bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome‐wide CRISPR‐Cas9 viability screen reveals genes involved in TNF‐α‐induced apoptosis of human umbilical vein endothelial cells
Authors: Cai Meng , Li Sitao , Shuai Yunfei , Li Jie , Tan Jieqiong , Zeng Qiyi
Published: October 2018

Tumor necrosis factor α (TNF‐α), a pivotal cytokine in sepsis, protects the host against pathogens by promoting an inflammatory response while simultaneously inducing apoptosis of the vascular endothelium. Unfortunately, inhibitors targeting certain components of the TNF‐α signaling pathway to reduce cellular apoptosis have failed to translate into clinical applications, partly due to the adverse effects of excessive immunosuppression. In an attempt to discover potential targets in the TNF‐α signaling pathway to modulate moderate inflammation and apoptosis during the development of sepsis, we performed a pooled genome‐wide CRISPR/Cas9 knockout screen in human umbilical vein endothelial cells (HUVECs). Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), B‐cell lymphoma 2 (BCL2), Bcl2‐associated death promoter (BAD), and NLR family member X1 (NLRX1) deficiencies were identified as the effective genetic suppressors of TNF‐α cytotoxicity on a list of candidate regulators. CRISPR‐mediated
NLRX1 knockout conferred cellular resistance to challenge with TNF‐α, and NLRX1 could be induced to colocalize with mitochondria following TNF‐α stimulation. Thus, our work demonstrates the advantage of genome‐scale screening with Cas9 and validates NLRX1 as a potential modulator of TNF‐α‐induced vascular endothelial apoptosis during sepsis.
Insulin resistance: Review of the underlying molecular mechanisms
Authors: Yaribeygi Habib , Farrokhi Farin Rashid , Butler Alexandra E. , Sahebkar Amirhossein
Published: October 2018

Most human cells utilize glucose as the primary substrate, cellular uptake requiring insulin. Insulin signaling is therefore critical for these tissues. However, decrease in insulin sensitivity due to the disruption of various molecular pathways causes insulin resistance (IR). IR underpins many metabolic disorders such as type 2 diabetes and metabolic syndrome, impairments in insulin signaling disrupting entry of glucose into the adipocytes, and skeletal muscle cells. Although the exact underlying cause of IR has not been fully elucidated, a number of major mechanisms, including oxidative stress, inflammation, insulin receptor mutations, endoplasmic reticulum stress, and mitochondrial dysfunction have been suggested. In this review, we consider the role these cellular mechanisms play in the development of IR.
Estradiol‐17β stimulates H2S biosynthesis by ER‐dependent CBS and CSE transcription in uterine artery smooth muscle cells in vitro
Authors: Lechuga Thomas J. , Bilg Amanpreet K. , Patel Bansari A. , Nguyen Nicole A. , Qi Qian‐rong , Chen Dong‐bao
Published: October 2018

Endogenous hydrogen sulfide (H2S), synthesized by cystathionine β‐synthase (CBS) and cystathionine γ‐lyase (CSE), is a potent vasodilator that can be stimulated by estradiol‐17β (E
2β) in uterine artery (UA) smooth muscle (UASMC) in vivo; however, the underlying mechanisms are unknown. This study tested a hypothesis that E
2β stimulates H
2S biosynthesis by upregulating CBS expression via specific estrogen receptor (ER). Treatment with E
2β stimulated time‐ and concentration‐ dependent CBS and CSE messenger RNA (mRNA) and protein expressions, and H
2S production in cultured primary UASMC isolated from late pregnant ewes, which were blocked by ICI 182,780. Treatment with specific ERα or ERβ agonist mimicked these E
2β‐stimulated responses, which were blocked by specific ERα or ERβ antagonist. Moreover, E
2β activated both
CBS and
CSE promoters and ICI 182,780 blocked the E
2β‐stimulated responses. Thus, E
2β stimulates H
2S production by upregulating CBS and CSE expression via specific ER‐dependent transcription in UASMC in vitro.
X‐box binding protein l splicing attenuates brain microvascular endothelial cell damage induced by oxygen‐glucose deprivation through the activation of phosphoinositide 3‐kinase/protein kinase B, extracellular signal‐regulated kinases, and hypoxia‐inducible factor‐1α/vascular endothelial growth factor signaling pathways
Authors: Shi Shupeng , Tang Mimi , Li Honglei , Ding Hui , Lu Yangfan , Gao Lijuan , Wu Qian , Zhou Luo , Fu Yujiao , Xiao Bo , Zhang Mengqi
Published: October 2018

