bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional anesthesia and analgesia after surgery in ICU
Authors: Capdevila Mathieu , Ramin Séverin , Capdevila Xavier
Published: August 2017

Purpose of review

The aim is to demonstrate that ICU physicians should play a pivotal role in developing regional anesthesia techniques that are underused in critically ill patients despite the proven facts in perioperative and long-term pain, organ dysfunction, and postsurgery patient health-related quality of life improvement.

Recent findings

Regional anesthesia and/or analgesia strategies in ICU reduce the surgical and trauma–stress response in surgical patients as well as complications incidence. Recent studies suggested that surgical/trauma ICU patients receive opioid–hypnotics continuous infusions to prevent pain and agitation that could increase the risk of posttraumatic stress disorder and chronic neuropathic pain symptoms, and chronic opioid use. Regional anesthesia use decrease the use of intravenous opioids and the ectopic activity of injured small fibers limiting those phenomena. In Cochrane reviews and prospective randomized trials in major surgery patients, regional anesthesia accelerates the return of the gastrointestinal transit and rehabilitation, decreases postoperative pain and opioids use, reduces ICU/hospital stay, improves pulmonary outcomes, including long period of mechanical ventilation and early extubation, reduces overall adverse cardiac events, and reduces ICU admissions when compared with general anesthesia and intravenous opiates alone. The reduction of long-term mortality has been reported in major vascular or orthopedic surgeries.

Promoting regional anesthesia/analgesia in ICU surgical/trauma patients could undoubtedly limit the risk of complications, ICU/hospital stay, and improve patient's outcome. The use of regional anesthesia permits a high doses opioid use limitation which is mandatory and should be considered as feasible and well tolerated in ICU.
How to better identify patients at high risk of postoperative complications?
Authors: Talmor Daniel , Kelly Barry
Published: August 2017

Purpose of review

Preoperative risk assessment and perioperative factors may help identify patients at increased risk of postoperative complications and allow postoperative management strategies that improve patient outcomes. This review summarizes historical and more recent scoring systems for predicting patients with increased morbidity and mortality in the postoperative period.

Recent findings

Most prediction scores predict postoperative mortality with, at best, moderate accuracy. Scores that incorporate surgery-specific and intraoperative covariates may improve the accuracy of traditional scores. Traditional risk factors including increased ASA physical status score, emergent surgery, intraoperative blood loss and hemodynamic instability are consistently associated with increased mortality using most scoring systems.

Preoperative clinical risk indices and risk calculators estimate surgical risk with moderate accuracy. Surgery-specific risk calculators are helpful in identifying patients at increased risk of 30-day mortality. Particular attention should be paid to intraoperative hemodynamic instability, blood loss, extent of surgical excision and volume of resection.
Lack of Association Between Interleukin 28B Polymorphism and Vertical Transmission of Hepatitis C
Authors: Psaros Einberg Afrodite , Duberg Ann-Sofi , Filipovich Olga , Nyström Jessica , Zhirkov Anton , Brenndörfer Erwin D. , Frelin Lars , Rukoiatkina Elena , Lobzin Yuriy , Sällberg Matti , Fischler Björn , Lutckii Anton
Published: August 2017

Objectives:

Single genetic nucleotide polymorphism (rs12979860) near the gene for interleukin 28B (IL28B) is known to be of importance for frequency of spontaneous clearance and treatment outcome in interferon-based therapies in patients with hepatitis C virus (HCV) infection. The aim of the present study was to investigate whether IL28B polymorphism in children and/or their mothers plays a role in vertical transmission of HCV (HCV-VT).

Methods:

Plasma samples from 59 infected women, 76 uninfected children born to infected mothers, and 47 children with known vertically transmitted HCV infection, were analysed for IL28B polymorphism and classified by the IL28B genotype (C/C, C/T, and T/T) and by viral genotype.

Results:

The proportion of children with genotype C/C was the same in the vertically infected (36%, 17/47) and the exposed uninfected children (38%, 29/76). No difference was seen when stratifying for viral genotype. There was no association between mothers’ IL28B genotype and the risk of vertical transmission.

Conclusions:

Regardless of viral genotype we found no association between IL28B genotype and the risk of HCV-VT. The IL28B genotype CC, which has been shown to be favourable in other settings, was not protective of HCV-VT. Thus, other factors possibly associated with the risk of HCV-VT need to be explored.
Cephalometric Predictors of Clinical Severity in Treacher Collins Syndrome
Authors: Esenlik Elçin , Plana Natalie M. , Grayson Barry H. , Flores Roberto L.
Published: August 2017

Background:

The aim of this study was to identify cephalometric measurements associated with clinical severity in patients with Treacher Collins syndrome.

Methods:

A retrospective single-institution review of patients with Treacher Collins syndrome was conducted. Preoperative cephalograms and computed tomographic scans (n = 30) were evaluated. Fifty cephalometric measurements were compared to age-specific normative data using analysis of variance. These cephalometric measurements and the patient’s Pruzansky classification were correlated to clinical severity using Spearman analysis. Clinical severity was defined as severe (required tracheostomy), moderate (obstructive sleep apnea, oral cleft, or gastrostomy-tube), or mild (absence of listed comorbidities). Cephalometric measurements with a strong correlation (r > 0.60) were identified as predictors of clinical severity.

