bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure of the
EmrE
multidrug transporter and its use for inhibitor peptide design
Authors: Ovchinnikov Victor , Stone Tracy A. , Deber Charles M. , Karplus Martin
Published: August 2018

Significance

Bacterial pathogens are developing resistance to antibiotic compounds at an alarming rate. We use computer simulations to design inhibitors of the
Escherichia coli
multidrug resistance protein
EmrE
(efflux-multidrug resistance E) from the small multidrug family. Starting with low-resolution X-ray data, we obtain an atomic structure of
EmrE
using extensive molecular simulations. Based on the structure, we design hydrocarbon-stapled peptide inhibitors of
EmrE
, which are synthesized and shown to be effective in vivo. The rational drug design approach described here holds promise for combating efflux-mediated drug resistance in microbes and, more generally, in cancer.
Mass spider silk production through targeted gene replacement in
Bombyx mori
Authors: Xu Jun , Dong Qinglin , Yu Ye , Niu Baolong , Ji Dongfeng , Li Muwang , Huang Yongping , Chen Xin , Tan Anjiang
Published: August 2018

Significance

The use of heterologous systems to express spider silk has become an attractive method. However, achieving cost-effective production and high yields is still challenging. Here, we describe the establishment of a targeted gene replacement system in
Bombyx mori
to express the major ampullate spidroin-1 gene (
MaSp1
) from the spider
Nephila clavipes
. With the aid of transcription activator-like effector nuclease-mediated homology-directed repair, we genetically replaced the silkworm fibroin heavy chain gene with MaSp1 with considerable transformation efficiency, and the chimeric MaSp1 yields reached up to 35.2% wt/wt of cocoon shells in transformed silkworms. The genetically modified silk fiber had significant changes in mechanical properties, with improved extensibility. This system will shed light on the future mass production of new biomaterials, including spider silk.
Evidence for a conducting surface ground state in high-quality single crystalline FeSi
Authors: Fang Yuankan , Ran Sheng , Xie Weiwei , Wang Shen , Meng Ying Shirley , Maple M. Brian
Published: August 2018

Significance

The compound FeSi has been the focus of intense research efforts due to its unusual electrical, magnetic, and lattice properties, which are not well understood. This study reveals a semiconducting-to-metallic cross-over with decreasing temperature at

∼

19 K, which is not accompanied by any bulk features, in single-crystal samples of FeSi. The low-temperature metallic behavior can be significantly enhanced by reducing the width/thickness of the sample. Application of an external magnetic field easily suppresses the electrical resistivity at low temperatures, but does not have a noticeable effect on the temperature below which metallic conduction occurs. Evidence for a conducting surface state on FeSi similar to the surface state on a topological insulator is presented.
Dynamic redox balance directs the oocyte-to-embryo transition via developmentally controlled reactive cysteine changes
Authors: Petrova Boryana , Liu Keke , Tian Caiping , Kitaoka Maiko , Freinkman Elizaveta , Yang Jing , Orr-Weaver Terry L.
Published: August 2018

Significance

Reactive oxygen species (ROS) increase with age and have been shown to negatively impact age-related diseases. However, the physiological roles they might play in development have not been extensively characterized. Here, we show that ROS have essential functions as oocytes complete meiosis, the specialized cell division that generates haploid eggs, and transition to embryonic development. Meiotic progression and early embryonic divisions are defective when ROS is misregulated. Furthermore, we document the effects of ROS on specific proteins. Our identification of proteins altered in redox state as the oocyte transitions to an embryo provides a valuable resource to guide future exploration of ROS functions in early development. The regulatory system described here has important implications for female fertility.
Insights into the origin of carbonaceous chondrite organics from their triple oxygen isotope composition
Authors: Tartèse Romain , Chaussidon Marc , Gurenko Andrey , Delarue Frédéric , Robert François
Published: August 2018

Significance

Refractory organic matter found in volatile-rich asteroidal materials essentially comprise the elements C, H, O, N, and S, which are thought to be important building blocks for life. Characterizing the origin(s) of these organics thus constitutes a key step to constrain the origin of life on Earth and appraise the habitability potential of other worlds. However, how and where these organics formed are still highly debated. In this study, we have determined the oxygen isotope composition of refractory organics from two families of carbonaceous chondrites. These data suggest that these organics formed in the nascent Solar System, possibly through chemical reactions occurring in the disk surrounding the young Sun.
Examining the Effectiveness of Support for UK Wave Energy Innovation since 2000. Lost at Sea or a New Wave of Innovation?
Authors: Kingston William
Published: August 2018

