bluuebunny/crossref_metadata_2025 huggingface dataset:
Backward evolution from gene network dynamics
Authors: Belete Merzu Kebede , Charlebois Daniel A. , Balázsi Gábor
Published: July 2018

Gene expression is controlled by regulator genes that together with effector genes form gene regulatory networks. How mutation in the genes comprising gene regulatory networks influences cell population dynamics has not been adequately investigated. In this study, we develop mathematical models to study how a mutation in a regulator gene that reaches the effector gene with a time delay affects short-term and long-term population growth. Using theory and experiment, we find a paradoxical outcome of evolution where a mutation in a regulator gene leads to an interaction between gene regulatory network and population dynamics, causing in certain cases a permanent decrease in population fitness in a constant environment.

Significance Statement

The properties of a cell are largely the products of its proteins, synthesized at rates depending on the regulation of protein coding genes. Single-cell measurements show that genetically identical cells can differ radically in their protein levels, partially due to the random production and degradation of proteins. It is currently unknown how mutants arise and spread in populations affected by such biological variability. We use computer simulations and evolution experiments to study how a mutant spreads in a population that carries a synthetic drug resistance gene network. Our results show for the first time a paradoxical outcome of evolution, where an initially beneficial mutation can interact with gene regulatory network dynamics and cause a permanent decrease in population fitness in the same environment.
The structural complexity of the Gammaproteobacteria flagellar motor is related to the type of its torque-generating stators
Authors: Kaplan Mohammed , Ghosal Debnath , Subramanian Poorna , Oikonomou Catherine M. , Kjær Andreas , Pirbadian Sahand , Ortega Davi R. , El-Naggar Mohamed Y. , Jensen Grant J.
Published: July 2018

The bacterial flagellar motor is a cell-envelope-embedded macromolecular machine that functions as a propeller to move the cell. Rather than being an invariant machine, the flagellar motor exhibits significant variability between species, allowing bacteria to adapt to, and thrive in, a wide range of environments. For instance, different torque-generating stator modules allow motors to operate in conditions with different pH and sodium concentrations and some motors are adapted to drive motility in high-viscosity environments. How such diversity evolved is unknown. Here we use electron cryo-tomography to determine thein situmacromolecular structures of the flagellar motors of three Gammaproteobacteria species:Legionella pneumophila,Pseudomonas aeruginosa, andShewanella oneidensisMR-1, providing the first views of intact motors with dual stator systems. Complementing our imaging with bioinformatics analysis, we find a correlation between the stator system of the motor and its structural complexity. Motors with a single H+-driven stator system have only the core P- and L-rings in their periplasm; those with dual H+-driven stator systems have an extra component elaborating their P-ring; and motors with Na+- (or dual Na+-H+)- driven stator systems have additional rings surrounding both their P- and L-rings. Our results suggest an evolution of structural complexity that may have enabled pathogenic bacteria likeL. pneumophilaandP. aeruginosato colonize higher-viscosity environments in animal hosts.
Reconstitution of a flexible SYCP3-DNA fibre suggests a mechanism for SYCP3 coating of the meiotic chromosome axis
Authors: Bollschweiler Daniel , Radu Laura , Plitzko Jürgen M. , Henderson Robert M. , Mela Ioanna , Pellegrini Luca
Published: July 2018

The synaptonemal complex (SC) keeps homologous chromosomes in close alignment during meiotic crossover. A hallmark of SC formation is the presence of its protein component SYCP3 on the chromosome axis. As SC assembly progresses, SYCP3 is deposited on both axes of the homologue pair, forming the lateral element (LE) in the tripartite structure of the mature SC. We have used cryo-electron tomography and atomic force microscopy to study the mechanism of assembly and DNA binding of the SYCP3 fibre. We find that the three-dimensional architecture of the fibre is built on a highly irregular arrangement of SYCP3 molecules displaying very limited local geometry. Interaction between SYCP3 molecules is driven by the intrinsically disordered tails of the protein, with no contact between the helical cores, resulting in a flexible fibre assembly. We demonstrate that the SYCP3 fibre can engage in extensive interactions with DNA, indicative of an efficient mechanism for incorporation of DNA within the fibre. Taken together, our findings suggest that, upon deposition on the chromosome axis, SYCP3 spreads by polymerising into a fibre that is fastened to the chromosome surface via DNA binding. The resulting layer of SYCP3 coating the chromosome axis might provide a structural basis for LE assembly in meiotic prophase.
Structural Determinants of the Interactions Between Influenza A Virus Matrix Protein M1 and Lipid Membranes
Authors: Höfer C.T. , Di Lella S. , Dahmani I. , Jungnick N. , Bordag N. , Bobone S. , Huang Q. , Keller S. , Herrmann A. , Chiantia S.
Published: July 2018

Influenza A virus is a pathogen responsible for severe seasonal epidemics threatening human and animal populations every year. One of the ten proteins encoded by the viral genome, the matrix protein M1, is abundantly produced in infected cells and plays a structural role in determining the morphology of the virus. During assembly of new viral particles, M1 is recruited to the host cell membrane where it associates with lipids and other viral proteins. The structure of M1 is only partially known. In particular, structural details of M1 interactions with the cellular plasma membrane as well as M1–protein interactions and multimerization have not been clarified, yet.