Results:

Cephalograms of the study population contained 30 measurements that were found to be significantly different from normative data (p < 0.01). These measurements were related largely to maxillary/mandibular projection, maxillary/mandibular plane angle, mandibular morphology, facial height, facial convexity, and mandible/throat position. Ten of these 30 statistically significant measurements in addition to Pruzansky classification were found to be strongly correlated (r > 0.60) to clinical severity. These measurements include the following: mandibular projection/position (sella-nasion-pogonion, r = −0.64; hyoid-menton, r = −0.62); posterior facial height (posterior facial height/anterior facial height, r = 0.60; condyle-gonion, r = −0.66); maxillary/mandibular plane angle (sella-nasion–mandibular plane, r = 0.62; Frankfort horizontal–mandibular plane, r = 0.61; sella-nasion–palatal plane, r = 0.69; sella-nasion-symphysis, r = −0.69); and Pruzansky classification (r = 0.82).

Conclusion:

Specific cephalometric measurements of increased mandibular retrognathia, decreased posterior facial height, more obtuse maxillary/mandibular plane angle and more obtuse symphysis notch angle are strongly correlated to increased clinical severity in patients with Treacher Collins syndrome.
Simultaneous Stiles-Bunnell Tendon Transfer Enhances Intrinsic Function of Second-Toe Transplantations
Authors: Lin Yu-Te , Loh Charles Yuen Yung , Lien Shwu-Huei , Lin Chih-Hung , Wei Fu-Chan
Published: August 2017

Claw finger is a sequela of fingers without intrinsic function. Claw toe deformity is common after toe transfer, as simultaneous intrinsic reconstruction has yet to be reported in the literature. The authors present their experience of simultaneous tendon transfer during second-toe transplantation. Seven second-toe transfers were performed in five metacarpal-like and metacarpal hands. The Stiles-Bunnell tendon transfer was incorporated into toe transfers. Toe lumbrical tendons were repaired to the flexor digitorum sublimis of the same recipient digit. The active motion values of the proximal interphalangeal joint were 61 ± 9.5 degrees and 36 ± 6.4 degrees in the middle and ring fingers, respectively. The extension lag overall was 19.9 ± 9.9 degrees. The transferred toe proximal interphalangeal joints had minimal extensor lag with the metacarpophalangeal joint in flexion position. The flexion sweep of the toe was improved by the intrinsic reconstruction. The patients were able to use the transferred toes for sophisticated daily activities. From the results seen, simultaneous intrinsic reconstruction appears to enhance the dexterity and thus function of transferred toes.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Oblique Osteotomy for the Correction of the Zigzag Deformity of Wassel Type IV Polydactyly
Authors: Kim Byung Jun , Choi Jun Ho , Kwon Sung Tack
Published: August 2017

Background:

Surgical treatment of Wassel type IV thumb polydactyly is technically challenging, especially when it has a zigzag deformity. However, the authors obtained good operative results by performing oblique osteotomy with autologous fat graft in 30 patients.

Methods:

After removal of the extra digit, the radially deviated distal phalanx was corrected by performing oblique osteotomy at the proximal phalanx. Free fat tissue was grafted to the areas with soft-tissue deficiency. Surgical outcomes were evaluated in terms of the thumb length ratio compared to the normal counterpart, the angulation between the proximal phalanx and the distal phalanx, and the Tada score. As a negative control, the data of 46 type IV polydactyly patients without a significant axis deviation were evaluated.

Results:

The thumb length ratio was maintained from 0.96 ± 0.06 preoperatively to 1.01 ± 0.07 4-year postoperatively. The angulation improved from 30.84 ± 14.78 degrees to 11.03 ± 7.67 degrees. In comparison, the length ratio and angulation of the control group changed from 0.97 ± 0.04 to 0.98 ± 0.02, and from 19.46 ± 8.27 degrees to 14.10 ± 6.61 degrees, respectively. The Tada scores were 5.3 ± 0.88 in the oblique osteotomy group and 6.59 ± 0.62 in the control group, both of which were graded as good.

Conclusions:

Oblique osteotomy with autologous fat graft is a good surgical option for treating the Wassel type IV polydactyly with zigzag deformity. This technique allows sufficient axis correction without bone shortening, and it provides adequate soft-tissue contouring.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Impact of Surgical Treatment for Recurrence After 2-Stage Hepatectomy for Colorectal Liver Metastases, on Patient Outcome
Authors: Imai Katsunori , Benitez Carlos Castro , Allard Marc-Antoine , Vibert Eric , Cunha Antonio Sa , Cherqui Daniel , Castaing Denis , Bismuth Henri , Baba Hideo , Adam René
Published: August 2017

Objective:

To evaluate the impact of repeat surgery for recurrence on the long-term survival after 2-stage hepatectomy (TSH) for extensive colorectal liver metastases (CRLM).

Background:

Although TSH is now deemed effective for selected patients with extensive bilobar CRLM, disease recurrence after TSH is very frequent because of the extensive tumor load.