This report, funded by UK Engineering and Physical Sciences Research Council and the International Public Policy Institute, has the great merit of being a study of innovation failure, rather than success, and the number of useful lessons it contains is consequently all the greater. From a massive database, it estimates that, between 2000 and 2017, the UK provided close to half a billion pounds of public sector funding to encourage the private sector to try to capture offshore wave energy. Investment by firms must have been even more. There was nothing tangible to show for all this in the end, primarily because of inadequacies ‘in government and industrial strategy to support wave energy innovation in the UK, most notably a premature emphasis on commercialisation and a lack of knowledge exchange.’ Public funding only partially covered R&D costs, so that developers tried to reach the stage where their equipment could actually produce saleable energy, without enough testing for faults. This attempt to ‘go too far too quickly’ was compounded by government’s investing heavily in test facilities without providing support for developers to use them. Also, reliance on patent protection caused developers to avoid sharing their information. The public sector did learn some lessons. Wave Energy Scotland was established to carry on the work in a much more modest way, but able to offer 100% funding and to insist that research results were shared among developers. In addition, the European Community introduced the Marinet initiative to fund access by developers to test facilities.
Oligomerization of the FERM-FA protein Yurt controls epithelial cell polarity
Authors: Gamblin Clémence L. , Parent-Prévost Frédérique , Jacquet Kévin , Biehler Cornélia , Jetté Alexandra , Laprise Patrick
Published: August 2018

Drosophila melanogaster Yurt (Yrt) and its mammalian orthologue EPB41L5 limit apical membrane growth in polarized epithelia. EPB41L5 also supports epithelial–mesenchymal transition and metastasis. Yrt and EPB41L5 contain a four-point-one, ezrin, radixin, and moesin (FERM) domain and a FERM-adjacent (FA) domain. The former contributes to the quaternary structure of 50 human proteins, whereas the latter defines a subfamily of 14 human FERM proteins and fulfills unknown roles. In this study, we show that both Yrt and EPB41L5 oligomerize. Our data also establish that the FERM-FA unit forms an oligomeric interface and that multimerization of Yrt is crucial for its function in epithelial cell polarity regulation. Finally, we demonstrate that aPKC destabilizes the Yrt oligomer to repress its functions, thereby revealing a mechanism through which this kinase supports apical domain formation. Overall, our study highlights a conserved biochemical property of fly and human Yrt proteins, describes a novel function of the FA domain, and further characterizes the molecular mechanisms sustaining epithelial cell polarity.
(Re)examining the Insurance Model of Judicial Independence across Democracies
Authors: Epperly Brad
Published: August 2018

Despite being a dominant explanation of judicial independence in democracies for over a decade, the “insurance” model has received little systematic attention. I argue that how we conceptualize democracy is especially important for analyses of judicial independence employing this insurance framework, demanding more careful attention from scholars. I illustrate that empirical results are contingent on specific conceptualizations by replicating the single existing study examining the insurance model across democracies globally. In doing so, I demonstrate that existing findings are largely driven by classifying electoral authoritarian regimes like Kazakhstan and Russia as democracies.
Effect of Cannabinoid Receptor Agonists on Isolated Rat Atria
Authors: Maggo Simran , Ashton John C.
Published: August 2018

Cannabinoid CB2 receptor agonists are under investigation for clinical use. At the same time, synthetic cannabinoids have been implicated in a number of deaths. One cause of death is thought to be cardiac arrest subsequent to extreme tachycardia. Central mechanisms are thought to play a role in this, with CB1 but not CB2 receptors thought to mediate central effects. However, the direct effects of cannabinoids on the heart are less well understood. We therefore tested the effects of cannabinoids on isolated rat atria to test whether activation of myocardial CB1 and CB2 receptors could contribute to tachycardia. Although we found a moderate effect that can be attributed to CB1 receptors, we did not find any evidence for chronotropic effects by a CB2 receptor activation. Our results indicate that cannabinoid cardiotoxicity may partially involve CB1 receptors in the myocardium, and that CB2 receptor agonists are unlikely to have significant effects on the heart.
A Preliminary Study of Early-Onset Dementia of Former Professional Football and Hockey Players
Authors: Willer Barry S. , Zivadinov Robert , Haider Mohammad N. , Miecznikowski Jeffrey C. , Leddy John J.
Published: August 2018

Objective:

To provide an overview of 3 studies of the same population of retired professional contact sport athletes compared with age-matched noncontact sport athlete controls on cognition, executive function, behavior, and advanced brain imaging.

Setting:

University Concussion Management Clinic.

Participants:

Twenty-two retired professional hockey and football athletes (average age 56 years) and 21 age-matched noncontact sport athlete controls.

Design:

Case control.

Main Measures:

Participants were assessed on a broad range of neuropsychological measures that are associated with identification of mild cognitive impairment and executive function. Athletes were also assessed using self-report measures of executive function and personality. Advanced structural and functional imaging techniques were utilized as well.

Results:

The former National Football League and National Hockey League athletes perceived themselves to have impaired executive function, but this was not confirmed by objective neurocognitive assessment. No significant differences were found when comparing contact-sport athletes with controls on the presence of mild cognitive impairment or brain structural and functional tissue injury. Contact sport athletes were more anxious and more likely to report unusual beliefs and experiences.

Conclusion:

None of the retired contact sport athletes qualified as having early-onset dementia consistent with chronic traumatic encephalopathy. There were no remarkable differences in imaging, cognition, behavior, or executive function from noncontact sport athletes. The results underscore an apparent disconnect between public perceptions and evidence-based conclusions about the inevitability of chronic traumatic encephalopathy and the potential neurodegenerative effect on former athletes from contact sports.
Evaluation of Executive Function and Mental Health in Retired Contact Sport Athletes
Authors: Willer Barry S. , Tiso Michael R. , Haider Mohammad N. , Hinds Andrea L. , Baker John G. , Miecznikowski Jeffery C. , Leddy John J.
Published: August 2018

Objective:

To compare retired professional contact sport athletes with age-matched noncontact sport athletes on measures of executive function and mental health.