In this work, we employed a set of complementary experimental and theoretical tools to tackle these issues. Using raster image correlation, surface plasmon resonance and circular dichroism spectroscopies, we quantified membrane association and oligomerization of full-length M1 and of different genetically engineered M1 constructs (i.e., N- and C-terminally truncated constructs and a mutant of the polybasic region, residues 95-105). Furthermore, we report novel information on structural changes in M1 occurring upon binding to membranes. Our experimental results are corroborated by an all-atom model of the full-length M1 protein bound to a negatively charged lipid bilayer.
Asymmetric effective connectivity between primate anterior cingulate and lateral prefrontal cortex revealed by electrical microstimulation
Authors: Nácher Verónica , Hassani Seyed Alireza , Womelsdorf Thilo
Published: July 2018

The anterior cingulate cortex (ACC) and lateral prefrontal cortex (IPFC) of the non-human primate show neural firing correlations and synchronize at theta and beta frequencies during the monitoring and shifting of attention. These functional interactions might be based on synaptic connectivity that is equally efficacious in both directions, but it might be that there are systematic asymmetries in connectivity consistent with reports of more effective inhibition within the ACC than IPFC, or with a preponderance of ACC projections synapsing onto inhibitory neurons in the IPFC. Here, we tested effective ACC-IPFC connectivity in awake monkeys and report systematic asymmetries in the temporal patterning and latencies of effective connectivity as measured using electrical microstimulation. We found that ACC stimulation triggered evoked fields (EFPs) were more likely to be multiphasic in the IPFC than in the reverse direction, with a large proportion of connections showing 2-4 inflection points resembling resonance in the 20-30 Hz beta frequency range. Stimulation of ACC → IPFC resulted, on average, in shorter-latency EFPs than IPFC → ACC. Overall, latencies and connectivity strength varied more than two-fold depending on the precise anterior-to-posterior location of the connections. These findings reveal systematic asymmetries in effective connectivity between ACC and IPFC in the awake non-human primate and document the spatial and temporal patchiness of effective synaptic connections. We speculate that measuring effective connectivity profiles will be essential for understanding how local synaptic efficacy and synaptic connectivity translates into functional neuronal interactions to support adaptive behaviors.
Facile real time detection of membrane colocalization of RAS superfamily GTPase proteins in living cells
Authors: Li Yao-Cheng , Wang Luke , Hayes Tikvah K. , Sutton Margie N. , Bast Robert C. , McCormick Frank , Der Channing J. , Wahl Geoffrey M.
Published: July 2018

Members of the RAS family of GTPases (KRAS4A, KRAS4B, HRAS, and NRAS) are the most frequently mutated oncogenes in human cancers. The CAAX motif in the C-terminal hypervariable region (HVR-CAAX domain) contains the cysteine residue that is critical for protein prenylation that enables RAS protein membrane localization, homodimer/oligomer formation, and activation of effector signaling and oncogenic activity. However, it remains unclear if RAS can interact with other prenylated proteins, and if so, how this impacts RAS function. Here we use a newly developed quantifiable Recombinase enhanced Bimolecular Luciferase Complementation strategy (ReBiL2.0) to investigate some of the requirements for RAS superfamily small GTPase protein interactions, and whether this requires cell membrane localization. ReBiL enables such analyses to be done at physiologic expression levels in living cells. Our results confirm that the C-terminal prenylated HVR-CAAX domain is sufficient to direct KRAS and heterologous proteins to colocalize in the cell membrane. We discovered that KRAS also colocalizes with a subset of small GTPase superfamily members including RAC1, RAC2 and DIRAS3 in a prenylation-dependent manner. KRAS colocalization or co-clustering with heterologous proteins can impact KRAS downstream signaling. ReBiL2.0 thus provides a rapid, simple and straightforward method to identify and characterize the colocalization of membrane-associated proteins and to discover agonists and antagonists thereof.
Bullous pemphigoid with hyperkeratosis and palmoplantar keratoderma: Three cases
Authors: Fania Luca , Didona Dario , Pacifico Valeria , Mariotti Feliciana , De Luca Naomi , Abeni Damiano , Mazzanti Cinzia , Di Zenzo Giovanni , Didona Biagio
Published: July 2018

The clinical features of bullous pemphigoid are extremely polymorphous. Several atypical forms of bullous pemphigoid have been described, and the diagnosis critically relies on immunopathological findings. We describe three bullous pemphigoid patients characterized by palmoplantar keratoderma, diffused hyperkeratotic cutaneous lesions and extremely high levels of immunoglobulin E serum. The diagnosis of bullous pemphigoid should be taken into account in patients presenting diffused hyperkeratotic cutaneous lesions and palmoplantar keratoderma, even in the absence of blisters. Alteration of the keratinization process, that could occur in patients with genetic mutations in desmosomal and hemidesmosomal genes, may also be due to circulating autoantibodies against hemidesmosomal proteins in these bullous pemphigoid patients.
Contribution of local rarity and climatic suitability to local extinction and colonization varies with species traits
Authors: White Hannah J. , Montgomery Ian W. , Lennon Jack J.
Published: July 2018

Changes in species distributions through local extinction and colonization events are a major consequence of climate change. The mechanisms underlying these processes, however, are yet to be fully understood.

We investigate the effects of climatic suitability and local rarity on local extinction and colonization of British birds. We test the hypothesis that local extinction and colonization on decadal scales are driven by both climatic suitability and the prevalence of the species within an area and that the balance between these two is affected by species traits.

We use spatially explicit conditional autoregressive models to determine the effect size of local rarity and climatic suitability (extracted from climate envelope models) on local extinction and colonization events. We then use phylogenetically constrained, generalized least‐square models to estimate the association of extinction and colonization predictors with body mass, clutch size and national range of each species.