Methods:

Among a total cohort of 1235 patients who underwent hepatectomy for CRLM between 1992 and 2012, 139 with extensive bilobar CRLM were scheduled for TSH. Of these, 93 patients had completion of TSH and were enrolled in this study.

Results:

The 5-year overall survival (OS) rate after TSH was 41.3%. Twenty-two patients (23.7%) had a concomitant extrahepatic disease (EHD), and curative resection of concomitant EHD was achieved in 13 patients. Among the 81 patients who achieved complete tumor removal for primary, CRLM, and concomitant EHD, 62 (76.5%) had recurrence. Repeat surgery was performed in 38 patients; 35 for recurrence after curative surgery and 3 for liver recurrence with unresected concomitant EHD or primary tumor. Of these 38 patients, 31 were salvaged. The patients who underwent repeat surgery had a significantly longer OS than those who did not (45.8% vs 26.3%; P = 0.0041). A multivariate analysis revealed that repeat surgery was an independent prognostic factor of the OS after TSH (hazard ratio 0.31, P = 0.0012).

Conclusions:

Repeat surgery for recurrence after TSH may be crucial for the long-term survival in patients with extensive bilobar CRLM. Intensive oncosurgical surveillance is essential to avoid missing the chance for repeat surgery after TSH.
A Comparative Study of the Predictive Values of Urinary Acute Kidney Injury Markers Angiogenin and Kidney Injury Molecule 1 for the Outcomes of Kidney Allografts
Authors: Tavernier Quentin , Tinel Claire , Rabant Marion , Morin Lise , Anglicheau Dany , Pallet Nicolas
Published: August 2017

Background

Whether injury-related molecules in urines of individuals with ischemia-reperfusion injury (IRI) are independent predictors of graft outcomes and provide additional information compared with usual risk factors remains to be established.

Methods

We explored a cohort of 244 kidney transplant recipients who systematically had a urine collection 10 days after transplantation. The injury-related markers kidney injury molecule-1 (KIM-1) and angiogenin (ANG) levels in urines were measured. We determined the prognostic values of these markers on graft outcomes.

Results

Urinary KIM-1 and ANG concentrations were strongly correlated to each other and were significantly and independently associated with cold ischemia time, delayed graft function, and plasma creatinine 10 days after transplantation, indicating that these markers reflect the severity of IRI. However, urinary ANG and KIM-1 were not predictive of histological changes on protocol biopsies performed 3 and 12 months after transplantation. Finally, urinary ANG and urinary KIM-1 were not associated with graft survival.

Conclusions

Together, our results indicate that, in a cohort of 244 kidney transplant recipients, urinary ANG and KIM-1 levels in a single measurement 10 days after transplantation reflect the severity of IRI after kidney transplantation, but are neither independent predictors of renal function, histological changes and graft survival.
N2-fixing tropical legume evolution: a contributor to enhanced weathering through the Cenozoic?
Authors: Epihov Dimitar Z. , Batterman Sarah A. , Hedin Lars O. , Leake Jonathan R. , Smith Lisa M. , Beerling David J.
Published: August 2017

Fossil and phylogenetic evidence indicates legume-rich modern tropical forests replaced Late Cretaceous palm-dominated tropical forests across four continents during the early Cenozoic (58–42 Ma). Tropical legume trees can transform ecosystems via their ability to fix dinitrogen (N2) and higher leaf N compared with non-legumes (35–65%), but it is unclear how their evolutionary rise contributed to silicate weathering, the long-term sink for atmospheric carbon dioxide (CO2). Here we hypothesize that the increasing abundance of N2-fixing legumes in tropical forests amplified silicate weathering rates by increased input of fixed nitrogen (N) to terrestrial ecosystems via interrelated mechanisms including increasing microbial respiration and soil acidification, and stimulating forest net primary productivity. We suggest the high CO2early Cenozoic atmosphere further amplified legume weathering. Evolution of legumes with high weathering rates was probably driven by their high demand for phosphorus and micronutrients required for N2-fixation and nodule formation.
Frequent lack of repressive capacity of promoter DNA methylation identified through genome-wide epigenomic manipulation
Authors: Ford Ethan , Grimmer Matthew R. , Stolzenburg Sabine , Bogdanovic Ozren , Mendoza Alex de , Farnham Peggy J. , Blancafort Pilar , Lister Ryan
Published: August 2017

It is widely assumed that the addition of DNA methylation at CpG rich gene promoters silences gene transcription. However, this conclusion is largely drawn from the observation that promoter DNA methylation inversely correlates with gene expression in natural conditions. The effect of induced DNA methylation on endogenous promoters has yet to be comprehensively assessed. Here, we induced the simultaneous methylation of thousands of promoters in the genome of human cells using an engineered zinc finger-DNMT3A fusion protein, enabling assessment of the effect of forced DNA methylation upon transcription, histone modifications, and DNA methylation persistence after the removal of the fusion protein. We find that DNA methylation is frequently insufficient to transcriptionally repress promoters. Furthermore, DNA methylation deposited at promoter regions associated with H3K4me3 is rapidly erased after removal of the zinc finger-DNMT3A fusion protein. Finally, we demonstrate that induced DNA methylation can exist simultaneously on promoter nucleosomes that possess the active histone modification H3K4me3, or DNA bound by the initiated form of RNA polymerase II. These findings suggest that promoter DNA methylation is not generally sufficient for transcriptional inactivation, with implications for the emerging field of epigenome engineering.

