bluuebunny/crossref_metadata_2025 huggingface dataset:
Batrachotoxin acts as a stent to hold open homotetrameric prokaryotic voltage-gated sodium channels
Authors: Finol-Urdaneta Rocio K. , McArthur Jeffrey R. , Goldschen-Ohm Marcel P. , Gaudet Rachelle , Tikhonov Denis B. , Zhorov Boris S. , French Robert J.
Published: December 2018

Batrachotoxin (BTX), an alkaloid from skin secretions of dendrobatid frogs, causes paralysis and death by facilitating activation and inhibiting deactivation of eukaryotic voltage-gated sodium (Nav) channels, which underlie action potentials in nerve, muscle, and heart. A full understanding of the mechanism by which BTX modifies eukaryotic Nav gating awaits determination of high-resolution structures of functional toxin–channel complexes. Here, we investigate the action of BTX on the homotetrameric prokaryotic Nav channels NaChBac and NavSp1. By combining mutational analysis and whole-cell patch clamp with molecular and kinetic modeling, we show that BTX hinders deactivation and facilitates activation in a use-dependent fashion. Our molecular model shows the horseshoe-shaped BTX molecule bound within the open pore, forming hydrophobic H-bonds and cation-π contacts with the pore-lining helices, leaving space for partially dehydrated sodium ions to permeate through the hydrophilic inner surface of the horseshoe. We infer that bulky BTX, bound at the level of the gating-hinge residues, prevents the S6 rearrangements that are necessary for closure of the activation gate. Our results reveal general similarities to, and differences from, BTX actions on eukaryotic Nav channels, whose major subunit is a single polypeptide formed by four concatenated, homologous, nonidentical domains that form a pseudosymmetric pore. Our determination of the mechanism by which BTX activates homotetrameric voltage-gated channels reveals further similarities between eukaryotic and prokaryotic Nav channels and emphasizes the tractability of bacterial Nav channels as models of voltage-dependent ion channel gating. The results contribute toward a deeper, atomic-level understanding of use-dependent natural and synthetic Nav channel agonists and antagonists, despite their overlapping binding motifs on the channel proteins.
Ate1-mediated posttranslational arginylation affects substrate adhesion and cell migration inDictyostelium discoideum
Authors: Batsios Petros , Ishikawa-Ankerhold Hellen C. , Roth Heike , Schleicher Michael , Wong Catherine C. L. , Müller-Taubenberger Annette
Published: December 2018

The highly conserved enzyme arginyl-tRNA-protein transferase (Ate1) mediates arginylation, a posttranslational modification that is only incompletely understood at its molecular level. To investigate whether arginylation affects actin-dependent processes in a simple model organism, Dictyostelium discoideum, we knocked out the gene encoding Ate1 and characterized the phenotype of ate1-null cells. Visualization of actin cytoskeleton dynamics by live-cell microscopy indicated significant changes in comparison to wild-type cells. Ate1-null cells were almost completely lacking focal actin adhesion sites at the substrate-attached surface and were only weakly adhesive. In two-dimensional chemotaxis assays toward folate or cAMP, the motility of ate1-null cells was increased. However, in three-dimensional chemotaxis involving more confined conditions, the motility of ate1-null cells was significantly reduced. Live-cell imaging showed that GFP-tagged Ate1 rapidly relocates to sites of newly formed actin-rich protrusions. By mass spectrometric analysis, we identified four arginylation sites in the most abundant actin isoform of Dictyostelium, in addition to arginylation sites in other actin isoforms and several actin-binding proteins. In vitro polymerization assays with actin purified from ate1-null cells revealed a diminished polymerization capacity in comparison to wild-type actin. Our data indicate that arginylation plays a crucial role in the regulation of cytoskeletal activities.
Cell fusion in yeast is negatively regulated by components of the cell wall integrity pathway
Authors: Hall Allison E. , Rose Mark D.
Published: December 2018

During mating, Saccharomyces cerevisiae cells must degrade the intervening cell wall to allow fusion of the partners. Because improper timing or location of cell wall degradation would cause lysis, the initiation of cell fusion must be highly regulated. Here, we find that yeast cell fusion is negatively regulated by components of the cell wall integrity (CWI) pathway. Loss of the cell wall sensor, MID2, specifically causes “mating-induced death” after pheromone exposure. Mating-induced death is suppressed by mutations in cell fusion genes ( FUS1, FUS2, RVS161, CDC42), implying that mid2Δ cells die from premature fusion without a partner. Consistent with premature fusion, mid2Δ shmoos had thinner cell walls and lysed at the shmoo tip. Normally, Cdc42p colocalizes with Fus2p to form a focus only when mating cells are in contact (prezygotes) and colocalization is required for cell fusion. However, Cdc42p was aberrantly colocalized with Fus2p to form a focus in mid2Δ shmoos. A hyperactive allele of the CWI kinase Pkc1p ( PKC1*) caused decreased cell fusion and Cdc42p localization in prezygotes. In shmoos, PKC1* increased Cdc42p localization; however, it was not colocalized with Fus2p or associated with cell death. We conclude that Mid2p and Pkc1p negatively regulate cell fusion via Cdc42p and Fus2p.
Illness Perceptions in Chronic Lymphocytic Leukemia: Testing Leventhal’s Self-regulatory Model
Authors: Westbrook Travis D , Morrison Eleshia J , Maddocks Kami J , Awan Farrukh T , Jones Jeffrey A , Woyach Jennifer A , Johnson Amy J , Byrd John C , Andersen Barbara L
Published: December 2018

Background

Leventhal’s Self-regulatory Model proposes that somatic characteristics of a health threat (e.g., symptom severity), and prior experience with the threat (e.g., unsuccessful treatment), are determinants of illness perceptions. Chronic lymphocytic leukemia (CLL) is appropriate for test of these postulates, having three phases differing in symptom severity and prior treatment experiences: indolent disease requiring no treatment (active surveillance; AS), symptomatic disease requiring a first treatment (FT), and highly symptomatic disease in those who have relapsed and/or failed to respond to prior treatments (relapsed/refractory; RR).