Both local rarity and climatic suitability of an area contributed to local extinctions and colonizations, but the importance of these predictors varied between species. This interspecific variation was explained, in part, by species traits, in particular national range, which influenced the importance of local rarity and climatic suitability to both local extinction and colonization.

These results further our knowledge of the mechanisms underlying changes in species occupancy due to climate change. This can inform predictive models as well as contribute to more focussed avian conservation efforts.
Covalent Whey Protein–Rosmarinic Acid Interactions: A Comparison of Alkaline and Enzymatic Modifications on Physicochemical, Antioxidative, and Antibacterial Properties
Authors: Ali Mostafa , Keppler Julia K. , Coenye Tom , Schwarz Karin
Published: July 2018

The covalent interactions between whey protein isolate (WPI) and rosmarinic acid (RosA) at two different conditions, alkaline (pH 9) and enzymatic (in the presence of tyrosinase, PPO), at room temperature with free atmospheric air were studied. The conjugates formed between WPI and RosA were characterized in terms of their physicochemical and functional properties. The changes in protein structure were analyzed by intrinsic fluorescence and binding of 8‐anilino‐1‐naphthalenesulfonic acid. The findings show that the covalent interactions caused a decrease in free amino and thiol groups and tryptophan content at both conditions. The decrease at enzymatic conditions was lower than at alkaline conditions. In addition, modified WPI at alkaline conditions exhibited higher antioxidative capacity compared to the modification at enzymatic conditions. However, WPI modified at enzymatic condition showed mild antimicrobial activity against Staphylococcus aureus LMG 10147 and MU50 compared to WPI modified at alkaline conditions and unmodified WPI (control). The modified WPI can be used as multifunctional ingredient into various food products with an additional health promoting effect of the bound phenolic compounds.
Risk factors for intracranial hemorrhage during vitamin K antagonist therapy in patients with nonvalvular atrial fibrillation: A case‐control study
Authors: Zanella Luca , Zoppellaro Giacomo , Marigo Lucia , Denas Gentian , Padayattil Jose Seena , Pengo Vittorio
Published: July 2018

Background

Intracranial hemorrhage (ICH) is the most fearful side effect of oral anticoagulant therapy. It is still unclear which risk factor is involved in ICH during vitamin K antagonists (VKAs) treatment and if commonly used bleeding risk scores are able to predict ICH.

Purpose

Search for individual risk factors and bleeding risk scores (HAS‐BLED, ATRIA and ORBIT) associated with ICHs in patients with atrial fibrillation treated with VKAs.

Methods

This is a retrospective case‐control study in a single Thrombosis Center. During a 7‐year period, patients with nonvalvular atrial fibrillation (NVAF) who developed ICH during VKAs were identified as cases. Four control patients matched for gender, age and length of VKAs were assigned to each case. The association between considered risk factors and ICHs was evaluated using a linear logistic regression method and expressed as odds ratio. Receiver operator characteristic (ROC) curves to assess the predictive ability of bleeding risk scores HAS‐BLED, ATRIA and ORBIT were also evaluated.

Results

Fifty‐one cases of ICH, most of whom were 80 years of age or older (72.5%), were retrieved from the Thrombosis Center's database. Compared to 204 controls, no individual risk factors were associated with ICH. Poor ability to predict ICH was also found using ROC curves (C‐statistic for HAS‐BLED, ATRIA, and ORBIT were 0.55, 0.53 and 0.54, respectively).

Conclusions

ICHs during VKA therapy preferentially occur in very elderly patients. The risk of ICH is not predicted by the commonly used risk scores.
Say‐on‐pay judgements: the two‐strikes rule and the pay‐performance link
Authors: Liang Yimeng , Moroney Robyn , Rankin Michaela
Published: July 2018

We undertake an experiment to explore shareholder voting behaviour when the pay‐performance link is weak or strong; and when there has (has not) been a first strike in the preceding year. We find shareholders are more supportive of a remuneration package evidencing a strong pay‐performance link than a weak link. Further, shareholders are less supportive of a remuneration package when there has been a first strike in the preceding year than when there has not been a first strike. Importantly, we find that a first strike reduces the effect of the pay‐performance link on voting intentions.
Return windows and the value relevance of earnings
Authors: He Wen , Tan Hwee Cheng , Wong Leon
Published: July 2018

Research on the value relevance of annual earnings commonly accumulate stock returns over a 12‐month period starting from the fourth month of the fiscal year, resulting in a mismatch between the return window and the earnings period (i.e. the fiscal year). By comparing this return window with alternative windows, we show that the mismatch produces a downward bias in the estimated R2 from the regression of stock returns on earnings, especially for firms that announce earnings early. Our results also show that both profits and losses are more value relevant when announced earlier, supporting regulatory calls for timely disclosure.
Negative effects of an invasive grass, but not of native grasses, on plant species richness along a cover gradient
Authors: Dresseno André L. P. , Guido Anaclara , Balogianni Vasiliki , Overbeck Gerhard E.
Published: July 2018

