bluuebunny/crossref_metadata_2025 huggingface dataset:
CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice
Authors: Bernard-Valnet Raphaël , Yshii Lidia , Quériault Clémence , Nguyen Xuan-Hung , Arthaud Sébastien , Rodrigues Magda , Canivet Astrid , Morel Anne-Laure , Matthys Arthur , Bauer Jan , Pignolet Béatrice , Dauvilliers Yves , Peyron Christelle , Liblau Roland S.
Published: September 2016

Significance

Narcolepsy with cataplexy is a sleep disorder characterized by excessive daytime sleepiness and sudden loss of muscle tone. These clinical manifestations are the result of selective loss of a neuronal population producing orexin. The etiology of the disease remains elusive, although converging evidence points to a key involvement of the immune system. We developed an animal model to study the autoimmune processes at play in narcolepsy. We demonstrate that cytotoxic CD8 T cells, but not Th1 CD4 cells, are able to target and destroy orexinergic neurons. This selective neuronal loss is responsible for clinical signs mimicking human narcolepsy. By identifying potential immune effectors of the immunopathological process in narcolepsy, these findings offer a rationale for the use of immunotherapies.
Molecular determinants of cadherin ideal bond formation: Conformation-dependent unbinding on a multidimensional landscape
Authors: Manibog Kristine , Sankar Kannan , Kim Sun-Ae , Zhang Yunxiang , Jernigan Robert L. , Sivasankar Sanjeevi
Published: September 2016

Significance

Multicellular assemblies rely on the robust binding of classical cadherin cell–cell adhesion proteins to maintain their integrity and withstand mechanical stress. Cadherins can form adhesive interactions that are insensitive to tugging forces; however, the biophysical mechanism for cadherin force insensitivity is unknown. Here, we integrate single-molecule biophysical measurements with computer simulations to show that cadherins, which are known to bind in two distinct conformations, adopt an intermediate structure as they transition between their alternate conformations. When this intermediate structure is pulled, it unbinds along a force-independent pathway that makes it insensitive to tugging forces. Force-independent unbinding is blocked when cadherins associate laterally, suggesting a physical mechanism by which mechanical force enhances cadherin clustering on the cell surface.
Tuning electronic transport via hepta-alanine peptides junction by tryptophan doping
Authors: Guo Cunlan , Yu Xi , Refaely-Abramson Sivan , Sepunaru Lior , Bendikov Tatyana , Pecht Israel , Kronik Leeor , Vilan Ayelet , Sheves Mordechai , Cahen David
Published: September 2016

Significance

Charge transport is a process that is central to redox reactions, enzyme catalysis, and electronics. Integrating biomolecules into electronic devices provides a route to using natural evolution in artificial technology. Charge transport across biomolecules depends on the molecular structure and molecule–electrode contacts. We show that “doping” (7-alanine) peptide-based devices by one tryptophan enhances transport ≥10-fold, regardless of tryptophan position, a result that can be described by superexchange-mediated tunneling through multiple sites. Remarkably, close physical proximity of tryptophan to a gold electrode further enhances transport, showing how crucial electronic coupling to the electrode is. Our results provide insight into charge transfer through biomolecules and offer a strategy for tailored bioelectronics by mix-and-match amino acid building blocks.
Engineering
Yarrowia lipolytica
as a platform for synthesis of drop-in transportation fuels and oleochemicals
Authors: Xu Peng , Qiao Kangjian , Ahn Woo Suk , Stephanopoulos Gregory
Published: September 2016

Significance

Cost-efficient production of fuels and oleochemicals requires the host strain to be highly lipogenic and suitable for large-scale production. We demonstrate that
Yarrowia lipolytica
represents a promising biorefinery platform for sustainable production of drop-in transportation fuels and oleochemicals. Understanding the mechanistic details of the lipogenic phenotype, particularly the cellular compartmentalization of distinct metabolic pathways, fatty acid synthase structure, activating free fatty acids to acyl-CoAs, and decoupling nitrogen starvation from lipogenesis, allowed us to efficiently produce fatty acid ethyl esters, fatty alkanes, medium chain-length fatty acids, fatty alcohols, and triacylglycerides (TAGs). We envision that this report constitutes foundational work in developing an oleaginous yeast platform to upgrade low-value carbons to high-value fuels and oleochemicals in the foreseeable future.
GIV/Girdin activates Gαi and inhibits Gαs via the same motif
Authors: Gupta Vijay , Bhandari Deepali , Leyme Anthony , Aznar Nicolas , Midde Krishna K. , Lo I-Chung , Ear Jason , Niesman Ingrid , López-Sánchez Inmaculada , Blanco-Canosa Juan Bautista , von Zastrow Mark , Garcia-Marcos Mikel , Farquhar Marilyn G. , Ghosh Pradipta
Published: September 2016