Purpose

To test symptom severity and prior treatment experiences as determinants of illness perceptions, illness perceptions were characterized and contrasted between CLL groups.

Methods

Three hundred and thirty CLL patients (AS, n = 100; FT, n = 78; RR, n = 152) provided illness perception data on one occasion during a surveillance visit (AS) or prior to beginning treatment (FT, RR).

Results

Analysis of variance with planned comparisons revealed that consequences, identity, and concern were least favorable among RR patients, followed by FT, then AS (ps < .01). AS patients endorsed the lowest levels of coherence (ps < .01), and the most chronic illness timeline (ps < .01). FT patients endorsed the highest levels of personal and treatment control (ps < .01).

Conclusions

Data provide preliminary empirical support for Self-regulatory Model postulates that symptom severity and prior disease experiences influence illness perceptions. Unique knowledge needs for AS patients and elevated psychological/physical symptoms for later-stage CLL patients may warrant clinical attention.
Mycorrhiza-Induced Resistance in Potato Involves Priming of Defense Responses Against Cabbage Looper (Noctuidae: Lepidoptera)
Authors: Schoenherr Andrew P , Rizzo Eric , Jackson Natasha , Manosalva Patricia , Gomez S Karen
Published: December 2018

Most plants form mutualistic associations with arbuscular mycorrhizal (AM) fungi that are ubiquitous in soils. Through this symbiosis, plants can withstand abiotic and biotic stresses. The underlying molecular mechanisms involved in mediating mycorrhiza-induced resistance against insects needs further research, and this is particularly true for potato (Solanum tuberosum L. (Solanales: Solanaceae)), which is the fourth most important crop worldwide. In this study, the tripartite interaction between potato, the AM fungus Rhizophagus irregularis (Glomerales: Glomeraceae), and cabbage looper (Trichoplusia ni Hübner) (Lepidoptera: Noctuidae) was examined to determine whether potato exhibits mycorrhiza-induced resistance against this insect. Plant growth, insect fitness, AM fungal colonization of roots, and transcript levels of defense-related genes were measured in shoots and roots after 5 and 8 d of herbivory on mycorrhizal and nonmycorrhizal plants. AM fungal colonization of roots did not have an effect on potato growth, but root colonization levels increased by herbivory. Larval weight gain was reduced after 8 d of feeding on mycorrhizal plants compared with nonmycorrhizal plants. Systemic upregulation of Allene Oxide Synthase 1 (AOS1), 12-Oxo-Phytodienoate Reductase 3 (OPR3) (jasmonic acid pathway), Protease Inhibitor Type I (PI-I) (anti-herbivore defense), and Phenylalanine Ammonia Lyase (PAL) transcripts (phenylpropanoid pathway) was found during the tripartite interaction. Together, these findings suggest that potato may exhibit mycorrhiza-induced resistance to cabbage looper by priming anti-herbivore defenses aboveground. This study illustrates how mycorrhizal potato responds to herbivory by a generalist-chewing insect and serves as the basis for future studies involving tripartite interactions with other pests.
Anticholinergic Drug Induced Cognitive and Physical Impairment: Results from the InCHIANTI Study
Authors: Sargent Lana , Nalls Mike , Amella Elaine J , Mueller Martina , Lageman Sarah K , Bandinelli Stefania , Colpo Marco , Slattum Patricia W , Singleton Andrew , Ferrucci Luigi
Published: December 2018

Background

The aims of this study were to evaluate the relationship between anticholinergic drug burden (ACB) cognitive impairment, physical frailty, and cognitive frailty, and to determine if ACB is predictive of these phenotypes when modeled with biological and genomic biomarkers.

Methods

In a retrospective cohort study, a total of 1,453 adults aged 20–102 years were used to examine ACB as a predictor for cognitive impairment, physical frailty, and cognitive frailty. Anticholinergic burden is examined as a predictor for all phenotypes in a cross-sectional analysis using logistic, ordinal regression models, and Extreme Gradient Boosting for population predictive modeling.

Results

A significant association was found between ACB and cognitive decline (p = .02), frailty (p < .001), and cognitive frailty (p < .001). The odds of cognitive impairment increased by 1.21 (95% confidence interval [CI] = 1.06–1.37, p < .001), odds of being frail increased by 1.33 (95% CI = 1.18–1.50, p < .001), and odds of having cognitive frailty increased by 1.36 (95% CI = 1.21–1.54, p < .001). Population modeling results indicated ACB score as one of the stronger predictors for cognitive impairment, physical frailty, and cognitive frailty with area under the curves ranging from 0.81 to 0.88.