Impacts of invasive plants on plant communities are not universal, and effects may differ depending on the life form of the invading species. At three sites in the Brazilian Pampa region, we assessed the effects of invasion by Eragrostis plana Nees, considered to be the most problematic invasive plant in South Brazilian grasslands, on local plant communities. Specifically, we evaluated effects on species richness, community evenness and richness of principal functional groups along an invasion gradient. Based on plant community data, we also evaluated the effects of dominant native species on the same plant community features, thus being able to assess the relative impacts of an invasive species compared to abundant native species. Eragrostis plana invasion reduced total plant richness, with some distinct effects regarding plant functional groups, and differently from other coexisting native species that did not show the same effects even when of high abundance. Grasses were the most affected plant group when E. plana cover increased, consistent with the limiting similarity hypothesis. Overall, our results indicate clear negative effects of this invasive plant on the grassland communities. Comparing the effects of an invasive species to those of coexisting natives is crucial for disentangling the real impact of an invader. Our results demonstrate that effects are consequence of species identity, and not only of high abundances.
Interactive effects of local and landscape factors on farmland carabids
Authors: Fusser Moritz S. , Holland John M. , Jeanneret Philippe , Pfister Sonja C. , Entling Martin H. , Schirmel Jens
Published: July 2018

As a result of migration and spillover from noncrop habitats, predacious insects in agricultural fields respond locally to adjacent field margins and on a larger spatial scale to habitats in the surrounding landscape. However, the relative importance of local and landscape effects and their possible interactions have rarely been studied.

We studied carabids in 18 pumpkin fields bordered by different field margins, along a gradient from simple to structural rich landscapes. Carabids were caught in pitfall traps along transects from the adjoining semi‐natural habitat towards the field centre.

Although estimated species richness generally increased towards the field edges, carabid abundance increased towards adjacent woody margins and other crop fields. By contrast, abundance decreased towards adjacent herbaceous margins. Estimated carabid species richness in organically managed fields increased with increasing landscape heterogeneity, whereas this effect was absent in conventional fields. However, estimated species richness did not differ between organic and conventional fields.

The differential response of carabid abundance to distance from the field edge in accordance with the type of field margin may explain the variability of patterns reported in the literature. The results of the present study show that both local and landscape parameters must be taken into account to promote carabids as natural enemies of crop pests.
Narcissism and Political Orientations
Authors: Hatemi Peter K. , Fazekas Zoltán
Published: July 2018

The connections between narcissism and political orientations have been theorized by scholars and increasingly evoked by political parties, politicians, public intellectuals, and the media. Yet surprisingly little research has been undertaken to empirically asses the veracity of these claims. We address this lacuna by identifying the relationship between narcissism, political ideologies, and partisanship in a nationally representative sample taken days before the 2016 U.S. presidential election. Overall, we find those on the left and right are equally narcissistic. However, liberals and conservatives differ in which dimensions drive their narcissism. Specifically, we find that the entitlement facet of narcissism is uniformly related to more conservative positions, whereas exhibitionism is related to more liberal values, including political party identification. Narcissism, as a complex multidimensional construct, has an important role in understanding political ideology.
Survey of Aboriginal smokers' and ex‐smokers’ knowledge, attitudes and behaviours in Central Australia 2016–2017
Authors: Wright Alyson
Published: July 2018

Objective

To examine tobacco knowledge, attitudes and behaviours of community members in Central Australia and to compare these by participant's location (town or remote community).

Design

Community‐based survey of 165 smokers and recent ex‐smokers.

Outcome measures

Knowledge was assessed using responses to questions on the health risk of smoking (e.g. lung cancer) and knowledge of quit support services. Attitudes towards smoking were assessed using statements that asked participant whether they agreed or disagreed. Smoking behaviours were assessed by asking participants about quit attempts, cigarettes per day and time to first cigarette (used to calculate the heaviness of smoking index).

Results

There were high levels of knowledge about most common diseases associated with smoking, including cancer (93%) and heart disease (89%). There was less knowledge about quit support services that are available through telephone (69%), online (27%) and apps (32%). Responses to attitude statements were suggestive of the normalised practices towards smoking in town and remote participants, with remote participants more likely to disagree that ‘ok to smoke close to a building’ and to disagree ‘if I had my time over again I would not have started’. Over 75% of the participants had attempted to quit smoking and 55% had a sustained quit attempt (>1 month).

Conclusion

There are greater challenges to reduce smoking in remote areas due to the social and communal practices of smoking and in providing service needs that encourage quit attempts. This supports the need for continued and increased investment for targeted tobacco control by remote health services.
Evaluation of a novel cricothyroidotomy introducer in a simulated obese porcine model: a randomised crossover comparison with scalpel cricothyroidotomy
Authors: Yeow C. , Greaney L. , Foy C. , King W. , Patel B.
Published: July 2018

The Difficult Airway Society 2015 guidelines for management of unanticipated difficulties in tracheal intubation in adults have generated much discussion regarding Plan D: emergency front‐of‐neck access with a scalpel‐bougie cricothyroidotomy technique. There is concern that this technique may not provide an adequate pathway for the bougie and subsequently the tracheal tube, especially in obese patients with deeper airway structures. This could lead to the formation of a false passage, trauma and failure. A novel cricothyroidotomy introducer, 8 mm wide and 170 mm long, with a sharp leading edge and guiding channel to pass a bougie into the trachea, has been designed to complement the scalpel cricothyroidotomy technique. A comparison study of the use of this novel introducer with the scalpel technique in a simulated obese porcine laryngeal model demonstrated shorter insertion times (median (IQR [range]) 85 (65–123 [48–224]) s vs. 84 (72–184 [46–377]) s, p = 0.030). All 26 (100%) participants successfully performed cricothyroidotomy in the introducer group, whereas only 24 (92%) participants were successful in the scalpel group. The introducer group required fewer attempts to access the trachea compared with the scalpel group (p = 0.046). False passages occurred eight (31%) times in the introducer group compared with 17 (65%) times in the scalpel group (p = 0.022). There were no statistical differences in tracheal trauma (p = 0.490), ease of use (p = 0.220) and device preference (p = 0.240). This novel cricothyroidotomy introducer has shown promising results in securing the airway in an emergency front‐of‐neck access situation. With robust training, this introducer could potentially be complementary to the scalpel‐bougie cricothyroidotomy technique.
The association of sex hormone‐binding globulin with mortality is mediated by age and testosterone in men with type 2 diabetes
Authors: Ramachandran S. , Strange R. C. , Fryer A. A. , Saad F. , Hackett G. I.
Published: July 2018