One Sentence Summary

Genome-wide epigenomic manipulation of thousands of human promoters reveals that induced promoter DNA methylation is unstable and frequently does not function as a primary instructive biochemical signal for gene silencing and chromatin reconfiguration.
Conformational states during vinculin unlocking differentially regulate focal adhesion properties
Authors: Chorev Dror S. , Volberg Tova , Livne Ariel , Eisenstein Miriam , Martins Bruno , Kam Zvi , Jockusch Brigitte M. , Medalia Ohad , Sharon Michal , Geiger Benny
Published: August 2017

Focal adhesions (FAs) are multi-protein complexes that connect the actin cytoskeleton to the extracellular matrix, via integrin receptors. The growth, stability and adhesive functionality of these structures are tightly regulated by mechanical stress, yet, despite the extensive characterization of the integrin adhesome, the mechanisms underlying FA mechanosensitivity are still poorly understood. One of the key candidates for regulating FA-associated mechanosensing is vinculin, a prominent FA component, which was proposed to possess either closed (“auto-inhibited”) or open (active) conformations. However, a direct demonstration of the nature of conformational transition between the two states is still absent. In this study we combined multiple structural and biological approaches to probe the transition from auto-inhibited to active conformation, and determine its effects on FA structure and dynamics. We further show here that the closed to open transition requires two sequential steps that can differentially regulate FA growth and stability.
A shift in aggregation avoidance strategy marks a long-term direction to protein evolution
Authors: Foy S.G. , Wilson B.A. , Bertram J. , Cordes M.H.J. , Masel J.
Published: August 2017

To detect a direction to evolution, without the pitfalls of reconstructing ancestral states, we need to compare “more evolved” to “less evolved” entities. But because all extant species have the same common ancestor, none are chronologically more evolved than any other. However, different gene families were born at different times, allowing us to compare young protein-coding genes to those that are older and hence have been evolving for longer. To be retained during evolution, a protein must not only have a function, but must also avoid toxic dysfunction such as protein aggregation. There is conflict between the two requirements; hydrophobic amino acids form the cores of protein folds, but also promote aggregation. Young genes avoid strongly hydrophobic amino acids, which is presumably the simplest solution to the aggregation problem. Here we show that young genes’ few hydrophobic residues are clustered near one another along the primary sequence, presumably to assist folding. The higher aggregation risk created by the higher hydrophobicity of older genes is counteracted by more subtle effects in the ordering of the amino acids, including a reduction in the clustering of hydrophobic residues until they eventually become more interspersed than if distributed randomly. This interspersion has previously been reported to be a general property of proteins, but here we find that it is restricted to old genes. Quantitatively, the index of dispersion delineates a gradual trend, i.e. a decrease in the clustering of hydrophobic amino acids over billions of years.
N6-Methyladenine DNA Modification in Human Genome
Authors: Xiao Chuan-Le , Zhu Song , He Minghui , Chen De , Zhang Qian , Chen Ying , Yu Guoliang , Liu Jinbao , Xie Shang-Qian , Luo Feng , Liang Zhe , Wang De-Peng , Bo Xiao-Chen , Gu Xiao-Feng , Wang Kai , Yan Guang-Rong
Published: August 2017

DNA N6-methyladenine (6mA) modification is the most prevalent DNA modification in prokaryotes, but whether it exists in human cells and whether it plays a role in human diseases remain enigmatic. Here, we showed that 6mA is extensively present in human genome, and we cataloged 881,240 6mA sites accounting for ∼0.051% of the total adenines. [G/C]AGG[C/T] was the most significantly associated motif with 6mA modification. 6mA sites were enriched in the coding regions and mark actively transcribed genes in human cells. We further found that DNA N6-methyladenine and N6-demethyladenine modification in human genome were mediated by methyltransferase N6AMT1 and demethylase ALKBH1, respectively. The abundance of 6mA was significantly lower in cancers, accompaning with decreased N6AMT1 and increased ALKBH1 levels, and down-regulation of 6mA modification levels promoted tumorigenesis. Collectively, our results demonstrate that DNA 6mA modification is extensively present in human cells and the decrease of genomic DNA 6mA promotes human tumorigenesis.
Variable dose analysis: A novel RNAi-based method for detection of synthetic lethal interactions
Authors: Housden Benjamin E. , Li Zhongchi , Kelley Colleen , Wang Yuanli , Hu Yanhui , Valvezan Alexander J. , Manning Brendan D. , Perrimon Norbert
Published: August 2017