Conclusions

Anticholinergic medications are a potentially modifiable risk factor for the prevention of cognitive and physical decline. Identification of reversible causes for cognitive and physical impairment is critical for the aging population. These findings encourage new research that may lead to effective interventions for deprescribing programs for the prevention of cognitive and physical decline in older adults.
Probable Donor-Derived Human Adenovirus Type 34 Infection in 2 Kidney Transplant Recipients From the Same Donor
Authors: Pettengill Matthew A , Babu Tara M , Prasad Paritosh , Chuang Sally , Drage Michael G , Menegus Marilyn , Lamson Daryl M , Lu Xiaoyan , Erdman Dean , Pecora Nicole
Published: December 2018

Human adenovirus type 34 (HAdV-34) infection is a recognized cause of transplant-associated hemorrhagic cystitis and, in rare cases, tubulointerstitial nephritis. The source of such infections is often difficult to assess, that is, whether acquired as a primary infection, exposure to a pathogen in the transplanted organ, or reactivation of an endogenous latent infection. We present here 2 cases of likely transplant-acquired HAdV-34 infection from the same organ donor, manifesting as tubulointerstitial nephritis in 1.
Reactivation of Hepatitis B Virus With Immune-Escape Mutations After Ocrelizumab Treatment for Multiple Sclerosis
Authors: Ciardi Maria R , Iannetta Marco , Zingaropoli Maria A , Salpini Romina , Aragri Marianna , Annecca Rosanna , Pontecorvo Simona , Altieri Marta , Russo Gianluca , Svicher Valentina , Mastroianni Claudio M , Vullo Vincenzo
Published: December 2018

Ocrelizumab is an anti-CD20 monoclonal antibody for the treatment of multiple sclerosis (MS) that is closely related to rituximab. We describe a case of hepatitis B virus (HBV) reactivation in an MS patient with resolved HBV infection receiving ocrelizumab. HBV reactivation was monitored with HBV-DNA and HBV surface antigen periodic assessment. Anti-HBV treatment with entecavir was started after HBV-DNA detection. Ocrelizumab can reactivate viral replication in patients with resolved HBV infection. HBV reactivation monitoring seems an effective and safe option for the management of these patients. More studies are needed to assess the optimal management of HBV reactivation in MS patients on ocrelizumab treatment.
Use of Closed-Incision Negative-Pressure Therapy in Aesthetic Surgery
Authors: Singh Devinder , Lobach Virginia , Holton Tripp
Published: December 2018

Background:

Recently published studies have demonstrated clinical effectiveness of closed-incision negative-pressure therapy (ciNPT) in many fields of surgery including vascular, cardiac, colorectal, orthopedic, and reconstructive surgery. A review of current literature was conducted to determine whether the application of negative-pressure therapy to closed incisions post aesthetic procedures was beneficial.

Methods:

The PubMed/MEDLINE databases were searched for preclinical and clinical studies published through June 2018. Higher quality publications that met the following criteria were included: adult patients undergoing aesthetic or body contouring procedures, comparison of ciNPT with conventional dressings, and documentation of wound complications and/or incision quality.

Results:

One animal and multiple small, retrospective comparison articles are discussed. Scientific mechanism of action and economic analysis are also discussed. There are no level 1 randomized prospective controlled trials that directly evaluate the effects of ciNPT dressings in cosmetic patients.

Conclusion:

For patients undergoing certain cosmetic procedures, preliminary data support the idea that ciNPT dressings provide aesthetic benefit, but more research is clearly needed.
Use of Closed-Incision Negative-Pressure Therapy in Obstetrics
Authors: Feinstein Glen I.
Published: December 2018

Background:

Cesarean delivery is one of the most commonly performed surgeries in the United States. Compared with other surgical procedures, surgical site infection tends to be a relatively uncommon outcome after cesarean delivery in the general population with an incidence rate between 1.46 and 3.82% in the United States in 2006–2008. Despite this lower incidence, surgical site infections following cesarean delivery result in a 6-day increase in mean length of stay at an additional cost of $13,968. Specifically, closed-incision negative-pressure therapy (ciNPT) has been developed for use over clean, closed surgical incisions. A brief literature review on ciNPT use over cesarean delivery incisions is described.

Methods:

A literature search was performed using PubMed and Google Scholar. The search included publications between January 1, 2005, and April 30, 2018, and focused on studies reporting the use of a specific ciNPT system (PREVENA Incision Management System; KCI, an Acelity Company, San Antonio, TX) over cesarean incisions.

Results:

Five published articles were identified in the literature search that compared ciNPT use to traditional dressings. Positive clinical outcomes were reported in 2 studies, similar outcomes between ciNPT and traditional dressings were reported in 2 studies, and negative outcomes were reported in 1 study.

Conclusions:

A lack of published literature reporting clinical outcomes following ciNPT use over cesarean delivery incisions exists, and the currently reported evidence is heterogeneous. As such, increased published evidence from large, randomized studies and a reexamination of ciNPT use over cesarean delivery incisions are needed.
Use of Closed-Incision Negative-Pressure Therapy: Cardiothoracic and Vascular Surgery
Authors: Wu Robin T. , Sumpio Brandon J. , Miller Samuel , Sumpio Bauer E.
Published: December 2018

Vascular groin wound and median sternotomy infections are challenging complications that may lead to serious sequela. Traditional gauze dressings have poor bacteria barrier properties, and so there has been a recent enthusiasm for the use of closed-incision negative-pressure therapy as an effective closed environment, which controls exudate and helps hold the incision edges together. Studies suggest that it may reduce surgical site infection in cardiothoracic and vascular surgery.
Inhibition of EZH2 ameliorates lupus-like disease inMRL/lprmice
Authors: Rohraff Dallas M. , He Ye , Farkash Evan A. , Schonfeld Mark , Tsou Pei-Suen , Sawalha Amr H.
Published: December 2018

Objectives

We previously revealed a role for EZH2 in inducing pro-inflammatory epigenetic changes in lupus CD4+ T cells. In this study, we sought to determine if inhibiting EZH2 ameliorates lupus-like disease in MRL/lprmice.