Significance

Guanine nucleotide-binding (G) protein α subunit (Gα)-interacting vesicle-associated protein (GIV)/Girdin has previously been shown to serve as a guanine nucleotide exchange factor (GEF) for the Gα activity-inhibiting polypeptide 1 (Gαi) via a conserved motif in its C terminus. Here we show that this motif serves as a guanine nucleotide dissociation inhibitor (GDI) for Gαs. Sequential phosphorylation of two serine residues that flank this motif by two kinases, cyclin-dependent kinase 5 and PKCθ, ensures that GIV exerts its GEF and GDI activities on Gαi and Gαs, respectively, in a temporally and spatially segregated manner. Through its bifunctional role as GEF and GDI, GIV serves as a pleiotropically acting G-protein modulator that integrates, reinforces, and compartmentalizes signals downstream of both growth factors and G proteins and orchestrates migration–proliferation dichotomy.
Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters
Authors: Darash-Yahana Merav , Pozniak Yair , Lu Mingyang , Sohn Yang-Sung , Karmi Ola , Tamir Sagi , Bai Fang , Song Luhua , Jennings Patricia A. , Pikarsky Eli , Geiger Tamar , Onuchic José N. , Mittler Ron , Nechushtai Rachel
Published: September 2016

Significance

Elevated expression of the iron–sulfur (Fe-S) protein nutrient-deprivation autophagy factor-1 (NAF-1) is associated with the progression of multiple cancer types. Here we demonstrate that the lability of the Fe-S cluster of NAF-1 plays a key role in promoting breast cancer cell proliferation, tumor growth, and resistance of cancer cells to oxidative stress. Our study establishes an important role for the unique 3Cys-1His Fe-S cluster coordination structure of NAF-1 in promoting the development of breast cancer tumors and suggests the potential use of drugs that suppress NAF-1 accumulation or stabilize its cluster in the treatment of cancers that display high expression levels of NAF-1.
Maize endosperm-specific transcription factors O2 and PBF network the regulation of protein and starch synthesis
Authors: Zhang Zhiyong , Zheng Xixi , Yang Jun , Messing Joachim , Wu Yongrui
Published: September 2016

Significance

Nutritional quality and yield are equally important considerations in crop breeding, although they sometimes appear at odds. In this work we made the discovery that these traits are linked through regulation by two transcription factors. Mutations that affect the expression of these transcription factors can improve the nutritional quality of the seed but also can reduce kernel yield and hardness. Therefore future corn-breeding programs should silence zein genes directly, not by blocking transcription factors.
Modelling the small punch tensile behaviour of an aerospace alloy
Authors: Lancaster R. J. , Illsley H. W. , Davies G. R. , Jeffs S. P. , Baxter G. J.
Published: September 2016

The small punch (SP) test is a widely accepted methodology for obtaining mechanical property information from limited material quantities. Much research has presented the creep, tensile and fracture responses of numerous materials gathered from small-scale testing approaches. This is of particular interest for alloy down selection of next-generation materials and in situ mechanical assessments. However, to truly understand the evolution of deformation of the miniature disc specimen, an accurate and detailed understanding of the progressive damage is necessary. This paper will utilise the SP test to assess the tensile properties of several Ti–6Al–4V materials across different temperature regimes. Fractographic investigations will establish the contrasting damage mechanisms and finite element modelling through DEFORM software is employed to characterise specimen deformation.

This paper is part of a thematic issue on the 9th International Charles Parsons Turbine and Generator Conference. All papers have been revised and extended before publication in Materials Science and Technology.
Scholarly Addiction:Doctor Faustusand the Drama of Devotion
Authors: Lemon Rebecca
Published: September 2016

WhenThe English Faust Bookdescribes Faustus as addicted to study and Marlowe’sDoctor Faustusdepicts necromantic books as “ravishing,” these texts draw on classical and Renaissance notions of laudable addiction. Following its Latin origin in contract law,addictionappears in sixteenth-century writings as service, dedication, and devotion. Tracing invocations of addiction from Cicero to Perkins, this essay explores the influence of Calvin and Calvinist-minded Cambridge divines throughDoctor Faustus’spreoccupation with the challenge of addicted commitment. If Calvinists praise committed devotion, Marlowe challenges such views by staging the terror as well as the wonder of addictive release.
Mapping the Frontier between Islam and Christendom in a Diplomatic Age: al-Ghassânî in Spain
Authors: Zhiri Oumelbanine
Published: September 2016

This essay analyzes the travel account authored by Moroccan ambassador Muhammad al-Ghassânî, who visited Spain in 1690–91. The account shows the evolution of the early modern frontier between Christian Europe and Islamic North Africa, from a militarized boundary to the development of diplomatic relations. Both an agent and witness of that history, al-Ghassânî describes a heterogeneous space: he surveys the border, explores the foreign land of modern Spain, and reimagines the memory of al-Andalus. His important account, based on sharp observation and serious research, helps nuance the prevailing view that Arab culture had ignored Europe before the nineteenth century.
Resistivity distribution from mid-crustal conductor to near-surface across the 1200 km long Liquiñe-Ofqui Fault System, southern Chile
Authors: Held Sebastian , Schill Eva , Pavez Maximiliano , Díaz Daniel , Muñoz Gerard , Morata Diego , Kohl Thomas
Published: September 2016