Angiogenesis is positively correlated with the survival rate of stroke patients. Therefore, studying factors that initiate and promote angiogenesis after ischemic stroke is crucial for finding novel and effective treatment targets that improve the prognosis of stroke. X‐box binding protein l splicing (XBP1s) plays a positive regulatory role in cell proliferation and angiogenesis. However, the role and mechanism of XBP1s on the proliferation of brain microvascular endothelial cells (BMECs) and angiogenesis after cerebral ischemia remains unclear. In the current study, we investigated the role XBP1s plays in BMEC proliferation and angiogenesis following cerebral ischemia. In this study, the roles of XBP1s on cell survival, apoptosis, cycle migration, and angiogenesis were determined in oxygen‐glucose deprivation (OGD) treated BMECs. The expression of XBP1s in BMECs, which were exposed to OGD at 0, 2, 4, and 6 hr, increased in a time‐dependent manner. The overexpression of XBP1s promoted cell survival, cell cycle, migration, and angiogenesis of BMECs, and inhibited the apoptosis in OGD‐treated BMECs. In addition, the overexpression of XBP1s promoted the expression of cyclin D1, matrix metalloproteinase (MMP‐2), and MMP‐9, but inhibited cleaved Caspase‐3 and cleaved Caspase‐9 expression in OGD‐treated BMECs. The overexpression of XBP1s also promoted the expression of hypoxia‐inducible factor 1‐alpha, vascular endothelial growth factor, phosphatidylinositol‐4,5‐bisphosphate 3‐kinase, p‐AKT, p‐mTOR, p‐GSK3β, and p‐extracellular signal‐regulated kinase1/2 in OGD‐treated BMECs. The effect of XBP1s silencing was opposite to that of XBP1s overexpression. In conclusion, using an in vitro OGD model, we demonstrated that XBP1s may be a promising target for ischemic stroke therapy to maintain BMECs survival and induce angiogenesis.
Proinsulin C‐peptide as an alternative or combined treatment with insulin for management of testicular dysfunction and fertility impairments in streptozotocin‐induced type 1 diabetic male rats
Authors: Nazmy Walaa Hassan , Elbassuoni Eman Abdelmonem , Ali Fatma Farrag , Rifaai Rehab Ahmed
Published: October 2018

Diabetes mellitus (DM) is closely associated with male infertility and sexual dysfunction. Recent data indicate that the proinsulin C‐peptide (CP) exerts important physiological effects and shows the characteristics of an endogenous peptide hormone. So, this study was done to investigate the effect of C‐peptide with or without insulin treatment on testicular function and architecture in diabetic rats. Rats were divided into the following groups: control, diabetic, and diabetic groups treated with either CP alone or combined with insulin. Tested parameters included, estimation of serum follicle‐stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and glucose levels, testicular samples for histopathology and estimation of malondialdehyde (MDA), total antioxidant capacity (TAC), and B‐cell leukemia/lymphoma‐2 (BCL‐2) levels as well as sperm count and motility. Results showed that DM caused a severe alteration in hormonal profile and reduced sperm parameters along with increased MDA and decrease in both TAC and BCL‐2 levels. CP alone or with insulin treatment efficiently reversed all the negative effects of DM on rat testes, with maximum improvement in the combined regimen. Proposed mechanisms may involve its hypoglycemic, antioxidant, and antiapoptotic properties. Thus, CP could substitute for or better combined with insulin to prevent or retard diabetic‐induced testicular dysfunction.
Auxiliary Partial Orthotopic Liver Transplantation for Selected Noncirrhotic Metabolic Liver Disease
Authors: Rammohan Ashwin , Reddy Mettu S. , Narasimhan Gomathy , Rajalingam Rajesh , Kaliamoorthy Ilankumaran , Shanmugam Naresh , Rela Mohamed
Published: October 2018

Auxiliary partial orthotopic liver transplantation (APOLT) in selected noncirrhotic metabolic liver diseases (NCMLDs) is a viable alternative to orthotopic liver transplantation (OLT) as it supplements the function of the native liver with the missing functional protein. APOLT for NCMLD is not universally accepted due to concerns of increased technical complications and longterm graft atrophy. Review of a prospectively collected database of all pediatric patients (age ≤16 years) who underwent liver transplantation for NCMLD from August 2009 up to June 2017 was performed. Patients were divided into 2 groups: group 1 underwent APOLT and group 2 underwent OLT. In total, 18 OLTs and 12 APOLTs were performed for NCMLDs during the study period. There was no significant difference in the age and weight of the recipients in both groups. All APOLT patients needed intraoperative portal flow modulation. Intraoperative peak and end of surgery lactate were significantly higher in the OLT group, and cold ischemia time was longer in the APOLT group. There were no differences in postoperative liver function tests apart from higher peak international normalized ratio in the OLT group. The incidence of postoperative complications, duration of hospital stay, and 1‐ and 5‐year survivals were similar in both groups. In conclusion, we present the largest series of APOLT for NCMLD. APOLT is a safe and effective alternative to OLT and may even be better than OLT due to lesser physiological stress and the smoother postoperative period for selected patients with NCMLD.
Synergism of antihypertensives and cholinesterase inhibitors in Alzheimer's disease
Authors: Hu Ziheng , Wang Lirong , Ma Shifan , Kirisci Levent , Feng Zhiwei , Xue Ying , Klunk William E. , Kamboh M. Ilyas , Sweet Robert A. , Becker James , Lv Qianzhou , Lopez Oscar L. , Xie Xiang‐Qun
Published: October 2018

Introduction

We investigated the effect of antihypertensive (aHTN) medications and cholinesterase inhibitors (ChEIs) on the cognitive decline in patients with Alzheimer's disease (AD) and analyzed synergism by chemogenomics systems pharmacology mapping.

Methods

We compared the effect of aHTN drugs on Mini‐Mental State Examination scores in 617 AD patients with hypertension, and studied the synergistic effects.

Results

The combination of diuretics, calcium channel blockers, and renin‐angiotensin‐aldosterone system blockers showed slower cognitive decline compared with other aHTN groups (Δβ = +1.46, P < .0001). aHTN medications slow down cognitive decline in ChEI users (Δβ = +0.56, P = .006), but not in non‐ChEI users (Δβ = −0.31, P = .53).