Methods

EZH2 expression levels in multiple cell types in lupus patients were evaluated using flow cytometry and mRNA expression data. Inhibition of EZH2 in MRL/lprmice was achieved by DZNep intraperitoneal administration using a preventative and a therapeutic treatment model. Effects of DZNep on animal survival, anti-dsDNA antibody production, proteinuria, renal histopathology, cytokine production, and T and B cell numbers and percentages were assessed.

Results

EZH2 expression levels were increased in whole blood, neutrophils, monocytes, B cells, and CD4+ T cells in lupus patients. In MRL/lprmice, inhibiting EZH2 with DZNep treatment before or after disease onset improved survival and significantly reduced anti-dsDNA antibody production. DZNep-treated mice displayed a significant reduction in renal involvement, splenomegaly, and lymphadenopathy.

Lymphoproliferation and numbers of double-negative T cells were significantly reduced in DZNep treated mice. Concentrations of circulating cytokines and chemokines, including TNF, IFN-γ, CCL2, RANTES/CCL5, IL-10, KC/CXCL1, IL-12, IL-12p40 and MIP-1β/CCL4 were decreased in DZNep treated mice.

Conclusions

ZH2 is upregulated in multiple cell types in lupus patients. Therapeutic inhibition of EZH2 abrogates lupus-like disease in MRL/lprmice, suggesting that EZH2 inhibitors may be repurposed as a novel therapeutic option in lupus patients.
The Salivary Microbiome: Analysis of by Pyrosequencing and the Relationship with Helicobacter pylori Infection
Authors: Ji Yingjie , Liang Xiao , Lu Hong
Published: December 2018

Backgrounds: There have been reports of Helicobacter pylori (H. pylori) in the oral cavity and it has been suggested that the oral cavity may be a reservoir for H. pylori reflux from the stomach. Objectives: High-throughput pyrosequencing was used to assess the structure and composition of oral microbiota communities in individuals with or without confirmed H. pylori infection. Methods: Saliva samples were obtained from 34 H. pylori infected and 24 H. pylori uninfected subjects. Bacterial genomic DNA was extracted and examined by pyrosequencing by amplification of the 16S rDNA V3-V4 hypervariable regions followed by bioinformatics analysis. Saliva sampling was repeated from 22 of the 34 H. pylori infected subjects 2 months after H. pylori eradication. Results: High-quality sequences (2,812,659) clustered into 95,812 operational taxonomic units (OTUs; 97% identity), representing 440 independent species belonging to 138 genera, 68 families, 36 orders, 21 classes, and 11 phyla. Species richness (alpha diversity) of H. pylori infected subjects was similar to that of uninfected subjects. Eradication treatment decreased saliva bacterial diversity. Beta diversity analysis showed that the salivary microbial community structure differed between H. pylori infected and uninfected subjects both before and after H. pylori eradication. Conclusions: Salivary microbiota diversity was similar in H. pylori infected and uninfected individuals. Antibiotic therapy was associated with a decline in salivary bacterial diversity. Both H. pylori infection and its eradication caused the oral microbiota alterations in community and structure. The present of H. pylori in oral cavity was not related with its infection status in stomach.
A pilot study of a novel molecular host response assay to diagnose infection in patients after high-risk gastro-intestinal surgery
Authors: Verboom Diana , Koster-Brouwer Marlies , Ruurda Jelle , Van Hillegersberg Richard , van Berge Henegouwen Mark , Gisbertz Suzanne , Scicluna Brendon , Bonten Marc , Cremer Olaf
Published: December 2018

Aim: SeptiCyte LAB measures the expression of four host-response RNAs in blood to distinguish sepsis from sterile inflammation. Sequential monitoring of this assay may have diagnostic utility in patients at high risk for postoperative infectious complications.
Methods: In this pilot study we studied esophagectomy patients who had developed a complication within 30 days following surgery as well as a random sample of 100 uncomplicated postoperative patients. PAXgene blood samples were collected postoperatively and whenever a complication occurred. SeptiCyte scores (ranging 0-10 with increasing likelihood of infection) were compared to post-hoc physician adjudication of infection likelihood using strict definitions.
Results: Among 370 esophagectomy patients, 120 (32%) subjects developed a complication requiring ICU (re)admission, 63 (53%) of whom could be analyzed. Immediate postoperative SeptiCyte LAB scores were highly variable, yet similar for patients having a complicated and uncomplicated postoperative course (median score of 2.4 (IQR 1.6-3.3) versus 2.2 (IQR 1.3-3), respectively). Scores increased as complications developed, but this rise was higher for 34 subjects having confirmed infection (median difference 4.7 (IQR 4.1-5.8)) then for 12 subjects with a non-infectious complication (2.1 (IQR 0.4-3.6); p<0.0001). When 17 cases with undetermined infectious status were excluded, addition of SeptiCyte LAB to CRP resulted in improved diagnostic discrimination (AUC 0.88 (95%CI 0.77-0.99)) compared to CRP alone (AUC 0.76 (95%CI 0.61-0.91); p=0.04).
Conclusions: Sequential measurement of SeptiCyte LAB may have clinical utility in surgical patients at high risk of postoperative infection, but its diagnostic performance in this setting needs to be further evaluated.
Extension of Colijn-Plazotta tree shape distance metric to unrooted trees
Authors: Morozov Alexey Anatolievich
Published: December 2018