Setting:

The University Concussion Management Clinic.

Participants:

Twenty-one retired National Football League (NFL) and National Hockey League (NHL) players (mean age 56 years) and 21 age-matched noncontact sport athlete controls.

Designs:

Case control.

Main Measure:

The self- and informant-reported Behavior Rating Inventory of Executive Function-Adult form (BRIEF-A); Wisconsin Card Sorting Test; Delis-Kaplan Executive Function System; Trail Making Part A and B; Wechsler Adult Intelligence Scale; Neuropsychological Assessment Battery; List Learning; Controlled Oral Word Association Test; Beck Depression Inventory; Beck Anxiety Inventory; and Personality Inventory of the DSM-5.

Results:

Former NFL and NHL players perceived themselves to have some impairment in 2 of the 9 domains of executive function on the BRIEF-A; however, their informants reported no difference when compared with informants of noncontact athletes. No significant differences were found when comparing contact sport athletes with noncontact athletes on objective neuropsychological testing. Contact sport athletes qualified as clinically anxious and had more “unusual beliefs and experiences,” although they remained within with age-based norms.

Conclusion:

Participation in contact sports at the professional level may not lead to later-life executive dysfunction, as the popular media and some research currently suggest.
OUTER RETINAL INJURY SECONDARY TO MEMBRANE PEELING WITH INTERNAL LIMITING MEMBRANE FORCEPS
Authors: Date Rishabh C. , Chang Emmanuel Y. , Shah Veeral S.
Published: August 2018

Purpose:

To present a case of visually significant retinal injury due to internal limiting membrane (ILM) peeling using ILM forceps alone.

Methods:

Case report.

Results:

A 60-year-old woman who underwent ILM peeling for an epiretinal membrane presented with linear central scotomata. Peeling had been initiated and performed with ILM forceps alone, without the use of other surgical instruments. Fundus examination and spectral domain optical coherence tomography imaging confirmed the presence of several discrete areas of inner and outer retinal injury in the macula, which corresponded to her scotomata.

Conclusion:

This is a case of visually significant retinal injury due to ILM peeling that was performed with ILM forceps alone. Improper peeling technique can transmit injurious forces to the retina. Surgeons must be mindful of the biomechanical forces involved in ILM peeling to minimize traction on the retina.
Comparative Analysis of Adverse Events From a Series of Proof-of-Principle Extended Wear Studies
Authors: Ozkan Jerome , Lazon de la Jara Percy , Willcox Mark
Published: August 2018

Aim:

A series of proof-of-principle extended wear (EW) contact lens studies were conducted to assess what effect different interventions had on adverse events (AEs). Comparative analysis of AEs across studies was conducted to determine whether some interventions were more effective at reducing inflammatory AEs.

Method:

Multiple logistic regression analysis of AEs from 30-day EW studies each with a different intervention including (1) nightly replacement (NR) of lenses, (2) morning replacement (MR) of lenses, (3) instillation of prophylactic antibiotic drops (AB) each morning/evening, (4) daily lens cleaning (LC) each morning. All studies conducted at the same site using same lens type (lotrafilcon A) and EW schedule.

Results:

Comparison of the different interventions to the individual control groups showed no difference in significant corneal infiltrative event (CIE) or mechanical events. Replacing lenses nightly, during an EW schedule, had the highest incidence of significant CIEs (4.9% [NR] vs. 2.5% [MR] vs. 1.8% [AB] vs. 0% [LC]); however, adjusted logistic regression analysis of the combined control data compared with the individual interventions showed no difference in significant CIEs (P=0.086) or mechanical AEs (P=0.140).

Conclusions:

Replacing lenses each night seemed to be inferior compared with the other interventions of replacing lenses each morning, daily lens cleaning, and daily antibiotic drop instillation during EW. The results of the collective studies and additional analysis suggest that overnight wear of contact lenses seems to create an adverse environment that remains, despite the various interventions intended to improve this adverse environment.
“It Had Only Been a Matter of Time Before I Had Relapsed Into Crime”: Aspects of Care and Personal Recovery in Forensic Mental Health
Authors: Pollak Charlotte , Palmstierna Tom , Kald Magnus , Ekstrand Per
Published: August 2018

Introduction

Forensic psychiatry has the dual task of focusing on the prevention of reoffending as well as maintaining psychiatric rehabilitation. No previous studies addressing the patients' own views on reducing their risk of serious reoffending were found.

Aim

This study describes forensic psychiatric inpatients' own views on what aspects of care and personal recovery are important in reducing their risk of serious reoffending.

Methods

A structured qualitative approach was used. Data were collected from semistructured interviews and analyzed with a systematic qualitative content analysis.

Results

The results highlight aspects of care and personal recovery. Four themes emerged: “time: opportunity for change,” “trust: creating a context with meaningful relations,” “hope: to reach a future goal,” and “toolbox: tools needed for recovery.”

