Ghezzi M. , Foresta C. , Ferlin A.
Published: January 2019

Background

Copy number variations (CNVs) play an important role in the onset of several diseases, and recently research focused on the relationship between these structural variants and diseases of the reproductive tract, including male infertility and cryptorchidism.

Objectives

To evaluate the contribution of copy number variations of E2F1 gene to idiopathic male infertility and the factors influencing expression of this gene.

Materials and Methods

We performed a retrospective study on 540 subjects recruited from September 2014 to February 2015. TaqMan CNV assay was used to analyze E2F1 CNV. Real‐time PCR was used to assess E2F1 and HSP70 expression level in heat stressed and transfected cells with three E2F1 copies.

Results

We found a significant difference in the frequency of altered E2F1 copies in patients (12/343, 3.5%) compared with controls (0/197) (p = 0.005). Six patients with E2F1 CNV had history of cryptorchidism, but the prevalence between men with idiopathic infertility (6/243, 2.5%) and infertile men with history of cryptorchidism (6/100, 6.0%) was not statistically different (p = 0.1). E2F1 expression increased under heat stress conditions, especially in cells carrying more copies of gene and this was associated with increased expression of HSP70.

Discussion

Our data suggest that an abnormal E2F1 expression caused by multiple copies of E2F1 gene predisposes to the onset of infertility and that the risk further increases if subjects with altered E2F1 copies have stressful conditions, such as heat stress or history of cryptorchidism.

Conclusion

This study shows a link between E2F1 CNV and male infertility, suggesting that the increased risk of spermatogenic impairment associated with higher E2F1 copies might be due to higher susceptibility to stressful conditions.
Early repolarization pattern as a predictor of atrial fibrillation recurrence following radiofrequency pulmonary vein isolation
Authors: Hunuk Burak , de Asmundis Carlo , Mugnai Giacomo , Velagic Vedran , Ströker Erwin , Moran Darragh , Ruggiero Diego , Hacioglu Ebru , Umbrain Vincent , Verborgh Christian , Beckers Stefan , Poelaert Jan , Brugada Pedro , Chierchia Gian‐Battista
Published: January 2019

Background

Early repolarization patterns (ERP) have been found to be associated with poor cardiovascular end points. We aimed to evaluate the ERP prevalence among patients with structurally normal hearts undergoing radiofrequency (RF) pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (AF) ablation and its association with the AF recurrence.

Methods

All consecutive patients who underwent RF‐PVI as index procedure for paroxysmal AF in our center were evaluated. Exclusion criteria: structural heart disease, ongoing use of Class I/III antiarrhythmics, complete‐bundle‐branch‐block. Lateral (I, aVL, V5–V6), inferior (II, III, aVF), or infero‐lateral (both) ERP were defined in baseline ECG as horizontal/downsloping J‐point elevation ≥1 mm in two consecutive leads with QRS slurring/notching. Documented episodes of AF lasting ≥30 s were considered recurrence.

Results

Of 701 cases, 434 patients (305 males, 58 ± 11 years) were included for analysis. ERP observed in 67 patients (15.4%) (Infero‐lateral n = 26, inferior n = 23, lateral n = 18) which were significantly younger, demonstrating longer PR‐interval and lower heart rates. At a mean follow‐up of 22.1 ± 9.7 months, AF recurrences were found in 107 patients (24.6%). In middle‐aged patients (≥40–<60 years; n = 206, 79% male), those with an infero‐lateral ERP had higher recurrence compared with the ones without (56.3% vs. 19%; p = 0.002). Infero‐lateral ERP was significantly predicting recurrence (HR 2.42, 95% CI 1.21–4.82; p = 0.01).

Conclusion

Early repolarization patterns was more prevalent in our AF population than in the general population. Infero‐lateral ERP in baseline ECG might predict AF recurrence in the follow‐up after RF‐PVI in middle‐aged patients.
Prenatal detection of esophageal atresia: A systematic review and meta‐analysis
Authors: Pardy Caroline , D'Antonio Francesco , Khalil Asma , Giuliani Stefano
Published: January 2019

Introduction

The primary aim of this systematic review was to quantify the diagnostic performance of ultrasound, magnetic resonance imaging and amniotic fluid analysis in detecting esophageal atresia prenatally. The secondary aim was to explore the accuracy of individual imaging signs in identifying this anomaly.