Discussion

aHTN and ChEI drugs showed synergistic effects. A combination of diuretics, renin‐angiotensin‐aldosterone system blockers, and calcium channel blockers had the slowest cognitive decline. The chemogenomics systems pharmacology–identified molecular targets provide system pharmacology interpretation of the synergism of the drugs in clinics. The results suggest that improving vascular health is essential for AD treatment and provide a novel direction for AD drug development.
Phenotyping from lab to field – tomato lines screened for heat stress using Fv/Fm maintain high fruit yield during thermal stress in the field
Authors: Poudyal Damodar , Rosenqvist Eva , Ottosen Carl-Otto
Published: October 2018

This study aimed to phenotype young tomato (Solanum lycopersicum L.) plants for heat tolerance by measuring Fv/Fm after short-term heat treatments in climate chambers and selected sensitive (low Fv/Fm) and tolerant (high Fv/Fm) cultivars to investigate their in-field performance. Twenty-eight genotypes were phenotyped at 40:28°C for 2 days in climate chambers. A second screening (four high Fv/Fm and four low Fv/Fm genotypes) was conducted for 4 days at 38:28°C, followed by 5 days’ recovery (26:20°C). The tolerant genotypes maintained high net photosynthesis (PN) and increased stomatal conductance (gs) at 38°C, allowing better leaf cooling. Sensitive genotypes had lower Fv/Fm and PN at 38°C, and gs increased less than in the tolerant group, reducing leaf cooling. Under controlled conditions, all eight genotypes had the same plant size and pollen viability, but after heat stress, plant size and pollen viability reduced dramatically in the sensitive group. Two tolerant and two sensitive genotypes were grown in the field during a heat wave (38:26°C). Tolerant genotypes accumulated more biomass, had a lower heat injury index and higher fruit yield. To our knowledge, this is the first time screening for heat tolerance by Fv/Fm in climate chambers was verified by a field trial under natural heat stress. The differences after heat stress in controlled environments were comparable to those in yield between tolerant and sensitive groups under heat stress in the field. The results suggest that Fv/Fm is effective for early detection of heat tolerance, and screening seedlings for heat sensitivity can speed crop improvement.
Integrated analysis of transcriptomic and metabolomic data reveals critical metabolic pathways involved in polyphenol biosynthesis in Nicotiana tabacum under chilling stress
Authors: Zhou Peilu , Li Qiyao , Liu Guangliang , Xu Na , Yang Yinju , Zeng Wenlong , Chen Aiguo , Wang Shusheng
Published: October 2018

Chilling stress increases the amount of polyphenols, especially lignin, which protects tobacco (Nicotiana tabacum L. cv. k326) from chilling stress. To clarify the molecular biosynthesis mechanism of the key representative compounds, specifically lignin, RNA sequencing and ultra-high pressure liquid chromatography coupled to quadrupole-time of flight mass spectrometry technologies were used to construct transcriptomic and metabolomic libraries from the leaves of tobacco plants subjected to normal (25°C) and chilling (4°C) temperature treatments. Transcriptomic libraries from the different samples were sequenced, generating more than 40million raw reads. Among nine samples, metabolomic analysis identified a total of 97 encoding enzymes that function in the key steps of pathways related to polyphenol biosynthesis, where 42 metabolites were also located. An integrated analysis of metabolic and transcriptomic data revealed that most of the intermediate metabolites and enzymes related to lignin biosynthesis were synthesised in the leaves under chilling stress, which suggests that the biosynthesis of lignin plays an important role in the response of tobacco leaves to cold temperatures. In addition, the cold insensitivity of chalcone synthase genes might be considered to be an important rate-limiting factor in the process of precursor substance flow to flavonoid biosynthesis under chilling stress. Furthermore, the upregulated expression of phenylalanine ammonia lyase (PAL), hydroxycinnamoyl transferase (HCT) and cinnamyl-alcohol dehydrogenase (CAD) under chilling stress is the key to an increase in lignin synthesis. This study provides a hypothetical basis for the screening of new active metabolites and the metabolic engineering of polyphenols in tobacco.
Methyl jasmonate improves tolerance to high salt stress in the recretohalophyte Limonium bicolor
Authors: Yuan Fang , Liang Xue , Li Ying , Yin Shanshan , Wang Baoshan
Published: October 2018

Limonium bicolor is a typical recretohalophyte with salt glands in the epidermis, which shows maximal growth at moderate salt concentrations (100mM NaCl) but reduced growth in the presence of excess salt (more than 200mM). Jasmonic acid (JA) alleviates the reduced growth of L. bicolor under salt stress; however, the underlying mechanism is unknown. In this study we investigated the effects of exogenous methyl jasmonate (MeJA) application on L. bicolor growth at high NaCl concentrations. We found that treatment with 300mM NaCl led to dramatic inhibition of seedling growth that was significantly alleviated by the application of 0.03mM MeJA, resulting in a biomass close to that of plants not subjected to salt stress. To determine the parameters that correlate with MeJA-induced salt tolerance (assessed as the biomass production in saline and control conditions), we measured 14 physiological parameters relating to ion contents, plasma membrane permeability, photosynthetic parameters, salt gland density, and salt secretion. We identified a correlation between individual indicators and salt tolerance: the most positively correlated indicator was net photosynthetic rate, and the most negatively correlated one was relative electrical conductivity. These findings provide insights into a possible mechanism underlying MeJA-mediated salt stress alleviation.
Intricate structure of the interphase chromocenter revealed by the analysis of a factor involved in species formation
Authors: Kochanova Natalia Y. , Schauer Tamas , Mathias Grusha Primal , Lukacs Andrea , Schmidt Andreas , Flatley Andrew , Schepers Aloys , Thomae Andreas W. , Imhof Axel
Published: October 2018