Discussion

The themes present with a continuum. At one end, there are patients who appreciated possibilities to participate actively in care and treatment. At the other end, patients felt they had no use for their care. Interestingly, although patients in our study were asked for their opinion on how they could reduce their dangerousness, all themes fit into established personal recovery processes found in general psychiatric populations. The theme “time: opportunity for change” seems to have an overarching importance.

Implications for Practice

By understanding the specific content along these themes, relevant to the individual patient, carers may be able to better support their personal recovery journey. Because time spent as inpatients in forensic psychiatry is an overarching issue, carers need to be persistent over time.
Incidence for Tip Foldover During Cochlear Implantation
Authors: Gabrielpillai Jennis , Burck Iris , Baumann Uwe , Stöver Timo , Helbig Silke
Published: August 2018

Objective:

Incidence and clinical presentation of tip foldover during cochlear implantation (CI).

Study Design:

Retrospective case review.

Setting:

Tertiary referral university hospital.

Patients:

One thousand three hundred twenty CI recipients who underwent postoperative Stenvers view, digital computed tomography (CT), or digital volume tomography (DVT).

Main Outcome Measure:

Tip foldover rates were evaluated with regard to perimodiolar (PM), lateral wall (LW), and mid-scalar (MS) electrode carriers; the electrode insertion angle was estimated and postoperative complications and the necessity for revisions were described.

Results:

One thousand three hundred twenty CI recipients (1,722 ears) had detailed surgery reports and postoperative imaging available for review. Tip foldover occurred in 15 ears (0.87%) with the highest rate (1.67%) for PM electrodes. In three patients tip foldover was accompanied by costimulation of the facial nerve and one patient reported vertigo. Eleven patients underwent revision surgery. In two of them revision was performed in the same surgical intervention due to abnormality in spread of excitation measurement. In four patients no revision was conducted due to uncompromised aided speech perception.

Conclusion:

In a large academic center with experienced surgeons, tip foldover verified by CT/DVT arose at a rate of 0.87%. PM electrode carriers inherited the highest risk for this electrode malposition. Revision surgery was feasible in these cases.
Hearing Preservation With Standard Length Electrodes in Pediatric Cochlear Implantation
Authors: Manjaly Joseph G. , Nash Robert , Ellis Wayne , Britz Anzel , Lavy Jeremy A. , Shaida Azhar , Saeed Shakeel R. , Khalil Sherif S.
Published: August 2018

Objective:

Preserving low frequencies following cochlear implantation improves outcomes and allows patients to use a combination of electrical and acoustic stimulation. This importance has been reflected in advances in electrode design and refined surgical techniques. Full insertion of standard length electrodes may be advantageous over shortened electrodes because more electrodes can be activated over time if low frequency hearing loss progresses. Surgeons must counsel patients over this choice but data is lacking regarding the degree and likelihood of hearing preservation achievable with standard length electrodes in children. We report our experience using standard length cochlear implant arrays for hearing preservation in children.

Methods:

Retrospective case series. Inclusion criteria: preoperative hearing ≤85 dB HL at 250 Hz and aged ≤18 years. Hearing preservation percentages are calculated using the HEARRING group formula.

JOURNAL/otneu/04.03/00129492-201810000-00008/inline-graphic1/v/2023-08-21T201615Z/r/image-tiff

Preservation of > 75% was considered complete, 25 to 75% partial, and 1 to 25% minimal. Patients were implanted with either MED-EL FLEX28 or Cochlear Nucleus CI522. Standardized operative technique with facial recess approach, posterior tympanotomy and minimally traumatic round window insertion.

Results:

Fifty-two implantations in 27 pediatric patients met inclusion criteria. Mean age at implantation: 9.8 years. Average latest audiogram: 8 months. Mean total pre- and postoperative pure-tone averages were 82.8 and 92.6 dB. Seventeen (33%) ears demonstrated complete hearing preservation, 22 (42%) ears partial hearing preservation, 7 (13%) minimal hearing preservation, and 6 (12%) exhibited no acoustic hearing postoperatively. Mean hearing preservation was 55.5%.

Conclusion:

Hearing preservation is achievable to varying degrees in pediatric cochlear implantation using standard length electrodes though it is difficult to predict preoperatively which children may benefit. This study is among the largest additions to the knowledge base for this patient group.
Assessing Cochlear Length Using Cone Beam Computed Tomography in Adults With Cochlear Implants
Authors: Alnafjan Fadwa F. , Allan Stuart M. , McMahon Catherine M. , da Cruz Melville J.
Published: August 2018

Developing a clinically viable technique for measuring cochlear length could enhance future electrode design of cochlear implants and surgical skills to improve clinical outcomes. While computed tomography (CT) has been used, metal artifact and the exposure to higher levels of radiation limits its use. More recently, cone beam CT (CBCT) has been used to assess the integrity of the implant array in situ, exposing implantees to lower levels of radiation while retaining image quality. The current study aims to develop a technique for measuring cochlear length in implanted adults, using CBCT images combined with known dimensions of implant arrays and lengths of cochlear structures from cadaveric human temporal bones.

Study Design:

One hundred CBCT temporal bone images of ears implanted with Cochlear straight or perimodiolar arrays were reviewed by two independent examiners.