Material and methods

MEDLINE, Embase and Cochrane databases were searched. The quality of studies was assessed using the revised tool for the quality assessment of diagnostic accuracy studies. Summary estimates of sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratio for the predictive accuracy of ultrasound, magnetic resonance imaging and amniotic fluid analysis in detecting esophageal atresia were computed using the hierarchical summary receiver operating characteristic or DerSimonian‐Laird random‐effect model, according to the number of studies included in each analysis. PROSPERO registration number: CRD42017055828.

Results

Twenty studies (73 246 fetuses, 1760 affected by esophageal atresia) were included. Overall, prenatal ultrasound had a sensitivity of 31.7%. Only two studies reported all data for diagnostic accuracy; based on these studies, prenatal ultrasound had a sensitivity of 41.9%, a specificity of 99.9%, a positive likelihood ratio of 88.1, a negative likelihood ratio of 0.58 and a diagnostic odds ratio of 153.7. Prenatal ultrasound correctly identified 77.9% of cases with esophageal atresia and 21.9% esophageal atresia with an associated tracheo‐esophageal fistula. Polyhydramnios was present in 56.3% of cases affected by esophageal atresia, and a small or absent stomach was identified in 50.0% cases. When performed following a suspicious ultrasound, fetal magnetic resonance imaging had an good overall diagnostic accuracy for esophageal atresia, with a sensitivity of 94.7%, a specificity of 89.3%, a positive likelihood ratio of 8.8, a negative likelihood ratio of 0.06 and a diagnostic odds ratio of 149.3. Finally, amniotic fluid analysis with an esophageal atresia index ≥3 had a sensitivity of 89.9% and a specificity of 99.6% in detecting esophageal atresia.

Conclusions

Ultrasound alone is a poor diagnostic tool for identifying esophageal atresia prenatally, and has a high rate of false positive diagnoses. Magnetic resonance imaging and amniotic fluid analysis have high diagnostic accuracy for esophageal atresia. We would recommend their use following a suspicious ultrasound.
Expanding a woman's options to include home use of misoprostol for medical abortion up until 76 days: an observational study of efficacy and safety
Authors: Larsson Amanda , Ronnberg Ann‐Kristin M.
Published: January 2019

Introduction

Home use of misoprostol for medical abortion is increasingly being practiced. With gestational length up to 70 days, it is considered effective, safe and acceptable by women. Knowledge of safety and efficacy with longer gestations is limited and studies are required to expand women's options to include this method of abortion.

Material and methods

A retrospective cohort study was designed to compare home use of misoprostol for medical abortion at gestational length 64‐76 days to its use at 57‐63 days. Primary outcome was success rate. Success was defined as complete uterine evacuation without the need of surgical intervention due to incomplete abortion and no failed abortion with ongoing pregnancy. Secondary outcomes were rates of unscheduled return visits, telephone consultations, admissions to hospital, infections and the need for blood transfusion.

Results

We included 397 women, 270 within 57‐63 days of gestation and 127 within 64‐76 days of gestation at abortion. Success rate was 95.6% at 57‐63 days and 93.7% at 64‐76 days. The difference was not statistically significant (P = .431). The rate of unscheduled return visits was high overall but not significantly different in relation to gestational length at abortion (> 63 days; 20.5% vs < 64 days; 16.3%, P = .308).

Conclusions

Our study indicates that home use of misoprostol for medical abortion at 64‐76 days gestation may be as safe and effective as at 57‐63 days. Further studies with larger sample sizes are needed to confirm our findings and to explore the acceptance of and experiences among women performing abortion at home at greater gestational length, before further implementation in clinical practice.
Operator experience affects the risk of obstetric anal sphincter injury in vacuum extraction deliveries
Authors: Bergendahl Sandra , Lindberg Petra , Brismar Wendel Sophia
Published: January 2019

Introduction

Delivery by vacuum extraction is a major risk factor for obstetric anal sphincter injury. The aim of this study was to assess risk factors for obstetric anal sphincter injury in vacuum extraction in nulliparous women, specifically operator‐related factors. A secondary aim was to assess other complications of vacuum extraction that are dependent on operator experience.