In higher eukaryotes centromeres often coalesce into a large intranuclear domain called the chromocenter. Chromocenters are important for the organization of pericentric heterochromatin and a disturbance of their formation results in an upregulation of repetitive elements and causes defects in chromosome segregation. Mutations in the gene encoding for the centromere associated Drosophila speciation factor HMR show very similar phenotypes suggesting a role of HMR in chromocenter architecture and function. We performed confocal and super resolution microscopy as well as proximity based biotinylation experiments of HMR and its associated protein HP1a to generate a molecular map of HMR and HP1a bound chromatin. Our work reveals an intricate internal structure of the centromeric chromatin region, which suggests a role of HMR in separating heterochromatin from centromeric chromatin.
Cryo-EM structures of the DCPIB-inhibited volume-regulated anion channel LRRC8A in lipid nanodiscs
Authors: Kern David M. , Oh SeCheol , Hite Richard K. , Brohawn Stephen G.
Published: October 2018

Hypoosmotic conditions activate volume-regulated anion channels in vertebrate cells. These channels are formed by leucine-rich repeat-containing protein 8 (LRRC8) family members and contain LRRC8A in homo- or hetero-hexameric assemblies. Here we present single-particle cryo-electron microscopy structures of LRRC8A in complex with the inhibitor DCPIB reconstituted in lipid nanodiscs. DCPIB plugs the channel like a cork in a bottle - binding in the extracellular selectivity filter and sterically occluding ion conduction. Constricted and expanded structures reveal coupled dilation of cytoplasmic LRRs and the channel pore, suggesting a mechanism for channel gating by internal stimuli. Conformational and symmetry differences between LRRC8A structures determined in detergent micelles and lipid bilayers related to reorganization of intersubunit lipid binding sites demonstrate a critical role for the membrane in determining channel structure. These results provide insight into LRRC8 gating and inhibition and the role of lipids in the structure of an ionic-strength sensing ion channel.
Components of genetic associations across 2,138 phenotypes in the UK Biobank highlight novel adipocyte biology
Authors: Tanigawa Yosuke , Li Jiehan , Justesen Johanne Marie , Horn Heiko , Aguirre Matthew , DeBoever Christopher , Chang Chris , Narasimhan Balasubramanian , Lage Kasper , Hastie Trevor , Park Chong Yon , Bejerano Gill , Ingelsson Erik , Rivas Manuel A.
Published: October 2018

Population-based biobanks with genomic and dense phenotype data provide opportunities for generating effective therapeutic hypotheses and understanding the genomic role in disease predisposition. To characterize latent components of genetic associations, we applied truncated singular value decomposition (DeGAs) to matrices of summary statistics derived from genome-wide association analyses across 2,138 phenotypes measured in 337,199 White British individuals in the UK Biobank study. We systematically identified key components of genetic associations and the contributions of variants, genes, and phenotypes to each component. As an illustration of the utility of the approach to inform downstream experiments, we report putative loss of function variants, rs114285050 (GPR151) and rs150090666 (PDE3B), that substantially contribute to obesity-related traits, and experimentally demonstrate the role of these genes in adipocyte biology. Our approach to dissect components of genetic associations across the human phenome will accelerate biomedical hypothesis generation by providing insights on previously unexplored latent structures.
Comparison between QSTand ΦSTindices in an endangeredBoswellia serrataRoxb: Implications for conservation
Authors: Mahesh Shashank , Kumar Pramod , Vaishnav Vivek , Mohammad Naseer , Ansari Shamim Akhtar
Published: October 2018

Boswellia serrata, an economically important indigenous tree of dry deciduous forests, provides oleoresin gum of pharmaceutical significance and excellent pulp for paper industries, but faces threat to extinction due to poor natural regeneration and commercial exploitation. 240 individuals of the species representing 12 locations of its natural distribution in central India were investigated to compare the genetic differentiation indices, QSTfor GBH and wood fiber length and ϕSTfor neutral (RAPD+ISSR) markers. The comparison for paired locations was more informative than for metapopulation. The most paired locations were either under the stabilizing selection (QST(L) < ΦST(L)) or in the genetic drift (QST(L) = ΦST(L)) whereas a relatively small number of paired locations was under the divergent selection (QS T(L) > ΦST(L)). The comparison for the metapopulation generating only a single trend of QST(P) > ΦST(P) is, therefore, misleading. For conservation, the genetically deficit locations (QST(L) < ΦST(L) and QST(L) = ΦST(L)) ofB. serratawarrant for reinforcement of their genetic diversity by introduction of genotypes from other genetically divergent locations (QST(L) > ΦST(L)), which would check the fragmentation and genetic drift, resulting in reproductive vigour, natural regeneration and reverse the endangered status of the species.
Novel Methods for Epistasis Detection in Genome-Wide Association Studies
Authors: Slim Lotfi , Chatelain Clément , Azencott Chloé-Agathe , Vert Jean-Philippe
Published: October 2018

More and more genome-wide association studies are being designed to uncover the full genetic basis of common diseases. Nonetheless, the resulting loci are often insufficient to fully recover the observed heritability. Epistasis, or gene-gene interaction, is one of many hypotheses put forward to explain this missing heritability. In the present work, we propose epiGWAS, a new approach for epistasis detection that identifies interactions between a target SNP and the rest of the genome. This contrasts with the classical strategy of epistasis detection through exhaustive pairwise SNP testing. We draw inspiration from causal inference in randomized clinical trials, which allows us to take into account linkage disequilibrium. EpiGWAS encompasses several methods, which we compare to state-of-the-art techniques for epistasis detection on simulated and real data. The promising results demonstrate empirically the benefits of EpiGWAS to identify pairwise interactions.
Measurement of the Topological Dimension of Hippocampal Place Cell Activity
Authors: Fox Steven E. , Ranck James B.
Published: October 2018