Results:

Outer-wall length, based on the position of the straight array within the cochlea and the reported average length of the organ of Corti, was 27.44 to 35.91 mm (mean = 32.24 mm). Inner-wall length, based on the position of the perimodiolar array and the reported average length of the spiral ganglion, ranged from 17.8 to 22.24 mm (mean = 19.43 mm).

Conclusion:

A novel method for calculating outer- and inner-wall cochlear length using CBCT images has been developed which is feasible in clinical settings.
Death and Dying in the ICU: Personal Reflection of 30 Years’ Experience
Authors: Butt Warwick W.
Published: August 2018

Objective:

To describe individual perspective over ~30 years in a mixed Cardiac and General ICU, which includes the State Trauma Center, National Cardiac Transplant and Complex Cardiac Center, Extracorporeal Membrane Oxygenation Center, Home Ventilation Program, and the major PICU for 6 million people.

Data Sources:

Personal experience and reflection, complemented by published local data.

Study Selection:

Illustrative publications of local other data.

Data Synthesis:

Narrative, experiential reflection.

Conclusions:

I have agreed to palliative care in many patients of diverse religious, social, and cultural beliefs while providing long-term ICU care to other patients with similar illnesses and prognosis. This can occur when family meetings allow honest and direct conversation with respect for differences; as a clinician, I listen to a family and understand their perspectives and together develop a clear and agreed plan.
Investigations After Death in Children
Authors: Bohn Desmond , Chiasson David , Huyer Dirk
Published: August 2018

Objectives:

To discuss the role of investigations after death in children as part of a supplement on “Death and Dying in the PICU.”

Data Sources:

Literature review, personal experience, and expert opinion.

Data Selection:

Not applicable.

Data Extraction:

Moderated by three experts on investigations after death in children.

Data Synthesis:

Not relevant.

Conclusions:

A multidisciplinary cliniciopathologic conference is important after the death of a child in order to help bring closure to the family and to attempt to address any concerns they may have about the care. It is also an important part of the quality of care process for a tertiary care institution and provides an unique opportunity for ongoing medical education. The model of a multidisciplinary cliniciopathologic conference used by the Ontario Coroner’s Office to investigate sudden and unexpected deaths in children under 5 years old, which has been functioning for over 30 years, is described. Reports from this Pediatric Death Review Committee have been influential in improving the care of children in the province of Ontario.
Nerve and skin biopsy in neuropathies
Authors: Sommer Claudia
Published: August 2018

Purpose of review

To give an overview of recent data on the use of nerve and skin biopsy as a diagnostic tool in neuropathies.

Recent findings

Axonal damage in a biopsy from a patient with chronic inflammatory demyelinating polyradiculoneuropathy may point to the presence of autoantibodies to paranodal proteins. In nonsystemic vasculitis of the peripheral nervous system, nerve biopsy is still the only means to make a definite diagnosis. Increased autophagy has been found in idiopathic neuropathy and may also be a common final pathway in various types of neuropathy. Nerve biopsy has unexpectedly revealed familial amyloid neuropathy in a number of cases that were taken for idiopathic, for Charcot-Marie-Tooth disease, or for chronic inflammatory demyelinating polyradiculoneuropathy. Skin biopsy can differentiate between length-dependent and non-length-dependent small fiber neuropathy, which aids in the etiological differential diagnosis. It can also be used to identify small fiber involvement in mixed neuropathies and for follow-up studies.

Nerve biopsy is still the gold standard for the diagnosis of peripheral nerve vasculitis. In other indications, sural or superficial peroneal nerve biopsies are less frequently done, because less invasive methods have become available. Modern imaging methods allow localization of nerve damage, such that targeted fascicular biopsies can be done. Immunofluorescence staining of teased nerve fibers has contributed to the understanding of the pathophysiology of inflammatory neuropathies. Skin biopsy has become a routine method to diagnose small fiber neuropathy.
Machine learning and genomics: precision medicine versus patient privacy
Authors: Azencott C.-A.
Published: August 2018

Machine learning can have a major societal impact in computational biology applications. In particular, it plays a central role in the development of precision medicine, whereby treatment is tailored to the clinical or genetic features of the patient. However, these advances require collecting and sharing among researchers large amounts of genomic data, which generates much concern about privacy. Researchers, study participants and governing bodies should be aware of the ways in which the privacy of participants might be compromised, as well as of the large body of research on technical solutions to these issues. We review how breaches in patient privacy can occur, present recent developments in computational data protection and discuss how they can be combined with legal and ethical perspectives to provide secure frameworks for genomic data sharing.