Colijn-Plazotta tree shape labeling scheme allows to describe an arbitrary phylogenetic tree topology by recursively labeling all nodes from tips to root with integers. The multisets of these labels can then be used to estimate the difference between topologies using eg Euclidean distance. In this work I propose an extension of the labeling scheme (and thus a distance metric) to unrooted trees, which is achieved by labeling all rooted subtrees within a given tree. To avoid exhaustively enumerating the subtrees, the labels are collected into a dependency graph and calculated in a single pass. A proof-of-concept implementation is available at https://github.com/synedraacus/metrics.
Urbanization drives the acoustic diversity of mangrove anurans and avifauna in Puerto Rico
Authors: Branoff Benjamin
Published: December 2018

The mangroves of Puerto Rico occupy a broad gradient of urbanization that offers a chance to test hypotheses on urban faunal communities from both terrestrial and mangrove systems. These hypotheses state that urban avifaunal communities are less diverse, with greater representation by generalists, but that certain mangrove specialists can utilize urban landscapes. Much of this is said to be driven by food resources, with frugivores and nectarivores benefiting from abundant residential flowers and fruits, while insectivores are driven away by low food resources. This study used passive acoustic monitoring to identify the audible anuran and avifaunal species in mangroves across the urban gradient of Puerto Rico. Three anurans and twenty-four avian species were detected across all sites, with eighteen species found at the most diverse site, and six at the least diverse site. The most urban communities were more similar to each other and characterized by low diversity, especially of invertivores, mangrove specialists, and endemics. The least urban communities, however, were less like each other and more diverse than their more urban counterparts. Greater surrounding vegetation cover was the strongest overall predictor of increased faunal diversity, although urban coverage and population density were also strongly correlated with some guilds and species. Soundscape analyses showed that acoustic space use was a strong predictor of site diversity and is thus a sufficiently accurate faster alternative to detecting individual species. This will be an important tool in the continued monitoring of these forests, which may experience changes associated with ongoing urbanization and sea-level rise.
CNN-based radiographic acute tibial fracture detection in the setting of open growth plates
Authors: Starosolski Zbigniew A , Kan Herman , Annapragada Ananth V
Published: December 2018

Pediatric tibial fractures are commonly diagnosed by radiographs and constitute one of the common tasks performed by pediatric radiologists. Here, we assess the performance of a convolutional neural network for the detection of acute tibial fractures trained with a limited number of cases in skeletally immature patients. This retrospective study was performed on radiology reports manually classified as normal or tibial fracture. Classified images of orthopaedic implants, casting, and images including other pathology were excluded. The remaining cases constituted 516 studies containing 2118 radiographs. These radiographs were truncated to include a limited investigated field of view which included the distal third of the leg, inclusive of the distal physis. After exclusions, the culled dataset was randomly divided into a training set containing 784 radiographs, a validation set containing 98 radiographs, and a test set 98 radiographs. We used a modified transfer learning approach based on the Xception architecture with additional fully convoluted reasoning and drop-out layers. Of 49 distal Tibial fractures, two were misdiagnosed as normal. Of 49 normal exams, none were misdiagnosed. This led to model accuracy of 97.9%, sensitivity 95.9%, and specificity 100%, comparable to or better than human radiologists. In no instances were normal physes or normal developmental epiphyseal fragmentation of the tibial tuberosity or medial malleolus misclassified as a fracture. We report an efficient method to use a pre-trained network and adapt it to a medical classification task using only a small number of radiographs dedicated to precise anatomical location.
Gpr158 deficiency impacts hippocampal CA1 neuronal excitability, dendritic architecture, and affects spatial learning
Authors: Çetereisi Demirhan , Kramvis Ioannis , Gebuis Titia , van der Loo Rolinka J. , Gouwenberg Yvonne , Mansvelder Huibert D. , Li Ka Wan , Smit August B , Spijker Sabine
Published: December 2018

G-protein-coupled receptor 158 (Gpr158) is highly expressed in striatum, hippocampus and prefrontal cortex. It gained attention as it was implicated in physiological responses to stress and depression. Recently, Gpr158 has been shown to act as a pathway-specific synaptic organizer in the hippocampus, required for proper mossy fiber-CA3 neurocircuitry establishment, structure, and function. Although rodent Gpr158 expression is highest in CA3, considerable expression occurs in CA1 especially after the first postnatal month. Here, we combined hippocampal-dependent behavioral paradigms with subsequent electrophysiological and morphological analyses from the same group of mice to assess the effects of Gpr158 deficiency on CA1 physiology and function. We demonstrate deficits in spatial memory acquisition and retrieval in the Morris water maze paradigm, along with deficits in the acquisition of extinction memory in the passive avoidance test in Gpr158 KO mice. Electrophysiological recordings from CA1 pyramidal neurons revealed normal basal excitatory and inhibitory synaptic transmission, however, Schaffer collateral stimulation yielded dramatically reduced post-synaptic currents. Interestingly, intrinsic excitability of CA1 pyramidals was found increased, potentially acting as a compensatory mechanism to the reductions in Schaffer collateral-mediated drive. Both ex vivo and in vitro, neurons deficient for Gpr158 exhibited robust reductions in dendritic architecture and complexity, i.e., reduced length, surface, bifurcations, and branching. This effect was localized in the apical but not basal compartment of adult CA1 pyramidals, indicative of pathway-specific alterations. A significant positive correlation between spatial memory acquisition and extent of complexity of CA1 pyramidals was found. Taken together, we provide first evidence of significant disruptions in hippocampal CA1 neuronal dendritic architecture and physiology, driven by Gpr158 deficiency. Importantly, the hippocampal neuronal morphology deficits appear to support the impairments in spatial memory acquisition observed in Gpr158 KO mice.
ORGaNICs: A Canonical Neural Circuit Computation
Authors: Heeger David J. , Mackey Wayne E
Published: December 2018