The fundamental property of topological dimension of neural activity has never been measured before. We measured the topological dimension of the activity of 89 rat hippocampal place cells recorded during foraging using the neighborhood boundary countdown method. Points were rate vectors forming a manifold in an 89 dimensional rate space Since a boundary has one less dimension than the neighborhood it encloses, reducing the dimension in sequential radial cuts finally arrives at boundary that is two points. The number of cuts required is the topological dimension of the set. Due to sparsity, we used a shell-like boundary with thickness. As expected, we found the large inductive dimension of this set of points to be two. To examine the robustness of the method, we used both real and modeled place cells and varied the number of neurons, duration of the time step and smoothing, radius and thickness for the boundary, decrement of the radius with each cut, requirements for the center point, and number of points in the final cluster. With the exception of shell thickness, the result was insensitive to these variations. Knowing the topological dimension allows application of rigorous topological principles to the activity of neuron populations. The method potentially can be applied to other neural classes and other behaviors, to enumerate firing variables when they are unknown, even count the factors influencing neural activity in sleep.
A novel signature derived from immunoregulatory and hypoxia genes predicts prognosis in liver and five other cancers
Authors: Chang Wai Hoong , Forde Donall , Lai Alvina G.
Published: October 2018

Background

Despite much progress in cancer research, it’s incidence and mortality continue to rise. A robust biomarker that would predict tumor behavior is highly desirable and could improve patient treatment and prognosis.

Methods

In a retrospective bioinformatics analysis involving patients with liver cancer (n=839), we developed a prognostic signature consisting of 45 genes associated with tumor-infiltrating lymphocytes and cellular responses to hypoxia. From this gene set, we were able to identify a second prognostic signature comprised of 8 genes. Its performance was further validated in five other cancers: head and neck (n=520), renal papillary cell (n=290), lung (n=515), pancreas (n=178) and endometrial (n=370).

Findings

The 45-gene signature predicted overall survival in three liver cancer cohorts: hazard ratio (HR)=1.82, P=0.006; HR=1.84, P=0.008 and HR=2.67, P=0.003. Additionally, the reduced 8-gene signature was sufficient and effective in predicting survival in liver and five other cancers: liver (HR=2.36, P=0.0003; HR=2.43, P=0.0002 and HR=3.45, P=0.0007), head and neck (HR=1.64, P=0.004), renal papillary cell (HR=2.31, P=0.04), lung (HR=1.45, P=0.03), pancreas (HR=1.96, P=0.006) and endometrial (HR=2.33, P=0.003). Receiver operating characteristic analyses demonstrated both signature’s superior performance over current tumor staging parameters. Multivariate Cox regression analyses revealed that both 45-gene and 8-gene signatures were independent of other clinicopathological features in these cancers. Combining the gene signatures with somatic mutation profiles increased their prognostic ability.

Conclusions

This study, to our knowledge, is the first to identify a gene signature uniting both tumor hypoxia and lymphocytic infiltration as a prognostic determinant in six cancer types (n=2,712). The 8-gene signature can be used for patient risk stratification by incorporating hypoxia information to aid clinical decision making.
Synaptic circuits for irradiance coding by intrinsically photosensitive retinal ganglion cells
Authors: Sabbah Shai , Papendorp Carin , Koplas Elizabeth , Beltoja Marjo , Etebari Cameron , Gunesch Ali Noel , Carrete Luis , Kim Min Tae , Manoff Gabrielle , Bhatia-Lin Ananya , Zhao Tiffany , Schreck Daniel , Dowling Henry , Briggman Kevin L. , Berson David M.
Published: October 2018

We have explored the synaptic networks responsible for the unique capacity of intrinsically photosensitive retinal ganglion cells (ipRGCs) to encode overall light intensity. This luminance signal is crucial for circadian, pupillary and related reflexive responses light. By combined glutamate-sensor imaging and patch recording of postsynaptic RGCs, we show that the capacity for intensity-encoding is widespread among cone bipolar types, including OFF types.

Nonetheless, the bipolar cells that drive ipRGCs appear to carry the strongest luminance signal. By serial electron microscopic reconstruction, we show that Type 6 ON cone bipolar cells are the dominant source of such input, with more modest input from Types 7, 8 and 9 and virtually none from Types 5i, 5o, 5t or rod bipolar cells. In conventional RGCs, the excitatory drive from bipolar cells is high-pass temporally filtered more than it is in ipRGCs. Amacrine-to-bipolar cell feedback seems to contribute surprisingly little to this filtering, implicating mostly postsynaptic mechanisms. Most ipRGCs sample from all bipolar terminals costratifying with their dendrites, but M1 cells avoid all OFF bipolar input and accept only ectopic ribbon synapses from ON cone bipolar axonal shafts. These are remarkable monad synapses, equipped with as many as a dozen ribbons and only one postsynaptic process.
The influenza A virus endoribonuclease PA-X usurps host mRNA processing machinery to limit host gene expression
Authors: Gaucherand Lea , Porter Brittany K. , Schmaling Summer K. , Rycroft Christopher Harley , Kevorkian Yuzo , McCormick Craig , Khaperskyy Denys A. , Gaglia Marta Maria
Published: October 2018