Material and methods

A historical cohort study of nulliparous women with a live single fetus ≥34 weeks, delivered by vacuum extraction at a teaching hospital in Sweden in 1 year (2013), using data from medical records. Risk of obstetric anal sphincter injury was assessed for obstetricians (reference), gynecologists, and residents, and adjusted for maternal, fetal, procedure‐related, and operator‐related covariates using unconditional logistic regression. Results are presented as prevalence and crude and adjusted odds ratio (aOR) with 95% CI.

Results

In total, 323 nulliparous women delivered by vacuum extraction were included. Obstetric anal sphincter injury occurred in 57 (17.6%) women. Fifteen (11.5%) obstetric anal sphincter injuries occurred in vacuum extractions performed by obstetricians, 10 (13.5%) by gynecologists (aOR 1.84, 95% CI 0.72‐4.70), and 32 (26.9%) by residents (aOR 5.13, 95% CI 2.20‐11.95). Maternal height ≤155 cm (aOR 4.63, 95% CI 1.35‐15.9) and conversion to forceps (aOR 19.4, 95% CI 1.50‐252) increased the risk of obstetric anal sphincter injury. Operator gender, night shift work, or being a frequent operator did not affect the risk of obstetric anal sphincter injury. Postpartum hemorrhage and fetal complications did not differ between operator categories.

Conclusions

The adjusted risk of obstetric anal sphincter injury in nulliparous women was five times higher in vacuum extractions performed by residents compared with those performed by obstetricians. Vacuum extractions performed by gynecologists did not carry an increased risk of obstetric anal sphincter injury. Experience in years of training, rather than frequency of the procedure, seemed to have the highest impact on reducing obstetric anal sphincter injury in vacuum extractions, which indicates a need for increased training and supervision.
Belief in conspiracy theories and intentions to engage in everyday crime
Authors: Jolley Daniel , Douglas Karen M. , Leite Ana C. , Schrader Tanya
Published: January 2019

Belief in conspiracy theories is associated with negative outcomes such as political disengagement, prejudice, and environmental inaction. The current studies – one cross‐sectional (N = 253) and one experimental (N = 120) – tested the hypothesis that belief in conspiracy theories would increase intentions to engage in everyday crime. Study 1 demonstrated that belief in conspiracy theories predicted everyday crime behaviours when controlling for other known predictors of everyday crime (e.g., Honesty–Humility). Study 2 demonstrated that exposure to conspiracy theories (vs. control) increased intentions to engage in everyday crime in the future, through an increased feeling of anomie. The perception that others have conspired may therefore in some contexts lead to negative action rather than inaction.
Blocking bacterial entry at the adhesion step reveals dynamic recruitment of membrane and cytosolic probes
Authors: Ciczora Yann , Janel Sébastien , Soyer Magali , Popoff Michka , Werkmeister Elisabeth , Lafont Frank
Published: January 2019

Background

Bacterial invasion covers two steps: adhesion and entry per se. The cell signalling response is triggered upon pathogen interaction at the cell surface. This response continues when the pathogen is internalised. It is likely that these two steps activate different molecular machineries. So far, it has not been possible to easily follow in physiological conditions these events separately. We thus developed an approach to uncouple adhesion from entry using atomic force microscopy (AFM)‐driven force and fluorescence measurements.

Results

We report nanometric‐scale, high‐resolution, functional dynamic measurements of bacterial interaction with the host cell surface using photonic and adhesion force analyses. We describe how to achieve a precise monitoring of iterative cell–bacterium interactions to analyse host cell signalling responses to infection. By applying this method to Yersinia pseudotuberculosis, we first unveil glycosylphosphatidylinositol‐anchored protein domains recruitment to the bacterium cell surface binding site and concomitant cytoskeleton rearrangements using super‐resolution fluorescence microscopy. Second, we demonstrate the feasibility of monitoring post‐translationally modified proteins, for example, via ubiquitylation, during the first step of infection.

Conclusion

We provide an approach to discriminate between cellular signalling response activated at the plasma membrane during host–pathogen interaction and that is triggered during the internalisation of the pathogen within the cell.

Significance

This approach adds to the technological arsenal to better understand and fight against pathogens and beyond the scope of microbiology to address conceptual issues of cell surface signalling.