A theory of cortical function is proposed, based on a family of recurrent neural circuits, called ORGaNICs (Oscillatory Recurrent GAted Neural Integrator Circuits). Here, the theory is applied to working memory and motor control. Working memory is a cognitive process for temporarily maintaining and manipulating information. Most empirical neuroscience research on working memory has measured sustained activity during delayed-response tasks, and most models of working memory are designed to explain sustained activity. But this focus on sustained activity (i.e., maintenance) ignores manipulation, and there are a variety of experimental results that are difficult to reconcile with sustained activity. ORGaNICs can be used to explain the complex dynamics of activity, and ORGaNICs can be use to manipulate (as well as maintain) information during a working memory task. The theory provides a means for reading out information from the dynamically varying responses at any point in time, in spite of the complex dynamics. When applied to motor systems, ORGaNICs can be used to convert spatial patterns of premotor activity to temporal profiles of motor control activity: different spatial patterns of premotor activity evoke different motor control dynamics. ORGaNICs offer a novel conceptual framework; Rethinking cortical computation in these terms should have widespread implications, motivating a variety of experiments.
Serial synapse formation through filopodial competition for synaptic seeding factors
Authors: Özel M. Neset , Kulkarni Abhishek , Hasan Amr , Brummer Josephine , Moldenhauer Marian , Daumann Ilsa-Maria , Wolfenberg Heike , Dercksen Vincent J. , Kiral F. Ridvan , Weiser Martin , Prohaska Steffen , von Kleist Max , Hiesinger P. Robin
Published: December 2018

Following axon pathfinding, growth cones transition from stochastic filopodial exploration to the formation of a limited number of synapses. How the interplay of filopodia and synapse assembly ensures robust connectivity in the brain has remained a challenging problem. Here, we developed a new 4D analysis method for filopodial dynamics and a data-driven computational model of synapse formation for R7 photoreceptor axons in developing Drosophila brains. Our live data support a ‘serial synapse formation’ model, where at any time point only a single ‘synaptogenic’ filopodium suppresses the synaptic competence of other filopodia through competition for synaptic seeding factors. Loss of the synaptic seeding factors Syd-1 and Liprin-α leads to a loss of this suppression, filopodial destabilization and reduced synapse formation, which is sufficient to cause the destabilization of entire axon terminals. Our model provides a filopodial ‘winner-takes-all’ mechanism that ensures the formation of an appropriate number of synapses.
Prediction and control of symmetry breaking in embryoid bodies by environment and signal integration
Authors: Sagy Naor , Slovin Shaked , Allalouf Maya , Pour Maayan , Savyon Gaya , Boxman Jonathan , Nachman Iftach
Published: December 2018

During early embryogenesis, mechanical signals, localized biochemical signals and neighboring cell layers interaction coordinate around anteroposterior axis determination and symmetry breaking. Deciphering their relative roles, which are hard to tease apart in vivo, will enhance our understanding of how these processes are driven. In recent years, in vitro 3D models of early mammalian development, such as embryoid bodies (EBs) and gastruloids, were successful in mimicking various aspects of the early embryo, providing high throughput accessible systems for studying the basic rules shaping cell fate and morphology during embryogenesis. Using Brachyury (Bry), a primitive streak and mesendoderm marker in EBs, we study how contact, biochemical and neighboring cell cues affect the positioning of a primitive streak-like locus, determining the AP axis. We show that a Bry-competent layer must be formed in the EB before Bry expression initiates, and that Bry onset locus selection depends on contact points of the EB with its surrounding. We can maneuver Bry onset to occur at a specific locus, a few loci, or in an isotropic peripheral pattern. By spatially separating contact and biochemical signal sources, we show these two modalities can be integrated by the EB to generate a single Bry locus. Finally, we show Foxa2+ cells are predictive of the future location of Bry onset, demonstrating an earlier symmetry-breaking event. By delineating the temporal signaling pathway dependencies of Bry and Foxa2, we were able to selectively abolish either, or spatially decouple the two cell types during EB differentiation. These findings demonstrate multiple inputs integration during an early developmental process, and may prove valuable in directing in vitro differentiation.
Ancient exapted transposable elements promote nuclear enrichment of human long noncoding RNAs
Authors: Carlevaro-Fita Joana , Polidori Taisia , Das Monalisa , Navarro Carmen , Zoller Tatjana I. , Johnson Rory
Published: December 2018