This article is part of a discussion meeting issue ‘The growing ubiquity of algorithms in society: implications, impacts and innovations’.
NHX-type Na+(K+)/H+ antiporter activity is required for endomembrane trafficking and ion homeostasis in Arabidopsis thaliana
Authors: Dragwidge Jonathan Michael , Scholl Stefan , Schumacher Karin , Gendall Anthony Richard
Published: August 2018

The regulation of ion and pH homeostasis of endomembrane organelles is critical for functional protein trafficking, sorting and modification in eukaryotic cells. pH homeostasis is maintained through the activity of vacuolar H+-ATPases (V-ATPases) pumping protons (H+) into the endomembrane lumen, and counter-action by cation/proton exchangers such as the NHX family of Na+(K+)/H+ exchangers. In plants, disturbing V-ATPase activity at the trans-Golgi network/early endosome (TGN/EE) impairs secretory and endocytic trafficking. However, it is unclear if the endosomal NHX-type antiporters NHX5 and NHX6 play functionally similar roles in endomembrane trafficking through maintaining ion and pH homeostasis. Here we show through genetic, pharmacological, and live-cell imaging approaches that double knockout of endosomal isoforms NHX5 and NHX6 results in impairment of endosome motility, protein recycling at the TGN/EE, but not in the secretion of integral membrane proteins. Furthermore, we report that nhx5 nhx6 mutants are partially insensitive to osmotic swelling of TGN/EE induced by the monovalent cation ionophore monensin. Similarly, nhx5 nhx6 cells are unresponsive to late endosomal swelling by the phosphatidylinositol 3/4-kinase inhibitor wortmannin, demonstrating that NHX5 and NHX6 are required for maintaining endosomal cation balance. Lastly, we report that the distal region of the cytosolic tail of NHX6 is required for mediating NHX6 localisation to late endosomes, but does not appear to be essential for NHX6 function.
A strain of an emerging Indian pathotype of Xanthomonas oryzae pv. oryzae defeats the rice bacterial blight resistance gene xa13 without inducing a clade III SWEET gene and is nearly identical to a recent Thai isolate
Authors: Carpenter Sara C. D. , Mishra Prashant , Ghoshal Chandrika , Dash Prasanta , Wang Li , Midha Samriti , Laha Gouri S. , Lore Jagjeet S , Kositratana Wichai , Singh Nagendra K. , Singh Kuldeep , Patil Prabhu B. , Oliva Ricardo , Patarapuwadol Sujin , Bogdanove Adam J , Rai Rhitu
Published: August 2018

The rice bacterial blight pathogen Xanthomonas oryzae pv. oryzae (Xoo) injects transcription activator-like effectors (TALEs) that bind and activate host ‘susceptibility’ (S) genes important for disease. Clade III SWEET genes are major S genes for bacterial blight. The resistance genes xa5, which reduces TALE activity generally, and xa13, a SWEET11 allele not recognized by the cognate TALE, have been effectively deployed. However, strains that defeat both resistance genes individually were recently reported in India and Thailand. To gain insight into the mechanism(s), we completely sequenced the genome of one such strain from each country and examined the encoded TALEs. Strikingly, the two strains are clones, sharing nearly identical TALE repertoires, including a TALE known to activate SWEET11 strongly enough to be effective even when diminished by xa5. We next investigated SWEET gene induction by the Indian strain. The Indian strain induced no clade III SWEET in plants harbouring xa13, indicating a pathogen adaptation that relieves dependence on these genes for susceptibility. The findings open a door to mechanistic understanding of the role SWEET genes play in susceptibility and illustrate the importance of complete genome sequence-based monitoring of Xoo populations in developing varieties with effective disease resistance.
An automated, high-throughput image analysis pipeline enables genetic studies of shoot and root morphology in carrot (Daucus carota L.)
Authors: Turner Sarah D. , Ellison Shelby L. , Senalik Douglas A. , Simon Philipp W. , Spalding Edgar P. , Miller Nathan D.
Published: August 2018

Carrot is a globally important crop, yet efficient and accurate methods for quantifying its most important agronomic traits are lacking. To address this problem, we developed an automated analysis platform that extracts components of size and shape for carrot shoots and roots, which are necessary to advance carrot breeding and genetics. This method reliably measured variation in shoot size and shape, leaf number, petiole length, and petiole width as evidenced by high correlations with hundreds of manual measurements. Similarly, root length and biomass were accurately measured from the images. This platform quantified shoot and root shapes in terms of principal components, which do not have traditional, manually-measurable equivalents. We applied the pipeline in a study of a six-parent diallel population and an F2 mapping population consisting of 316 individuals. We found high levels of repeatability within a growing environment, with low to moderate repeatability across environments. We also observed co-localization of quantitative trait loci for shoot and root characteristics on chromosomes 1, 2, and 7, suggesting these traits are controlled by genetic linkage and/or pleiotropy. By increasing the number of individuals and phenotypes that can be reliably quantified, the development of a high-throughput image analysis pipeline to measure carrot shoot and root morphology will expand the scope and scale of breeding and genetic studies.
Bayesian Nonparametric Models Characterize Instantaneous Strategies in a Competitive Dynamic Game
Authors: McDonald Kelsey R. , Broderick William F. , Huettel Scott A. , Pearson John M.
Published: August 2018