Many viruses globally shut off host gene expression to inhibit activation of cell-intrinsic antiviral responses. However, host shutoff is not indiscriminate, since viral proteins and host proteins required for viral replication are still synthesized during shutoff. The molecular determinants of target selectivity in host shutoff remain incompletely understood. Here, we report that the influenza A virus shutoff factor PA-X usurps RNA splicing to selectively target host RNAs for destruction. PA-X preferentially degrades spliced mRNAs, both transcriptome-wide and in reporter assays. Moreover, proximity-labeling proteomics revealed that PA-X interacts with cellular proteins involved in RNA splicing. The interaction with splicing contributes to target discrimination and is unique among viral host shutoff nucleases. This novel mechanism sheds light on the specificity of viral control of host gene expression and may provide opportunities for development of new host-targeted antivirals.
Hippocampal State Transitions at the Boundaries between Trial Epochs
Authors: Bulkin David A. , Sinclair David G. , Law L. Matthew , Smith David M.
Published: October 2018

The hippocampus encodes distinct environmental and behavioral contexts with unique patterns of activity. Representational shifts with changes in the context, referred to as remapping, have been extensively studied. However, less is known about the nature of transitions between representations. In this study, we leverage a large dataset of 2056 neurons recorded while rats performed an olfactory memory task with a predictable temporal structure involving trials and inter-trial intervals, separated by salient boundaries at the trial start and trial end. We found that trial epochs were associated with stable hippocampal population representations, despite moment to moment variability in stimuli and behavior. Representations of trial and inter-trial interval epochs were far more distinct than spatial factors would predict and the transitions between the two were abrupt, with a sharp boundary suggestive of a dynamic shift in the representational state. This boundary was associated with a large spike in multi-unit activity, with many individual cells specifically active at the start or end of each trial. Both epochs and boundaries were encoded by hippocampal populations, and these representations carried information on orthogonal axes readily identified using principal component analysis. We suggest that the activity spike at trial boundaries might serve to drive hippocampal activity from one stable state to another, and may play a role in segmenting continuous experience into discrete episodic memories.
A flexible and generalizable model of online latent-state learning
Authors: Cochran Amy L , Cisler Josh M
Published: October 2018

Many models of classical conditioning fail to describe important phenomena, notably the rapid return of fear after extinction. To address this shortfall, evidence converged on the idea that learning agents rely on latent-state inferences, i.e. an ability to index disparate associations from cues to rewards (or penalties) and infer which index (i.e. latent state) is presently active. Our goal was to develop a model of latent-state inferences that uses latent states to predict rewards from cues efficiently and that can describe behavior in a diverse set of experiments. The resulting model combines a Rescorla-Wagner rule, for which updates to associations are proportional to prediction error, with an approximate Bayesian rule, for which beliefs in latent states are proportional to prior beliefs and an approximate likelihood based on current associations. In simulation, we demonstrate the model’s ability to reproduce learning effects both famously explained and not explained by the Rescorla-Wagner model, including rapid return of fear after extinction, the Hall-Pearce effect, partial reinforcement extinction effect, backwards blocking, and memory modification. Lastly, we derive our model as an online algorithm to maximum likelihood estimation, demonstrating it is an efficient approach to outcome prediction. Establishing such a framework is a key step towards quantifying normative and pathological ranges of latent-state inferences in various contexts.

Author summary

Computational researchers are increasingly interested in a structured form of learning known as latent-state inferences. Latent-state inferences is a type of learning that involves categorizing, generalizing, and recalling disparate associations between observations in one’s environment and is used in situations when the correct association is latent or unknown. This type of learning has been used to explain overgeneralization of a fear memory and the cognitive role of certain brain regions important to cognitive neuroscience and psychiatry. Accordingly, latent-state inferences are an important area of inquiry. Through simulation and theory, we establish a new model of latent-state inferences. Moving forward, we aim to use this framework to measure latent-state inferences in healthy and psychiatric populations.
A role for long-range, through-lattice coupling in microtubule catastrophe
Authors: Kim Tae , Rice Luke M.
Published: October 2018

Microtubules are cylindrical polymers of αβ-tubulin that play critical roles in fundamental processes like chromosome segregation and vesicular transport. Microtubules display dynamic instability, switching stochastically between growing and rapid shrinking as a consequence of GTPase activity in the lattice. The molecular mechanisms behind microtubule catastrophe, the switch from growing to rapid shrinking, remain poorly defined. Indeed, two-state stochastic models that seek to describe microtubule dynamics purely in terms of the biochemical properties of GTP- and GDP-bound αβ-tubulin incorrectly predict the concentration-dependence of microtubule catastrophe. Recent studies provided evidence for three distinct conformations of αβ-tubulin in the lattice that likely correspond to GTP, GDP.Pi, and GDP. The incommensurate lattices observed for these different conformations raises the possibility that in a mixed nucleotide state lattice, neighboring tubulin dimers might modulate each other’s conformations and hence their biochemistry. We explored whether incorporating a GDP.Pistate or the likely effects of conformational accommodation can improve predictions of catastrophe. Adding a GDP.Piintermediate did not improve the model. In contrast, adding neighbor-dependent modulation of tubulin biochemistry improved predictions of catastrophe. Conformational accommodation should propagate beyond nearest-neighbor contacts, and consequently our modeling demonstrates that long-range, through-lattice effects are important determinants of microtubule catastrophe.
Endovascular stroke treatment does not preclude high thrombolysis rates
Authors: Feda S. , Nikoubashman O. , Schürmann K. , Matz O. , Tauber S. C. , Wiesmann M. , Schulz J. B. , Reich A.
Published: October 2018

Background and purpose

In 1995 intravenous recombinant tissue plasminogen activator (IVRTPA) was the first reperfusion therapy to be approved in patients with acute ischaemic stroke (AIS). The significance and impact of IVRTPA in times of modern endovascular stroke treatment (EST) were analysed in a German academic stroke centre.