The sequence domains underlying long noncoding RNA (lncRNA) activities, including their characteristic nuclear enrichment, remain largely unknown. It has been proposed that these domains can originate from neofunctionalized fragments of transposable elements (TEs), otherwise known as RIDLs (repeat insertion domains of lncRNA), although just a handful have been identified. It is challenging to distinguish functional RIDL instances against a numerous genomic background of neutrally evolving TEs. We here show evidence that a subset of TE types experience evolutionary selection in the context of lncRNA exons. Together these comprise an enrichment group of 5374 TE fragments in 3566 loci. Their host lncRNAs tend to be functionally validated and associated with disease. This RIDL group was used to explore the relationship between TEs and lncRNA subcellular localization. By using global localization data from 10 human cell lines, we uncover a dose-dependent relationship between nuclear/cytoplasmic distribution and evolutionarily conserved L2b, MIRb, and MIRc elements. This is observed in multiple cell types and is unaffected by confounders of transcript length or expression. Experimental validation with engineered transgenes shows that these TEs drive nuclear enrichment in a natural sequence context. Together these data reveal a role for TEs in regulating the subcellular localization of lncRNAs.
Rituximab therapy for refractory autoimmune bullous diseases: A multicenter, open‐label, single‐arm, phase 1/2 study on 10 Japanese patients
Authors: Kurihara Yuichi , Yamagami Jun , Funakoshi Takeru , Ishii Maki , Miyamoto Julia , Fujio Yumi , Kakuta Risa , Tanikawa Akiko , Aoyama Yumi , Iwatsuki Keiji , Ishii Norito , Hashimoto Takashi , Nishie Wataru , Shimizu Hiroshi , Kouyama Keisuke , Amagai Masayuki
Published: December 2018

This was a multicenter study of rituximab, a chimeric monoclonal immunoglobulin G antibody directed against CD20, for the treatment of refractory autoimmune bullous diseases (pemphigus and pemphigoid). Ten patients (three with pemphigus vulgaris, six with pemphigus foliaceus and one with bullous pemphigoid) were treated with a single cycle of rituximab (four weekly infusions at a dose of 375 mg/m2 of body surface area). The primary end‐points were the number of serious adverse events and rate of complete remission at 40 weeks. Five patients (50%) achieved complete remission with minimal therapy (defined as no active lesions with lower doses of systemic corticosteroids compared to that with prednisolone 10 mg/day). Improvements in clinical scores (Pemphigus Disease Area Index) and decreases in autoantibody titers in the sera were observed in the four pemphigus patients who failed to achieve complete remission. This suggests that rituximab was effective in nine of 10 cases. Two serious adverse events (Pneumocystis carinii pneumonia and septic shock due to infectious arthritis) were observed and adequately treated with hospitalization. CD19‐positive B lymphocytes in the peripheral blood decreased on day 29 following rituximab treatment, and remained at low levels throughout the observation period (280 days). Our results confirmed the efficacy of rituximab therapy for refractory autoimmune bullous diseases in Japan.
Microbial metal‐sulfide oxidation in inactive hydrothermal vent chimneys suggested by metagenomic and metaproteomic analyses
Authors: Meier Dimitri V. , Pjevac Petra , Bach Wolfgang , Markert Stephanie , Schweder Thomas , Jamieson John , Petersen Sven , Amann Rudolf , Meyerdierks Anke
Published: December 2018

Metal‐sulfides are wide‐spread in marine benthic habitats. At deep‐sea hydrothermal vents, they occur as massive sulfide chimneys formed by mineral precipitation upon mixing of reduced vent fluids with cold oxygenated sea water. Although microorganisms inhabiting actively venting chimneys and utilizing compounds supplied by the venting fluids are well studied, only little is known about microorganisms inhabiting inactive chimneys. In this study, we combined 16S rRNA gene‐based community profiling of sulfide chimneys from the Manus Basin (SW Pacific) with radiometric dating, metagenome (n = 4) and metaproteome (n = 1) analyses. Our results shed light on potential lifestyles of yet poorly characterized bacterial clades colonizing inactive chimneys. These include sulfate‐reducing Nitrospirae and sulfide‐oxidizing Gammaproteobacteria dominating most of the inactive chimney communities. Our phylogenetic analysis attributed the gammaproteobacterial clades to the recently described Woeseiaceae family and the SSr‐clade found in marine sediments around the world. Metaproteomic data identified these Gammaproteobacteria as autotrophic sulfide‐oxidizers potentially facilitating metal‐sulfide dissolution via extracellular electron transfer. Considering the wide distribution of these gammaproteobacterial clades in marine environments such as hydrothermal vents and sediments, microbially accelerated neutrophilic mineral oxidation might be a globally relevant process in benthic element cycling and a considerable energy source for carbon fixation in marine benthic habitats.
Differential ratio amplicons (Ramp) for the evaluation of RNA integrity extracted from complex environmental samples
Authors: Cholet Fabien , Ijaz Umer Z. , Smith Cindy J.
Published: December 2018