Background

Serum sex hormone‐binding globulin levels have been associated with mortality in adult men with type 2 diabetes (T2DM).

Objectives

To confirm the association of serum sex hormone‐binding globulin with mortality and then determine whether this association is mediated by age and total testosterone concentration.

Materials and Methods

We studied 364 men (median age: 66 years) with T2DM over a median follow‐up of 4.3 years using the Cox regression to study associations between sex hormone‐binding globulin, age, total testosterone, and mortality.

Results

Mortality was significantly and independently associated with sex hormone‐binding globulin, age, and total testosterone. In pairwise combinations of age and sex hormone‐binding globulin dichotomized by median values, the association of sex hormone‐binding globulin with mortality was age‐dependent. Relative to the combination of age >66 years/SHBG >35 nmol/L (mortality 22.5%), the other combinations were associated with significantly less mortality (mortality in men ≤66 years/SHBG ≤ 35 nmol/L was 3.23%). In men >66 years, SHBG ≤ 35 nmol/L was associated with decreased mortality (HR: 0.41, p = 0.037) compared with SHBG > 35 nmol/L. In men ≤66 years, there was no significant difference between those with sex hormone‐binding globulin above or below the median (HR: 1.73, p = 0.56, reference: SHBG ≤ 35 nmol/L). TT < 12 nmol/L was associated with increased mortality in both age categories. Men >66 years with the reference combination of SHBG > 35 nmol/L and TT < 12 nmol/L (36.84%) nmol/L had significantly higher mortality than those with SHBG > 35 nmol/L and TT ≥ 12 (18.06%) and those with SHBG ≤ 35 nmol/L and TT < 12 nmol/L (13.79%).

Discussion

Our data suggest sex hormone‐binding globulin and total testosterone have particular impact on mortality in men aged over 66 years. Further, in older men, the combination of high sex hormone‐binding globulin levels and low total testosterone is associated with greater risk than either high sex hormone‐binding globulin or low total testosterone individually.

Conclusions

Our findings are compatible with data suggesting the importance of sex hormone‐binding globulin lies in mediating free testosterone levels.
The cost of facing fear: Visual working memory is impaired for faces expressing fear
Authors: Curby Kim M. , Smith Stephen D. , Moerel Denise , Dyson Amy
Published: July 2018

Previous research has identified numerous factors affecting the capacity and accuracy of visual working memory (VWM). One potentially important factor is the emotionality of the stimuli to be encoded and held in VWM. We often must hold in VWM information that is emotionally charged, but much is still unknown about how the emotionality of stimuli impacts VWM performance. In the current research, we performed four studies examining the impact of fearful facial expressions on VWM for faces. Fearful expressions were found to produce a consistent cost to VWM performance. This cost was modulated by encoding time, but not set size. This cost was only present for faces in an upright orientation consistent with this cost being a product of the emotionality of the faces rather than lower‐level perceptual differences between neutral and fearful faces. These findings are discussed in the context of existing theoretical accounts of the impact of emotion on information processing. We suggest that a number of competing effects drive both costs and benefits and are at play when emotional information must be stored in VWM, with the task context determining the balance between them.
Erosion rates of 3.5‐cm artificial urinary sphincter cuffs are similar to larger cuffs
Authors: McKibben Maxim J. , Shakir Nabeel , Fuchs Joceline S. , Scott Jeremy M. , Morey Allen F.
Published: July 2018

Objective

To compare long‐term outcomes and erosion rates of 3.5‐cm artificial urinary sphincter (AUS) cuffs vs larger cuffs amongst men with stress urinary incontinence (SUI), with and without a history of pelvic radiotherapy (RT).

Patients and methods

We reviewed the records of all men who underwent AUS placement by a single surgeon between September 2009 and June 2017 at our tertiary urban medical centre. A uniform perineal approach was used to ensure cuff placement around the most proximal corpus spongiosum after precise spongiosal measurement. Patients were stratified by cuff size and RT status, and patient demographics and surgical outcomes were analysed. Cases of AUS revision in which a new cuff was not placed were excluded. Success was defined as patient‐reported pad use of ≤1 pad/day.

Results

Amongst 410 cases included in the analysis, the 3.5‐cm cuff was used in 166 (40.5%), whilst 244 (59.5%) received larger cuffs (≥4.0 cm). Over a median follow‐up of 50 months, there was AUS cuff erosion in 44 patients at a rate nearly identical in the 3.5‐cm cuff (10.8%, 18/166) and the ≥4‐cm cuff groups (10.7%, 26/244, P = 0.7). On multivariate logistic regression, clinical factors associated with AUS cuff erosion included a history of pelvic RT, prior AUS cuff erosion, prior urethroplasty, and a history of inflatable penile prosthesis (IPP) placement. Patient demographics were similar between the cuff‐size groups; including age, body mass index, comorbidities, smoking history, RT history, prior AUS, and prior IPP placement. Continence rates were high amongst all AUS patients, with similar success in both groups (82% for 3.5‐cm cuff, 90% for ≥4‐cm cuff, P = 0.1).