Previous approaches to investigating strategic social interaction in game theory have predominantly used games with clearly-defined turns and limited choices. However, most real-world social behaviors involve dynamic, coevolving decisions by interacting agents, which pose challenges for creating tractable models of behavior. Here, using a competitive game in which human participants control the dynamics of an on-screen avatar against either another human or a computer opponent, we show that it is possible to quantify the dynamic coupling between agents using nonparametric models. We use Gaussian Processes to model the joint distributions of players’ actions and identities (human or computer) as a function of game state. Borrowing from a reinforcement learning framework, we successfully approximated both the policy and the value functions used by each human player in this competitive context. This approach offers a natural set of metrics for facilitating analysis at multiple timescales and suggests new classes of tractable paradigms for assessing human behavior.
Monte-Carlo Diffusion-Enhanced Photon Inference: Distance Distributions And Conformational Dynamics In Single-Molecule FRET
Authors: Ingargiola Antonino , Weiss Shimon , Lerner Eitan
Published: August 2018

Single-molecule Förster Resonance Energy Transfer (smFRET) is utilized to study the structure and dynamics of many bio-molecules, such as proteins, DNA and their various complexes. The structural assessment is based on the well-known Förster relationship between the measured efficiency of energy transfer between a donor (D) and an acceptor (A) dye and the distance between them. Classical smFRET analysis methods called photon distribution analysis (PDA) take into account photon shot-noise, D-A distance distribution and, more recently, interconversion between states in order to extract accurate distance information. It is known that rapid D-A distance fluctuations on the order of the D lifetime (or shorter) can increase the measured mean FRET efficiency and thus decrease the estimated D-A distance. Nonetheless, this effect has been so far neglected in smFRET experiments, potentially leading to biases in estimated distances.

Here we introduce a PDA approach dubbed Monte-Carlo-diffusion-enhanced photon inference (MC-DEPI). MC-DEPI recolor detected photons of smFRET experiments taking into account dynamics of D-A distance fluctuations, multiple interconverting states and photo-blinking. Using this approach, we show how different underlying conditions may yield identical FRET histograms and how the additional information from fluorescence decays helps distinguishing between the different conditions. We also introduce a machine learning fitting approach for retrieving the D-A distance distribution, decoupled from the above-mentioned effects. We show that distance interpretation of smFRET experiments of even the simplest dsDNA is nontrivial and requires decoupling the effects of rapid D-A distance fluctuations on FRET in order to avoid systematic biases in the estimation of the D-A distance distribution.
Why panmictic bacteria are rare
Authors: Yang Chao , Cui Yujun , Didelot Xavier , Yang Ruifu , Falush Daniel
Published: August 2018

Background

Bacteria typically have more structured populations than higher eukaryotes, but this difference is surprising given high recombination rates, enormous population sizes and effective geographical dispersal in many bacterial species.

Results

We estimated the recombination scaled effective population sizeNerin 21 bacterial species and find that it does not correlate with synonymous nucleotide diversity as would be expected under neutral models of evolution. Only two species have estimates substantially over 100, consistent with approximate panmixia, namelyHelicobacter pyloriandVibrio parahaemolyticus. Both species are far from demographic equilibrium, with diversity predicted to increase more than 30 fold inV. parahaemolyticusif the current value ofNerwere maintained, to values much higher than found in any species. We propose that panmixia is unstable in bacteria, and that persistent environmental species are likely to evolve barriers to genetic exchange, which act to prevent a continuous increase in diversity by enhancing genetic drift.

Conclusions

Our results highlight the dynamic nature of bacterial population structures and imply that overall diversity levels found within a species are poor indicators of its size.
Mapping the human kinome in response to DNA damage
Authors: Owusu Michel , Bannauer Peter , Mourikis Athanasios , Jones Alistair , Silva Joana Ferreira da , Caldera Michael , Wiedner Marc , Lardeau Charles-Hugues , Menche Jörg , Kubicek Stefan , Ciccarelli Francesca , Loizou Joanna I.
Published: August 2018

We provide a catalog for the effects of the human kinome on cell survival in response to DNA damaging agents, selected to cover all major DNA repair pathways. By treating 313 kinase-deficient cell lines with ten diverse DNA damaging agents, including seven commonly used chemotherapeutics, we were able to identify kinase specific vulnerabilities and resistances. In order to identify novel synthetic lethal interactions, we investigate the cellular response to carmustine for 25 cell lines, by establishing a phenotypic FACS assay designed to mechanistically investigate and validate gene-drug interactions. We show apoptosis, cell cycle, DNA damage and proliferation after alkylation or crosslink-induced damage for selected cell lines and rescue the cellular sensitivity of DYRK4, EPHB6, MARK3, PNCK as a proof of principle for our study. Our data suggest that some cancers with inactivated DYRK4, EPHB6, MARK3 or PNCK gene could be particularly vulnerable to treatment by alkylating chemotherapeutic agents carmustine or temozolomide.
Spatiotemporal ontogeny of brain wiring
Authors: Goulas Alexandros , Betzel Richard F. , Hilgetag Claus C.
Published: August 2018