Reliability and reproducibility of transcriptomics‐based studies are dependent on RNA integrity. In microbial ecology, microfluidics‐based techniques, such as the Ribosomal Integrity Number (RIN), targeting rRNA are currently the only approaches to evaluate RNA integrity. However, the relationship between rRNA and mRNA integrity is unknown. Here, we present an integrity index, the Ratio Amplicon, Ramp, adapted from human clinical studies, to directly monitor mRNA integrity from complex environmental samples. We show, in a suite of experimental degradations of RNA extracted from sediment, that while the RIN generally reflected the degradation status of RNA the Ramp mapped mRNA degradation better. Furthermore, we examined the effect of degradation on transcript community structure by amplicon sequencing of 16S rRNA, amoA and glnA transcripts. We successfully sequenced transcripts for all three targets even from highly‐degraded RNA samples. While RNA degradation changed the community structure of the mRNA profiles, no changes were observed for the 16S rRNA transcript profiles. Since both RT‐Q‐PCR and sequencing results were obtained, even from highly degraded samples, we strongly recommend evaluating RNA integrity prior to downstream processing to ensure meaningful results. For this, both the RIN and Ramp are useful, with the Ramp better evaluating mRNA integrity in this study.
Religious Radicalization and Lone‐Actor Terrorism: A Matter for Psychiatry?
Authors: Prats Manon , Raymond Sophie , Gasman Ivan
Published: December 2018

This article discusses the place of the psychiatric field in the ongoing phenomenon of religious radicalization. First, the article provides an overview of the existing literature on lone‐actor terrorists and the link with mental illness. Current research is focusing increasingly on lone‐actor terrorists. This is the most recent and rising development on the global terrorism scene. The literature is currently developing a more precise and informed definition of lone‐actor terrorism. The article then describes and discusses the case study of a mentally ill patient arrested following his assault on a military serviceman on the grounds of religious radicalization. The patient, diagnosed with schizophrenia, is taken as an example of the specific case of religious radicalization in patients with schizophrenia. Finally, the article discusses the curative and preventive roles that can be played by psychiatrists and other professionals who are in contact with these types of patients.
Family routines and family satisfaction in Singapore: work–family fit as a moderator
Authors: Jones Blake L , Hill Edward J , Miller Richard B
Published: December 2018

This study explored the relationships between five types of everyday family routines (leisure, chores,TVviewing, worship, and meals) with family satisfaction, and the degree to which work–family fit (WFF) moderated this relationship. Data come from a nationally representative sample of workers in Singapore, using a subset of 623 married, employed parents. Results revealed that family routines were differentially related to family satisfaction, withTVviewing having the strongest positive relationship.WFFitself was directly related to greater family satisfaction and also moderated the relationships between family routines and family satisfaction. Findings suggestWFF– the perception of successfully integrating work and personal/family life – is strongly related to family satisfaction and may play a role in helping employed parents to experience benefits in the home, in the workplace, and even in their health and well‐being.
Social vocalizations of big‐footed myotis (Myotis macrodactylus) during foraging
Authors: GUO Dongge , LUO Bo , ZHANG Kangkang , LIU Muxun , METZNER Walter , LIU Ying , FENG Jiang
Published: December 2018

Acoustic signals play a crucial role in transmitting information and maintaining social stability in gregarious animals, especially in echolocating bats, which rely primarily on biological sonar for navigating in the dark. In the context of foraging without relying on tactile, visual or olfactory cues, acoustic signals convey information not only on food but also on ownership and defense of resources. However, studies on such information remain fragmentary. In the present study, we aim to document the social vocal repertoire of Myotis macrodactylus at natural foraging sites. Multiple acoustic analyses and spectrographic classification revealed a rich foraging vocal repertoire comprising 6 simple syllables and 2 composites. Discriminant function analyses associated with a subset‐validation procedure provided an optimal method to spectrographically classify all recorded sounds into different syllable types. Multidimensional scaling of median values of multiple parameters further confirmed notable differences among these syllables in a 3‐D space. In addition, Euclidean distance analysis showed that there were some spectral similarities between specific social vocal syllables and feeding buzzes, which implied a potential jamming role. Altogether, the data indicate that bats at foraging sites under natural conditions used variant social vocalizations with different functions in addition to echolocation calls, providing supporting evidence for further work on the function and vocal mechanisms of acoustic communication in mammals.
Testing the effectiveness of conservation management within biosphere reserves: the case of the Mexican deer mouse (Peromyscus mexicanus) as a bioindicator
Authors: COBO‐SIMÓN Irene , MÉNDEZ‐CEA Belén , PORTILLO Héctor , ELVIR Fausto , VEGA Hermes , GALLEGO Francisco Javier , FONTECHA Gustavo
Published: December 2018

Biosphere reserves are protected areas whose purpose is to combine conservation and sustainable development. However, their effectiveness has not been tested sufficiently, especially from an ecological and genetic approach. In this sense, thePeromyscusgenus represents an excellent bioindicator to address these questions, due to its short life and high evolutionary rate and fecundity. For conservation managers, genetic structure can increase the rate of loss of genetic diversity because alleles exclusive of a subpopulation are more likely to disappear as a consequence of genetic drift in comparison with a panmictic population. Here we analyzed the abundance, movement distances, morphology/morphometry and genetic structure of 3 populations of Mexican deer mouse (Peromyscus mexicanus) located in different protected zones of La Tigra National Park (Honduras). Our results are consistent among the 3 approaches and showed the highest values of abundance, morphometry and genetic diversity in the population located at the core zone, whereas non‐statistically significant differences were found between buffer and transition zone populations, suggesting suitable effectiveness of conservation management in the core zone but a lack of ecological buffering function of the other zones. In addition, the low movement distances and high genetic structure among the studied populations provide evidence of poor conservation management in the buffer and transition zone. Thus, we discuss the utility of the novel methodology used in this work, combining morphometry, abundance and genetics, in testing the effectiveness of conservation strategies in biosphere reserves, and the value of thePeromyscusgenus as a bioindicator.