Conclusions

After 8 years of experience and extended follow‐up, the outcomes of the 3.5‐cm AUS cuff appear to be similar to ≥4‐cm cuffs for effectiveness and rates of urethral erosion. RT patients have a higher risk of cuff erosion regardless of cuff size.
Early and rapid prediction of postoperative infections following percutaneous nephrolithotomy in patients with complex kidney stones
Authors: Chen Dong , Jiang Chonghe , Liang Xiongfa , Zhong Fangling , Huang Jian , Lin Yongping , Zhao Zhijian , Duan Xiaolu , Zeng Guohua , Wu Wenqi
Published: July 2018

Objectives

To obtain more accurate and rapid predictors of postoperative infections following percutaneous nephrolithotomy (PCNL) in patients with complex kidney stones, and provide evidence for early prevention and treatment of postoperative infections.

Patients and Methods

A total of 802 patients with complex kidney stones who underwent PCNL, from September 2016 to September 2017, were recruited. Urine tests, urine cultures (UCs) and stone cultures (SCs) were performed, and the perioperative data were prospectively recorded.

Results

In all, 19 (2.4%) patients developed postoperative urosepsis. A multivariate logistic regression analysis revealed that an operating time of ≥100 min, urine test results with both positive urine white blood cells (WBC+) and positive urine nitrite (WBC+NIT+), positive UCs (UC+), and positive SCs (SC+) were independent risk factors of urosepsis. The incidence of postoperative urosepsis was higher in patients with WBC+NIT+ (10%) or patients with both UC+ and SC+ (UC+SC+; 8.3%) than in patients with negative urine test results or negative cultures (P < 0.01). Preoperative WBC+NIT+ was predictive of UC+SC+, with an accuracy of >90%. The main pathogens found in kidney stones were Escherichia coli (44%), Proteus mirabilis (14%) and Staphylococcus (7.4%); whilst the main pathogens found in urine were E. coli (54%), Enterococcus (9.4%) and P. mirabilis (7.6%). The incidence of E. coli was more frequent in the group with urosepsis than in the group without urosepsis (P < 0.05).

Conclusions

WBC+NIT+ in preoperative urine tests could be considered as an early and rapid predictor of UC+SC+ and postoperative urosepsis. Urosepsis following PCNL was strongly associated with E. coli infections in patients with complex kidney stones.
Stimulation of brain nicotinic acetylcholine receptors activates adrenomedullary outflow via brain inducible NO synthase‐mediated S‐nitrosylation
Authors: Higashi Youichirou , Shimizu Takahiro , Yamamoto Masaki , Tanaka Kenjiro , Yawata Toshio , Shimizu Shogo , Zou Suo , Ueba Tetsuya , Yuri Kazunari , Saito Motoaki
Published: July 2018

Background and Purpose

We have demonstrated that i.c.v.‐administered (±)‐epibatidine, a nicotinic ACh receptor (nAChR) agonist, induced secretion of noradrenaline and adrenaline (catecholamines) from the rat adrenal medulla with dihydro‐β‐erythroidin (an α4β2 nAChR antagonist)‐sensitive brain mechanisms. Here, we examined central mechanisms for the (±)‐epibatidine‐induced responses, focusing on brain NOS and NO‐mediated mechanisms, soluble GC (sGC) and protein S‐nitrosylation (a posttranslational modification of protein cysteine thiol groups), in urethane‐anaesthetized (1.0 g·kg−1, i.p.) male Wistar rats.

Experimental Approach

(±)‐Epibatidine was i.c.v. treated after i.c.v. pretreatment with each inhibitor described below. Then, plasma catecholamines were measured electrochemically after HPLC. Immunoreactivity of S‐nitrosylated cysteine (SNO‐Cys) in α4 nAChR subunit (α4)‐positive spinally projecting neurones in the rat hypothalamic paraventricular nucleus (PVN, a regulatory centre of adrenomedullary outflow) after i.c.v. (±)‐epibatidine administration was also investigated.

Key Results

(±)‐Epibatidine‐induced elevation of plasma catecholamines was significantly attenuated by L‐NAME (non‐selective NOS inhibitor), carboxy‐PTIO (NO scavenger), BYK191023 [selective inducible NOS (iNOS) inhibitor] and dithiothreitol (thiol‐reducing reagent), but not by 3‐bromo‐7‐nitroindazole (selective neuronal NOS inhibitor) or ODQ (sGC inhibitor). (±)‐Epibatidine increased the number of spinally projecting PVN neurones with α4‐ and SNO‐Cys‐immunoreactivities, and this increment was reduced by BYK191023.

Conclusions and Implications

Stimulation of brain nAChRs can induce elevation of plasma catecholamines through brain iNOS‐derived NO‐mediated protein S‐nitrosylation in rats. Therefore, brain nAChRs (at least α4β2 subtype) and NO might be useful targets for alleviation of catecholamines overflow induced by smoking.
Analgesic effects of ASP3662, a novel 11β‐hydroxysteroid dehydrogenase 1 inhibitor, in rat models of neuropathic and dysfunctional pain
Authors: Kiso Tetsuo , Sekizawa Toshihiro , Uchino Hiroshi , Tsukamoto Mina , Kakimoto Shuichiro
Published: July 2018

Background and Purpose

Glucocorticoids are a major class of stress hormones known to participate in stress‐induced hyperalgesia. Although 11β‐hydroxysteroid dehydrogenase 1 (11β‐HSD1) is a key enzyme in the intracellular regeneration of glucocorticoids in the CNS, its role in pain perception has not been assessed. Here, we examined the effects of ASP3662, a novel 11β‐HSD1 inhibitor, on neuropathic and dysfunctional pain.