Methods

A retrospective observational cohort analysis of 1034 patients with suspected AIS presenting at the emergency department in 2014 was performed. Patients were evaluated for baseline characteristics, reperfusion procedures, IVRTPA eligibility, clinical outcome, symptomatic intracranial haemorrhage (sICH) and mortality. Data acquisition was part of an investigator‐initiated, prospective and blinded end‐point registry.

Results

In 718 (69%) patients the diagnosis of symptomatic AIS was confirmed. 419 (58%) patients presented within 4.5 h of symptom onset and of those 260 (62%) received reperfusion therapy (IVRTPA alone, n = 183; combination or bridging therapy, n = 60; EST alone, n = 17). Subtracting cases with absolute contraindications for IVRTPA resulted in an effective thrombolysis rate of 82%. sICH occurred in two patients treated with IVRTPA alone (1.1%). The median door‐to‐needle interval was 30 min. Fifty (17%) non‐EST eligible AIS patients presenting within 4.5 h without absolute contraindications did not receive IVRTPA mainly due to mild or regressive symptoms. Most of these untreated IVRTPA eligible patients (82%) were discharged with a good clinical outcome (modified Rankin Scale ≤ 2).

Conclusions

Intravenous recombinant tissue plasminogen activator remains the most frequently applied reperfusion therapy in AIS patients presenting within 4.5 h of onset in a tertiary stroke centre. An effective thrombolysis rate of over 80% can be achieved without increased rates of sICH.
Effectiveness of complementary irrigation routines in debriding pulp tissue from root canals instrumented with a single reciprocating file
Authors: Varela P. , Souza E. , de Deus G. , Duran‐Sindreu F. , Mercadé M.
Published: October 2018

Aim

To compare histologically the debridement efficacy of four irrigation techniques in root canals instrumented with a reciprocating single file.

Methodology

From recently extracted premolars with vital pulp, 68 were selected and classified as having round canals (mesiodistal diameter similar to buccolingual) or oval‐shaped canals (mesiodistal diameter 2.5 times larger than buccolingual) (n = 32, each) by means of bidirectional radiographs. Four additional uninstrumented samples served as histological controls. The root canals of the specimens were accessed and then instrumented with Reciproc R25® and further assigned to one of four experimental groups according to the complementary irrigation technique: Group I, conventional syringe; Group II, passive ultrasonic irrigation; Group III, manual dynamic activation (MDA); and Group IV, EndoActivator®. Roots were then demineralized and the apical 3 mm was multi‐sliced and processed for histologic examination. The percentage of residual pulp tissue was calculated at each cross section. Kruskal–Wallis and Mann–Whitney tests were used to evaluate the effects of irrigation technique, root canal shape and level of cross section on the percentage of residual pulp tissue (P < 0.05).

Results

Irrigation technique and root canal shape significantly influenced the percentage of residual pulp tissue (P < 0.05) of canals instrumented with the R25 instrument. Percentage of residual pulp tissue was significantly less using ultrasonic irrigation (P < 0.05), but there was no difference between other irrigation techniques (P > 0.05). Round canals retained significantly less percentage of residual pulp tissue compared to oval‐shaped canals (P = 0.001). At 3 mm, there was less pulp tissue compared to levels 2 and 1 mm (P < 0.05).

Conclusions

In canals instrumented with R25 files, ultrasonic irrigation was more effective in removing pulp tissue in the apical level, especially for the debridement of oval‐shaped canals.
Novel four‐session treatment intervention for anxiety and high‐functioning autism: A single case report for Externalizing Metaphors Therapy
Authors: McGuinty Everett F. , Bird Brian M. , Nelson John , McGuinty Jazlyn L. , Cashin Andrew
Published: October 2018

Topic

The Brief Services psychotherapy paradigm has evolved to produce cost‐effective and clinically significant outcomes in children's mental health. Though its clinical evaluation is still in its infancy, it has been utilized to a much lesser degree with autism spectrum disorders, which typically require a longer‐term approach to psychotherapy treatment.

Purpose

The current paper introduces a novel, four‐session intervention that aims to decrease anxiety experienced by clients presenting with high‐functioning autism. Externalizing Metaphors Therapy is based upon the externalization of problems, transformation of metaphoric imagery, shifting of maladaptive emotional schemas, and the generalization of problems. A case study is utilized to visually aid in the understanding of this new treatment intervention.

Source

A composite literature review was conducted with regards to significant works in Narrative Therapy, treatment interventions for anxiety and high functioning autism, evidence‐based treatments for anxiety, and practice based approaches in psychotherapy. Works were selected based on their relevance to the research filed of anxiety and autism.

Conclusions

This clinical research challenges the children's mental health field in addressing anxiety and high‐functioning autism from a brief framework. Further clinical research is needed to clinically evaluate the current model.
Long‐term efficacy and safety of ixekizumab in Japanese patients with erythrodermic or generalized pustular psoriasis: subgroup analyses of an open‐label, phase 3 study (UNCOVER‐J)
Authors: Okubo Y. , Mabuchi T. , Iwatsuki K. , Elmaraghy H. , Torisu‐Itakura H. , Morisaki Y. , Nakajo K.
Published: October 2018

Background

Erythrodermic and generalized pustular psoriasis are rare, difficult to treat forms of psoriasis. In previous reports, we documented 24‐ and 52‐week findings of an open‐label, phase 3 trial (UNCOVER‐J) of ixekizumab in Japanese patients with erythrodermic or generalized pustular psoriasis; most patients responded to treatment and maintained response through 52 weeks.