Synthetic sick or synthetic lethal (SS/L) screens are a powerful way to identify candidate drug targets to specifically kill tumor cells but such screens generally suffer from low reproducibility. We found that many SS/L interactions involve essential genes and are therefore detectable within a limited range of knockdown efficiency. Such interactions are often missed by overly efficient RNAi reagents. We therefore developed an assay that measures viability over a range of knockdown efficiency within a cell population. This method, called variable dose analysis (VDA), is highly sensitive to viability phenotypes and reproducibly detects SS/L interactions. We applied the VDA method to search for SS/L interactions withTSC1andTSC2, the two tumor suppressors underlying tuberous sclerosis complex (TSC) and generated a SS/L network for TSC. Using this network, we identified four FDA-approved drugs that selectively affect viability of TSC deficient cells, representing promising candidates for repurposing to treat TSC-related tumors.
Sex-Biased Gene Expression Resolves Sexual Conflict through the Evolution of Sex-Specific Genetic Architecture
Authors: Wright Alison E. , Fumagalli Matteo , Cooney Christopher R. , Bloch Natasha I. , Vieira Filipe G. , Buechel Severine D. , Kolm Niclas , Mank Judith E.
Published: August 2017

Many genes are subject to contradictory selection pressures in males and females, and balancing selection resulting from sexual conflict has the potential to substantially increase standing genetic diversity in populations and thereby act as an important force in adaptation. However, the underlying causes of sexual conflict, and the potential for resolution, remains hotly debated. Using transcriptome resequencing data from male and female guppies, we use a novel approach, combining patterns of genetic diversity and inter-sexual divergence in allele frequency, to distinguish the different scenarios that give rise to sexual conflict, and how this conflict may be resolved through regulatory evolution. We show that reproductive fitness is the main source of sexual conflict, and this is resolved via the evolution of male-biased expression. Furthermore, resolution of sexual conflict produces significant differences in genetic architecture between males and females, which in turn leads to specific alleles influencing sex-specific viability. Together, our findings suggest an important role for sexual conflict in shaping broad patterns of genome diversity, and show that regulatory evolution is a rapid and efficient route to the resolution of conflict.
Small Molecules Attenuate the Interplay between Conformational Fluctuations, Early Oligomerization and Amyloidosis of Alpha Synuclein
Authors: Kundu Amrita , Ghosh Sumanta , Chattopadhyay Krishnananda
Published: August 2017

Aggregation of alpha synuclein has strong implications in Parkinson’s disease. The heterogeneity of folding/aggregation landscape and transient nature of the early intermediates result in difficulty in developing a successful therapeutic intervention. Here we used fluorescence measurements at ensemble and single molecule resolution to study how the late and early events of alpha synuclein aggregation modulate each other. The in-vitro aggregation data was complemented using measurements inside live neuroblastoma cells by employing a small molecule labeling technique. An inhibitor molecule (arginine), which delayed the late event of amyloidosis, was found to bind to the protein, shifting the early conformational fluctuations towards a compact state. In contrast, a facilitator of late aggregation (glutamate), was found to be excluded from the protein surface. The presence of glutamate was found to speed up the oligomer formation at the early stage. We found that the effects of the inhibitor and facilitator were additive and as a result they maintained a ratio at which they cancelled each other’s influence on different stages of alpha synuclein aggregation.
Hydrogen peroxide formation by Nox4 limits malignant transformation
Authors: Helfinger Valeska , von Gall Florian Freiherr , Henke Nina , Kunze Michael M. , Schmid Tobias , Heidler Juliana , Wittig Ilka , Radeke Heinfried H. , Marschall Viola , Anderson Karen , Shah Ajay M. , Fulda Simone , Brüne Bernhard , Brandes Ralf P. , Schröder Katrin
Published: August 2017

Reactive oxygen species (ROS) can cause cellular damage and are thought to promote cancer-development. Nevertheless, under physiological conditions, all cells constantly produce ROS, either as chemical by-products or for signaling purpose. During differentiation cells induce the NADPH oxidase Nox4, which constitutively produces low amounts of H2O2. We infer that this constitutive H2O2is unlikely to be carcinogenic and may rather maintain basal activity of cellular surveillance systems.

Utilizing two different murine tumor models we demonstrate that Nox4 prevents malignant transformation and facilitated the recognition of DNA-damage. Upon DNA-damage repair is initiated as consequence of phosphorylation of H2AX (γH2AX). Repair only occurs if nuclear activity of the γH2AX-dephosphorylating phosphatase PP2A is kept sufficiently low, a task fulfilled by Nox4: Nox4 continuously oxidizes AKT, and once oxidized AKT captures PP2A in the cytosol. Absence of Nox4 facilitates nuclear PP2A translocation and dephosphorylation of γH2AX. Simultaneously the proportion of active, phosphorylated AKT is increased. Thus, DNA-damage is not recognized and the increase in AKT activity promotes proliferation. The combination of both events resulted in genomic instability and tumor initiation.

With the identification of the first cancer-protective source of reactive oxygen species, Nox4, the paradigm of reactive-oxygen species-induced initiation of malignancies should be revised.

Significance

The stereotype of ROS produced by NADPH oxidases as cause of malignant diseases persists generalized since decades. We demonstrate that the NADPH oxidase Nox4, as constitutive source of ROS, prevents malignant transformation and that its pharmacological inhibition as currently aspired by several companies will potentially increase the risk of malignant cell transformation and eventually tumor formation.