Experimental Approach

The enzyme inhibitory activities and pharmacokinetics of ASP3662 were examined, and its antinociceptive effects were evaluated in models of neuropathic pain, fibromyalgia and inflammatory pain in Sprague‐Dawley rats.

Key Results

ASP3662 inhibited human, mouse and rat 11β‐HSD1 but not human 11β‐HSD2, in vitro. ASP3662 had no significant effect on 87 other possible targets (enzymes, transporters and receptors). ASP3662 inhibited in vitro conversion of glucocorticoid from its inactive to active form in extracts of rat brain and spinal cord. Pharmacokinetic analysis in Sprague‐Dawley rats showed that ASP3662 has CNS‐penetrability and long‐lasting pharmacokinetic properties. Single oral administration of ASP3662 ameliorated mechanical allodynia in spinal nerve ligation (SNL) and streptozotocin‐induced diabetic rats and thermal hyperalgesia in chronic constriction nerve injury rats. ASP3662 also restored muscle pressure thresholds in reserpine‐induced myalgia rats. Intrathecal administration of ASP3662 was also effective in SNL rats. However, ASP3662 had no analgesic effects in adjuvant‐induced arthritis rats.

Conclusions and Implications

ASP3662 is a potent, selective and CNS‐penetrable inhibitor of 11β‐HSD1. The effects of ASP3662 suggest that selective inhibition of 11β‐HSD1 may be an attractive approach for the treatment of neuropathic and dysfunctional pain, as observed in fibromyalgia.
Calprotectin protects against experimental colonic inflammation in mice
Authors: Aranda Carlos J , Ocón Borja , Arredondo‐Amador María , Suárez María Dolores , Zarzuelo Antonio , Chazin Walter J , Martínez‐Augustin Olga , Sánchez de Medina Fermín
Published: July 2018

Background and Purpose

Calprotectin is a heterodimer composed of two myeloid‐related proteins, S100A8 and S100A9, that is abundant in neutrophils and monocytes/macrophages. Faecal levels of calprotectin are used routinely to monitor inflammatory bowel disease activity.

Experimental Approach

We aimed to assess the role of calprotectin in intestinal inflammation, using the dextran sulfate sodium model of colitis in mice. Calprotectin was administered (50 or 100 μg·day−1) by the intrarectal or by i.p. injection (50 μg·day−1 only). The condition of the mice was characterized by morphological and biochemical methods.

Key Results

Intrarectal calprotectin protected significantly against colitis, as shown by lower levels of macroscopic and microscopic damage, colonic myeloperoxidase activity and decreased expression of TNFα and toll‐like receptor 4. IL‐17 production by spleen and mesenteric lymph node cells was reduced. Calprotectin had no effect on body weight loss or colonic thickening. There were no effects of calprotectin after i.p. injection. Calprotectin had virtually no effects in control, non‐colitic mice. Calprotectin had almost no effect on the colonic microbiota but enhanced barrier function. Treatment of rat IEC18 intestinal epithelial cells in vitro with calprotectin induced output of the chemokines CXL1 and CCL2, involving the receptor for advanced glycation end products‐ and NFκB.

Conclusion and Implications

Calprotectin exerted protective effects in experimental colitis when given by the intrarectal route, by actions that appear to involve effects on the epithelium.
The power of the Mediator complex—Expanding the genetic architecture and phenotypic spectrum of MED12‐related disorders
Authors: Charzewska A. , Maiwald R. , Kahrizi K. , Oehl‐Jaschkowitz B. , Dufke A. , Lemke J.R. , Enders H. , Najmabadi H. , Tzschach A. , Hachmann W. , Jensen C. , Bienek M. , Poznański J. , Nawara M. , Chilarska T. , Obersztyn E. , Hoffman‐Zacharska D. , Gos M. , Bal J. , Kalscheuer V.M.
Published: July 2018

MED12 is a member of the large Mediator complex that controls cell growth, development, and differentiation. Mutations in MED12 disrupt neuronal gene expression and lead to at least three distinct X‐linked intellectual disability syndromes (FG, Lujan‐Fryns, and Ohdo). Here, we describe six families with missense variants in MED12 (p.(Arg815Gln), p.(Val954Gly), p.(Glu1091Lys), p.(Arg1295Cys), p.(Pro1371Ser), and p.(Arg1148His), the latter being first reported in affected females) associated with a continuum of symptoms rather than distinct syndromes. The variants expanded the genetic architecture and phenotypic spectrum of MED12‐related disorders. New clinical symptoms included brachycephaly, anteverted nares, bulbous nasal tip, prognathism, deep set eyes, and single palmar crease. We showed that MED12 variants, initially implicated in X‐linked recessive disorders in males, may predict a potential risk for phenotypic expression in females, with no correlation of the X chromosome inactivation pattern in blood cells. Molecular modeling (Yasara Structure) performed to model the functional effects of the variants strongly supported the pathogenic character of the variants examined. We showed that molecular modeling is a useful method for in silico testing of the potential functional effects of MED12 variants and thus can be a valuable addition to the interpretation of the clinical and genetic findings.
Late recurrent bleeding episodes from duodenojejunostomy after pancreas transplantation
Authors: Messner Franka , Bösmüller Claudia , Oberhuber Rupert , Maglione Manuel , Cardini Benno , Resch Thomas , Scheidl Stefan , Öfner Dietmar , Schneeberger Stefan , Margreiter Christian
Published: July 2018