Objective

To assess the long‐term (>3 years) efficacy and safety of ixekizumab in Japanese patients with erythrodermic or generalized pustular psoriasis.

Methods

These subgroup analyses were of a partial population of patients from UNCOVER‐J (NCT01624233; Sponsored by Eli Lilly and Company), specifically those with erythrodermic psoriasis (N = 8) or generalized pustular psoriasis (N = 5). These patients received 160 mg ixekizumab at Week 0, ixekizumab 80 mg every 2 weeks through Week 12, and ixekizumab 80 mg every 4 weeks thereafter up to Week 244. This regimen is consistent with the regimen approved in Japan for plaque, erythrodermic, and generalized pustular psoriasis and psoriatic arthritis. Efficacy assessments included Global Improvement Score (GIS), Psoriasis Area and Severity Index (PASI), dermal symptoms (for patients with generalized pustular psoriasis), Dermatology Life Quality Index (DLQI) and Itch Numeric Rating Scale (NRS). Safety assessments included treatment‐emergent adverse events and adverse events of special interest.

Results

Most patients had a GIS of resolved or improved from Week 12 onwards, and all patients had early and sustained improvement in PASI and dermal symptom (generalized pustular psoriasis only) scores. Mean improvements in DLQI and Itch NRS at Week 12 were sustained through Week 244. Ixekizumab was well tolerated over 3 years of treatment in patients with erythrodermic psoriasis or generalized pustular psoriasis, and no new safety concerns were identified.

Conclusion

These findings suggest that ixekizumab can be an effective long‐term treatment option for erythrodermic or generalized pustular psoriasis.
Intra‐cortical myelin mediates personality differences
Authors: Toschi Nicola , Passamonti Luca
Published: October 2018

Objective

Differences in myelination in the cortical mantle are important neurobiological mediators of variability in cognitive, emotional, and behavioral functioning. Past studies have found that personality traits reflecting such variability are linked to neuroanatomical and functional changes in prefrontal and temporo‐parietal cortices. Whether these effects are partially mediated by the differences in intra‐cortical myelin remains to be established.

Method

To test this hypothesis, we employed vertex‐wise intra‐cortical myelin maps in n = 1,003 people from the Human Connectome Project. Multivariate regression analyses were used to test for the relationship between intra‐cortical myelin and each of the five‐factor model’s personality traits, while accounting for age, sex, intelligence quotient, total intracranial volume, and the remaining personality traits.

Results

Neuroticism negatively related to frontal‐pole myelin and positively to occipital cortex myelin. Extraversion positively related to superior parietal myelin. Openness negatively related to anterior cingulate myelin, while Agreeableness positively related to orbitofrontal myelin. Conscientiousness positively related to frontal‐pole myelin and negatively to myelin content in the dorsal anterior cingulate cortex.

Conclusions

Intra‐cortical myelin levels in brain regions with prolonged myelination are positively associated with personality traits linked to favorable outcome measures. These findings improve our understanding of the neurobiological underpinnings of variability in common behavioral dispositions.
Adeylithon bosencei gen. et sp. nov. (Corallinales, Rhodophyta): a new reef‐building genus with anatomical affinities with the fossil Aethesolithon
Authors: Peña Viviana , Le Gall Line , Rösler Anja , Payri Claude E. , Braga Juan Carlos
Published: October 2018

Adeylithon gen. nov. with one species, A. bosencei sp. nov., belonging to the subfamily Hydrolithoideae is described from Pacific coral reefs based on psbA sequences and morpho‐anatomy. In contrast with Hydrolithon, A. bosencei showed layers of large polygonal “cells,” which resulted from extensive lateral fusions of perithallial cells, interspersed among layers of vegetative cells. This anatomical feature is shared with the fossil Aethesolithon, but lacking DNA sequences from the fossils and the fragmentary nature of Aethesolithon type material, we cannot ascertain if Adeylithon and Aethesolithon are congeneric. Morpho‐anatomical features of A. bosencei were generally congruent with diagnostic features of the subfamily Hydrolithoideae: (i) outline of cell filaments entirely lost in large portions due to pervasive and extensive cell fusions, (ii) trichocytes not arranged in tightly packed horizontal fields, (iii) basal layer without palisade cells, and (iv) cells lining the canal pore oriented more or less perpendicular to roof surface and not protruding into the canal. However, it showed a predominant monomerous thallus organization and trichocytes were disposed in large pustulate, horizontal fields, although they were not tightly packed and did not become distinctly buried in the thallus. Only mature tetrasporangial conceptacles were observed, therefore the type of conceptacle roof formation remained undetermined. Adeylithon bosencei occurs on shallow coral reefs, in Australia, Papua New Guinea, and South Pacific islands (Fiji, Vanuatu). Fossil Aethesolithon is considered an important component of shallow coral reefs since the Miocene; fossil records showed a broad Indo‐Pacific distribution, but a long‐term process of range contraction in the last 2.6 million years, resulting in an overlap with the distribution of the extant Adeylithon. While the congeneric nature of extant and fossil taxa remained uncertain, similarities in morpho‐anatomy, habitat, and distribution may indicate that both taxa likely shared a common ancestor.