Precis

By oxidizing AKT and keeping PP2A in the cytosol, the NADPH oxidase Nox4 allows proper DNA damage repair and averts cancer development.
PTE, a novel module to target Polycomb Repressive Complex 1 to theCyclin D2oncogene
Authors: Cameron Sarina R. , Nandi Soumyadeep , Kahn Tatyana G. , Barrasa Juan I. , Stenberg Per , Schwartz Yuri B.
Published: August 2017

Polycomb Group proteins are essential epigenetic repressors. They form multiple protein complexes of which two kinds, PRC1 and PRC2, are indispensable for repression. Although much is known about their biochemical properties, how PRC1 and PRC2 are targeted to specific genes is poorly understood. Here we establish theCyclin D2(CCND2) oncogene as a simple model to address this question. We provide the evidence that coordinated recruitment of PRC1 and PRC2 complexes toCCND2involves a combination of a specialized PRC1 targeting element (PTE) and an adjacent CpG-island, which together act as a human Polycomb Response Element. Chromatin immunoprecipitation analysis ofCCND2in different transcriptional states indicates that histone modifications produced by PRC1 and PRC2 are not sufficient to recruit either of the complexes. However, catalytic activity of PRC2 helps to anchor PRC1 at the PTE. Our analyses suggest that coordinated targeting of PRC1 and PRC2 complexes by juxtaposed AT-rich PTEs and CpG-islands may be a general feature of Polycomb repression in mammals.
Simulating extracted connectomes
Authors: Gornet Jonathan , Scheffer Louis K.
Published: August 2017

Connectomes derived from volume EM imaging of the brain can generate detailed physical models of every neuron, and simulators such as NEURON or GENESIS are designed to work with such models. In principal, combining these technologies, plus transmitter and channel models, should allow detailed and accurate simulation of real neural circuits. Here we experiment with this combination, using a well-studied system (motion detection inDrosophila). Since simulation requires both the physical geometry (which we have) and the models of the synapses (which are not currently available), we built approximate synapses corresponding to their known and estimated function. Once we did so, we reproduced direction selectivity in T4 cells, one of the main functions of this neural circuit. This verified the basic functionality of both extraction and simulations, and provided a biologically relevant computation we could use in further experiments. We then compared models with different degrees of physical realism, from full detailed models down to models consisting of a single node, to examine the tradeoff of simulation resources required versus accuracy achieved.

Our results show that much simpler models may be adequate, at least in the case of medulla neurons inDrosophila. Such models can be easily derived from fully detailed models, and result in simulations that are much smaller, much faster, and accurate enough for many purposes. Biologically, we show that a lumped neuron model reproduces the main motion detector operation, confirming the result of Gruntman[1], that dendritic compution is not required for this function.
Gradual Cerebral Hypoperfusion Impair Fear Conditioning and Object Recognition Learning and Memory in Mice: Potential Roles of Neurodegeneration and Cholinergic Dysfunction
Authors: Mehla Jogender , Lacoursiere Sean , Stuart Emily , McDonald Robert J. , Mohajerani Majid H.
Published: August 2017

In the present study, male C57BL/6J mice were subjected to gradual cerebral hypoperfusion by implanting an ameroid constrictor (AC) on the left common carotid artery (CCA) and a stenosis on the right CCA. In the sham group, all surgical procedures were kept the same except no AC was implanted and stenosis was not performed. One month following the surgical procedures, fear conditioning and object recognition tests were conducted to evaluate learning and memory functions and motor functions were assessed using a balance beam test. At the experimental endpoint, mice were perfused and brains were collected for immunostaining and histology. Learning and memory as well as motor functions were significantly impaired in the hypoperfusion group. The immunoreactivity to choline acetyltransferase was decreased in dorsal striatum and basal forebrain of the hypoperfusion group indicating that cholinergic tone in these brain regions was compromised. In addition, an increased number of Fluoro-Jade positive neurons was also found in cerebral cortex, dorsal striatum and hippocampus indicating neurodegeneration in these brain regions. Based on this pattern of data, we argued that this mouse model would be a useful tool to investigate the therapeutic interventions for the treatment of vascular dementia. Additionally, this model could be employed to exploit the effect of microvascular occlusions on cognitive impairment in the absence and presence of Alzheimer pathology.
The Oyster River Protocol: A Multi Assembler and Kmer Approach Forde novoTranscriptome Assembly
Authors: MacManes Matthew D.
Published: August 2017

Characterizing transcriptomes in non-model organisms has resulted in a massive increase in our understanding of biological phenomena. This boon, largely made possible via high-throughput sequencing, means that studies of functional, evolutionary and population genomics are now being done by hundreds or even thousands of labs around the world. For many, these studies begin with ade novotranscriptome assembly, which is a technically complicated process involving several discrete steps. The Oyster River Protocol (ORP), described here, implements a standardized and benchmarked set of bioinformatic processes, resulting in an assembly with enhanced qualities over other standard assembly methods. Specifically, ORP produced assemblies have higherDetonateandTransRatescores and mapping rates, which is largely a product of the fact that it leverages a multi-assembler and kmer assembly process, thereby bypassing the shortcomings of any one approach. These improvements are important, as previously unassembled transcripts are included in ORP assemblies, resulting in a significant enhancement of the power of downstream analysis. Further, as part of this study, I show that assembly quality is unrelated with the number of reads generated, above 30 million reads.Code Availability:The version controlled open-source code is available athttps://github.com/macmanes-lab/Oyster_River_Protocol. Instructions for software installation and use, and other details are available athttp://oyster-river-protocol.rtfd.org/.
Neurobiology of fear and specific phobias
Authors: Garcia René
Published: August 2017