In response to a number of late, repetitive bleeding episodes from the site of the enteric anastomosis, we herein analyze the clinical courses and etiologies of 379 consecutively performed pancreas transplants between January 2000 and December 2016. Duodenojejunostomies for enteric drainage were performed at the upper jejunum in a side to side, double layer fashion. Five patients (1.3%) developed recurrent late hemorrhagic episodes originating from the graft duodenal anastomosis. Bleeding from the anastomotic site was associated with hematochezia, hemodynamic instability and decrease in serum hemoglobin. Mean onset was 6.4(±2.8) years after transplantation. Bleeding was recurrent (mean 5.2 ± 2.6) and required 9(±2.5) interventions. Hypervascularization, mucosal vulnerability, and bleeding at the site of the enteric anastomosis could be identified in all cases. In four patients, the enteric pancreas anastomosis was resected and a new duodenojejunostomy was performed. No pancreas graft loss occurred due to bleeding. In two patients, hepatic cirrhosis and portal hypertension were identified, one patient had a liver fibrosis as putative cause for the repetitive bleeding episodes. Late anastomotic hemorrhage is a rare but severe complication following pancreas transplantation. The treatment is challenging and includes endoscopy, interventional radiology, and surgery. Hepatic conditions with an increased portal pressure may be the underlying cause.
Expression of phosphatase and tensin homologue in imprint smears of endometrial carcinoma
Authors: Kosmas Konstantinos , Mitropoulou Georgia , Provatas Ioannis , Stamoulas Marios , Marouga Anna
Published: July 2018

Objective

The aims of this study were to determine the expression of phosphatase and tensin homologue (PTEN) in endometrial adenocarcinomas (as a potential prognostic indicator before treatment) in imprint smears and to correlate the results with clinicopathological parameters of primary untreated endometrial cancer patients.

Methods

A total of 126 patients with endometrial carcinoma were evaluated with samples freshly resected after a total abdominal hysterectomy during a 29‐month period. The expression of PTEN was assessed by immunocytochemistry.

Results

In total, 102 cases were type I and 24 type II endometrial adenocarcinomas. High expression of PTEN was more frequent in type I (42/102) compared to type II (6/24) adenocarcinomas, to less advanced and aggressive clinical stage (stage I: 41/79, stage II: 5/13, stage III: 2/19, stage IV: 1/15) as well as in low grade (grade 1: 26/42, grade 2: 20/57) compared to high‐grade (grade 3: 8/27) carcinomas. The nonaffected lymph nodes showed high expression of PTEN (in 43.3%) than the affected lymph nodes (in 5.9%). Also, in 45 out of 74 cases with myometrial invasion <50%, there was positive expression of PTEN in contrast to 12 out of 52 cases with depth of myometrial invasion >50%.

Conclusions

Immunocytochemical findings from PTEN stain, in addition to cytomorphological features, appeared to be a useful marker in the diagnosis and in the postoperative prognosis of endometrial carcinoma in endometrial cytology with imprint smears and that high PTEN expression is related to morphological features of less aggressiveness tumours.
Cytomorphological clues for a correct diagnosis of anaplastic lymphoma kinase‐positive large B‐cell lymphoma
Authors: Guleria Prerna , Mallick Saumya Ranjan , Ramteke Prashant , Jain Deepali
Published: July 2018

Suspicion of ALK+LBCL should be high whenever lymph node aspirates reveal malignant cells with immunoblast‐like morphology and accompanying amorphous extracellular eosinophilic/ magenta coloured material. The importance of considering all cytological details including important background findings while assessing cytological samples is emphasized in this case report.
Donor cell‐derived acute promyelocytic leukemia after allogeneic hematopoietic stem cell transplantation
Authors: Bouvier Anne , Ribourtout Bénédicte , François Sylvie , Orvain Corentin , Luque Paz Damien , Beucher Annaëlle , Guérard Alexandre , Guardiola Philippe , Ugo Valérie , Blanchet Odile , Geneviève Franck , Schmidt Aline , Hunault‐Berger Mathilde
Published: July 2018

Donor cell leukemia (DCL) is an infrequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). Its true incidence is difficult to assess, although improvements in chimerism studies contributed to a better diagnosis of DCL. We report two rare cases of donor cell‐derived acute promyelocytic leukemia (APL). To our knowledge, only two cases have been described in the literature. Here, we report one male and one female patients with acute myeloid leukemia (AML), who developed an APL in donor cells after HSCT. The latency between HSCT and DCL was 279 and 43 months, respectively. Fluorescent in situ hybridation and chimerism monitoring analysis proved the donor origin of APL. Surprisingly, donor lymphocyte infusion provided a hematological response during 19 months in the female patient. The mechanisms associated with pathogenesis of DCL are unclear and seem to be multifactorial. Increasing worldwide allogeneic hematopoietic stem cell transplantation activity and potentially the age of donor could explain the increasing incidence of DCL in the future. It is highlighted that long‐term follow up of recipients will allow to report all cases of DCL, to clarify the genetic landscape and factors which contribute to DCL, to understand the response to DLI.