The wiring of the brain provides the anatomical skeleton for cognition and behavior. Connections among brain regions have a diverse and characteristic strength. This strength heterogeneity is captured by the wiring cost and homophily principles. Moreover, brains have a characteristic global network topology, including modularity and short path lengths. However, the mechanisms underlying the inter-regional wiring principles and global network topology of brains are unknown. Here, we address this issue by modeling the ontogeny of brain connectomes. We demonstrate that spatially embedded and heterochronous neurogenetic gradients, without the need of axonal-guidance molecules or activity-dependent plasticity, can reconstruct the wiring principles and shape the global network topology observed in adult brain connectomes. Thus, two fundamental dimensions, that is, space and time, are key components of a plausible neurodevelopmental mechanism with a universal scope, encompassing vertebrate and invertebrate brains.
Assessment of Functional Connectome Construction Strategies in Neurodegeneration
Authors: Vanhoecke J , McColgan P , Razi A , Gregory S , Seunarine K , Durr A , Roos R , Leavitt B , Scahill RI , Clark C , Tabrizi SJ , Rees G ,   Track On-HD Investigators
Published: August 2018

Connectomics can be used to investigate functional brain networks in neurodegenerative diseases including Huntington’s disease (HD). In this developing field, different connectome construction strategies have emerged in parallel. However, there is a need to understand the influences of different strategies on subsequent analyses when constructing a connectome. This study systematically compares connectome construction strategies based on their biological relevance to functional networks in neurodegeneration.

We asked which functional connectome construction strategy was best able to discriminate HD gene carriers from healthy controls, and how such a strategy affected modular organization of the network. The major factors compared were principal component-based correction versus wavelet decomposition for physiological noise correction, the type of parcellation atlas (functional, structural and multi-modal), weighted versus binarized networks, and unthresholded versus proportionally thresholded networks. We found that principal component-based correction generated the most discriminatory connectomes, while binarization and proportional thresholding did not increase discrimination between HD gene carriers and healthy controls. When a functional parcellation atlas was used, the highest discrimination rates were obtained. We observed that the group differences in modular organization of the functional connectome were greatly affected by binarization and thresholding, showing no consistent pattern of modularity.

This study suggests that functional connectome construction strategies using principal component-based correction and weighted unthresholded connectivity matrices may outperform other strategies.
Bile Acid Biosynthesis Avoiding Cholesterol
Authors: Griffiths William J. , Abdel-Khalik Jonas , Crick Peter J. , Yutuc Eylan , Ogundare Michael , Bigger Brian W. , Morris Andrew A. , Shackleton Cedric H. , Clayton Peter T. , Iida Takashi , Sircar Ria , Marschall Hanns-Ulrich , Sjövall Jan , Björkhem Ingemar , Rohatgi Rajat , Wang Yuqin
Published: August 2018

Bile acids are the end products of cholesterol metabolism secreted into bile. They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have investigated the bile acid content of plasma and urine from patients with a defect in cholesterol biosynthesis, i.e. Smith-Lemli-Opitz syndrome (SLOS), resulting in elevated levels of 7-dehydrocholesterol (7-DHC), an immediate precursor of cholesterol. Using liquid chromatography – mass spectrometry (LC-MS) we have identified a novel pathway of bile acid biosynthesis in SLOS avoiding cholesterol starting with 7-DHC. This pathway also proceeds to a minor extent in healthy individuals. Monitoring of the pathway products could provide a rapid diagnostic for SLOS while elevated levels of pathway intermediates could be responsible for some of the features of the disease. Importantly, intermediates in the pathway are modulators of the activity of Smoothened, an oncoprotein that mediates Hedgehog signalling during embryogenesis and regeneration of postembryonic tissue.
Spatiotemporal analysis for detection of pre-symptomatic shape changes in neurodegenerative diseases: applied to GENFI study
Authors: Cury Claire , Durrleman Stanley , Cash David , Lorenzi Marco , Nicholas Jennifer M , Bocchetta Martina , van Swieten John C. , Borroni Barbara , Galimberti Daniela , Masellis Mario , Carmela Tartaglia Maria , Rowe James B , Graff Caroline , Tagliavini Fabrizio , Frisoni Giovanni B. , Laforce Robert , Finger Elizabeth , de Mendonca Alexandre , Sorbi Sandro , Ourselin Sebastien , Rohrer Jonathan D. , Modat Marc ,   on behalf of the Genetic FTD Initiative, GENFI
Published: August 2018

Brain atrophy as measured from structural MR images, is one of the primary imaging biomarkers used to track neurodegenerative disease progression. In diseases such as frontotemporal dementia or Alzheimer’s disease, atrophy can be observed in key brain structures years before any clinical symptoms are present. Atrophy is most commonly captured as volume change of key structures and the shape changes of these structures are typically not analysed despite being potentially more sensitive than summary volume statistics over the entire structure.

In this paper we propose a spatiotemporal analysis pipeline based Large Diffeomorphic Deformation Metric Mapping (LDDMM) to detect shape changes from volumetric MRI scans. We applied our framework to a cohort of individuals with genetic variants of frontotemporal dementia and healthy controls from the Genetic FTD Initiative (GENFI) study. Our method, take full advantage of the LDDMM framework, and relies on the creation of a population specific average spatiotemporal trajectory of a relevant brain structure of interest, the thalamus in our case. The residuals from each patient data to the average spatiotemporal trajectory are then clustered and studied to assess when presymptomatic mutation carriers differ from healthy control subjects.

We found statistical differences in shape in the anterior region of the thalamus at least five years before the mutation carrier subjects develop any clinical symptoms. This region of the thalamus has been shown to be predominantly connected to the frontal lobe, consistent with the pattern of cortical atrophy seen in the disease.