Fear, which can be expressed innately or after conditioning, is triggered when a danger or a stimulus predicting immediate danger is perceived. Its role is to prepare the body to face this danger. However, dysfunction in fear processing can lead to psychiatric disorders in which fear outweighs the danger or possibility of harm. Although recognized as highly debilitating, pathological fear remains insufficiently treated, indicating the importance of research on fear processing. The neurobiological basis of normal and pathological fear reactions is reviewed in this article. Innate and learned fear mechanisms, particularly those involving the amygdala, are considered. These fear mechanisms are also distinguished in specific phobias, which can indeed be nonexperiential (implicating innate, learning-independent mechanisms) or experiential (implicating learning-dependent mechanisms). Poor habituation and poor extinction are presented as dysfunctional mechanisms contributing to persistence of nonexperiential and experiential phobias, respectively.
Breaking boundaries: optimizing reconsolidation-based interventions for strong and old memories
Authors: Elsey James W.B. , Kindt Merel
Published: August 2017

Recent research has demonstrated that consolidated memories can enter a temporary labile state after reactivation, requiring restabilization in order to persist. This process, known as reconsolidation, potentially allows for the modification and disruption of memory. Much interest in reconsolidation stems from the possibility that maladaptive memory traces—a core feature of several psychiatric conditions—could be tackled by disrupting their reconsolidation. However, research has indicated a range of supposed boundary conditions on the induction of reconsolidation. Stronger memories, often resulting from exposure to stressful conditions, or older memories, appear to be relatively resistant to undergoing reconsolidation. This may be taken as a potential stumbling block for reconsolidation-based interventions: in clinical practice, old and strong maladaptive memories are the norm rather than the exception. Yet, boundary conditions have been derived from limited experimental evidence, are not unique to reconsolidation-based interventions, and do not seem to be absolute. In this paper, we review a range of experimental studies that have aimed to disrupt old memories, or memories that were strengthened by stress manipulations, through reconsolidation. Such research highlights several techniques that could be used to optimize reconsolidation-based approaches and overcome putative boundary conditions. We supplement this review of experimental literature with a case study of a reconsolidation-based treatment of a strong and decades-old phobia for mice, further suggesting that age and strength of memory may not be insurmountable barriers. Translating findings from basic science, to human experiments, to clinical applications and back again, can potentially unlock powerful new treatments for the many people who suffer daily from anxiety disorders.
A phase transition caught in mid-course: independent and concomitant analyses of the monoclinic and triclinic structures of (nBu4N)[Co(orotate)2(bipy)]·3H2O
Authors: Castro Miguel , Falvello Larry R. , Forcén-Vázquez Elena , Guerra Pablo , Al-Kenany Nuha A. , Martínez Gema , Tomás Milagros
Published: August 2017

The preparation and characterization of thenBu4N+salts of two bis-orotate(2−) complexes of cobalt, namely bis(tetra-n-butylammonium) diaquabis(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ide-6-carboxylato-κ2N1,O6)cobalt(II) 1.8-hydrate, (C16H36N)2[Co(C5H2N2O4)2(H2O)2]·1.8H2O, (1), and tetra-n-butylammonium (2,2′-bipyridine-κ2N,N′)bis(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ide-6-carboxylato-κ2N1,O6)cobalt(III) trihydrate, (C16H36N)[Co(C5H2N2O4)2(C10H8N2)]·3H2O, (2), are reported. The CoIIIcomplex, (2), which is monoclinic at room temperature, presents a conservative single-crystal-to-single-crystal phase transition below 200 K, producing a triclinic twin. The transition, which involves a conformational change in one of thenBu groups of the cation, is reversible and can be cycled. Both end phases have been characterized structurally and the system was also characterized structurally in a two-phase intermediate state, using single-crystal diffraction techniques, with both the monoclinic and triclinic phases present. Thermal analysis allows a rough estimate of the small energy content,viz.0.25 kJ mol−1, for both the monoclinic-to-triclinic transformation and the reverse transition, in agreement with the nature of the structural changes involving only thenBu4N+cation.
Mechanical design and error prediction of a flexible manipulator system applied in nuclear fusion environment
Authors: Shi Shanshuang , Wu Huapeng , Song Yuntao , Handroos Heikki
Published: August 2017

Purpose

The purpose of this paper is to introduce a development and error modeling of a serial redundant manipulator system applied in nuclear fusion environment. Detailed mechanical design of vacuum-compatible arms and actuators are presented, and manipulator flexibility is studied through experiments and model identification algorithm to evaluate the deformation.

Design/methodology/approach

First, the manipulator is designed to be several modular segments to obtain enough and flexible workspace inside the fusion device with narrow and complex geometries. Joint actuators with “rotation-linear-rotation” chains are developed to provide both huge reduction ratios and vacuum sealing. The redundant manipulator system has 11 degree of freedoms in total with a storage cask system to dock with the device vacuum vessel. In addition, to improve the position accuracy, an error prediction model is built based on the experimental study and back-propagation neural network (BPNN) algorithm.

Findings

Currently, the implementation of the manipulator system has been successfully carried out in both atmosphere and vacuum condition. Excellent performance indicates that the mechanical design is suitable. The validation of BPNN model shows an acceptable prediction accuracy (94∼98 per cent) compared with the real measurement.

Originality/value

This is a special robot system which is practically used in a nuclear fusion device in China. It will allow remote inspection and maintenance of plasma facing components in the vacuum vessel of fusion device without breaking the ultra-high vacuum condition during physical experiments. Its design, mechanism and error prediction strategy have great reference values to the similar robots in vacuum and temperature applications.
Study on dual peg-in-hole insertion using of constraints formed in the environment
Authors: Su Jianhua , Li Rui , Qiao Hong , Xu Jing , Ai Qinglin , Zhu Jiankang
Published: August 2017

Purpose

The purpose of this paper is to develop a dual peg-in-hole insertion strategy. Dual peg-in-hole insertion is the most common task in manufacturing. Most of the previous work develop the insertion strategy in a two- or three-dimensional space, in which they suppose the initial yaw angle is zero and only concern the roll and pitch angles. However, in some case, the yaw angle could not be ignored due to the pose uncertainty of the peg on the gripper. Therefore, there is a need to design the insertion strategy in a higher-dimensional configuration space.

Design/methodology/approach

In this paper, the authors handle the insertion problem by converting it into several sub-problems based on the attractive region formed by the constraints. The existence of the attractive region in the high-dimensional configuration space is first discussed. Then, the construction of the high-dimensional attractive region with its sub-attractive region in the low-dimensional space is proposed. Therefore, the robotic insertion strategy can be designed in the subspace to eliminate some uncertainties between the dual pegs and dual holes.

Findings

Dual peg-in-hole insertion is realized without using of force sensors. The proposed strategy is also used to demonstrate the precision dual peg-in-hole insertion, where the clearance between the dual-peg and dual-hole is about 0.02 mm.

Practical implications

The sensor-less insertion strategy will not increase the cost of the assembly system and also can be used in the dual peg-in-hole insertion.

Originality/value

The theoretical and experimental analyses for dual peg-in-hole insertion are proposed without using of force sensor.
The role of social capital in the perception of images of the Islamic State
Authors: Koshkin Andrey Petrovich , Zhidkih Vladimir Aleksandrovich , Novikov Andrey Vadimovich
Published: August 2017

Purpose

The terrorism of “Islamic State” (IS) is increasingly coming to be seen as a complicated and complex phenomenon permeated with various political goals and personal interests. The effectiveness of terrorist recruiters determines the need to identify the reasons for the appeal of the IS image and for the effectiveness of IS propaganda in different population layers and social groups. From this perspective, it is crucial to identify the significant social factors that are most affecting the perception of the terrorist activities of “IS” and their role in creating and shaping IS images. The purpose of this paper is to determine the role of social capital in the perception of the IS image.

Design/methodology/approach

The study is based on the findings of a sociological survey of a sample comprising 881 Russian students. In this research, six scales were used to identify the attitude of Russian students toward IS: informational awareness of IS; the image of IS fighters; the image of IS as an organization; attitude to an anti-terrorist policy; the role of the mass media; the level of social capital. Factorial analysis of the main components was conducted for each of the scales.

Findings

Subsequently, the correlation analysis of the relationship of social capital to the perception of the image of “IS” was conducted. Six main IS images were identified in the minds of the students. The research results show that survey participants with high levels of social capital are significantly more negative in their perception of the activities of the terrorist organization in question.

Originality/value

From this perspective, it is crucial to identify the significant social factors that are most affecting the perception of the terrorist activities of “IS” and their role in creating and shaping IS images. This study focuses on determining the role of social capital in the perception of the IS image.
Direct and mediated associations among earnings quality, book-tax differences and the audit quality
Authors: Riguen Koubaa Rakia , Jarboui Anis
Published: August 2017

Purpose

The purpose of this paper is to investigate the direct and indirect links between book-tax differences (BTDs) and audit quality using accounting conservatism (proxy of earnings quality). Hence, this paper seeks to extend prior audit quality research.

Design/methodology/approach

This study uses a sample of Tunisian listed firms on the Tunis Stock Exchange and operating in the industrial and commercial sectors during 2005-2012. This investigation is motivated by structural equations system models that specify both a direct link and an indirect link that is mediated by information reflected in BTDs.

Findings

The results show that for the Tunisians companies, firms with large BTDs are associated with higher audit quality implies that such BTDs represent an observable proxy for earnings quality that affects auditor decisions. The authors find statistically an indirect link between abnormal BTDs and audit quality that is mediated by earnings quality. The current study also provides evidence that information reflected in BTDs can improve audit quality.

Practical implications

The findings may be of interest to the academic researchers, practitioners and regulators who are interested in discovering the informational value of BTDs in the audit process.

Originality/value

This paper extends the existing literature by examining the mediation effect of information reflected in BTDs on relationship between BTDs and audit quality.