Mid-crustal conductors are a common phenomenon in magnetotelluric studies. In the Andean Cordillera of southern Chile, they appear to concentrate along major fault zones. A high-resolution, broad-band magnetotelluric survey including 31 stations has been carried out along two profiles perpendicular to (1) the Liquiñe-Ofqui Fault Systems (LOFS) and (2) the Villarrica-Quetrupillán-Lanín volcanic lineament running parallel to the Mocha-Villarrica Fault Zone (MVFZ). The survey aimed at tracing one of the known conductors from mid-crustal depth to near-surface along these faults. Directionality and dimensionality were analysed using tensor decomposition. Phase tensors and induction arrows reveal two major geoelectric strike directions following the strike of LOFS and MVFZ. 2-D inversion shows low resistivity zones along both fault systems down to a depth of >10 km, where the brittle-ductile transition is expected. Along the LOFS, the two anomalies are linked to (1) Lake Caburgua, where the LOFS broadens to about 2 km of lateral extension and seems to represent a pull-apart structure, and (2) the intersection with the Villarrica-Quetrupillán-Lanín volcanic lineament, where seismic activity was observed during the latest eruption in March 2015. A connection of the mid-crustal conductor to the ESE-WNW-striking fault zones is indicated from the presented data.
Precision prediction of the log power spectrum
Authors: Repp A. , Szapudi I.
Published: September 2016

At translinear scales, the log power spectrum captures significantly more cosmological information than the standard power spectrum. At high wavenumbers k, the Fisher information in the standard power spectrum P(k) fails to increase in proportion to k, in part due to correlations between large- and small-scale modes. As a result, P(k) suffers from an information plateau on these translinear scales, so that analysis with the standard power spectrum cannot access the information contained in these small-scale modes. The log power spectrum PA(k), on the other hand, captures the majority of this otherwise lost information. Until now there has been no means of predicting the amplitude of the log power spectrum apart from cataloging the results of simulations. We here present a cosmology-independent prescription for the log power spectrum; this prescription displays accuracy comparable to that of Smith et al., over a range of redshifts and smoothing scales, and for wavenumbers up to 1.5 h Mpc−1.
Evidence for multiple populations in the intermediate-age cluster Lindsay 1 in the SMC
Authors: Hollyhead K. , Kacharov N. , Lardo C. , Bastian N. , Hilker M. , Rejkuba M. , Koch A. , Grebel E. K. , Georgiev I.
Published: September 2016

Lindsay 1 is an intermediate-age (≈8 Gyr) massive cluster in the Small Magellanic Cloud. Using VLT FORS2 spectra of 16 probable cluster members on the lower red giant branch of the cluster, we measure CN and CH band strengths (at ≃ 3883 and 4300 Å, respectively), along with carbon and nitrogen abundances and find that a sub-population of stars has significant nitrogen enrichment. A lack of spread in carbon abundances excludes evolutionary mixing as the source of this enrichment, so we conclude that this is evidence of multiple populations. Therefore, Lindsay 1 is the youngest cluster to show such variations, implying that the process triggering the onset of multiple populations must operate until at least redshift ∼1.
Composition, Nutritional Value, and Health Benefits of Pulses
Authors: Hall Clifford , Hillen Cassandra , Garden Robinson Julie
Published: September 2016

The United Nations has declared 2016 as the International Year of Pulses. Pulses are narrowly defined as leguminous crops that are harvested as dry seeds. Although some pulse crops are harvested green (e.g., green peas), these are classified as vegetables because the pods are often consumed along with the mature and sometimes immature seeds. Other dried legumes such as soybean and peanut meet the definition of being a leguminous crop that is harvested as dry seeds; however, these crops are grown primarily for oil content and, thus, are not categorized as pulses. There are hundreds of pulse varieties grown worldwide; these include, for example, dry edible beans, chickpeas, cowpeas, and lentils. This review will cover the proximate (e.g., protein, carbohydrates, vitamins, and minerals), and phytonutrient (e.g., polyphenolics and carotenoid) composition of dry edible beans, peas, lentils, and chickpeas. Soybean and peanuts will not be covered in this review. The effects of processing on composition will also be covered. The health benefits related to folates, fiber, and polyphenolics will be highlighted. The health benefits discussed will include cardiovascular disease, cancer, diabetes, and weight control. The current review will not cover antinutrient compounds; this topic will be covered in a separate review article published in the same issue.
Italian Guidelines
Authors: Annibale Bruno , Carabotti Marilia , Cuomo Rosario
Published: September 2016

Diverticular disease (DD) is a widespread condition, however limited evidences are available about its management and complications. In the last years, an Italian Consensus Conference promoted by GRIMAD (Gruppo Italiano Malattia Diverticolare, Italian Group on Diverticular Diseases) and a Guideline, by Italian Society of Colorectal Surgery (SICCR) were published. The aim of the Consensus was to provide clinical recommendation for appropriate definition, diagnosis, and management of DD, in particular 4 areas of interest were identified, namely: (i) definition and epidemiology, (ii) pathophysiology, (iii) diagnosis, and (iv) medical and surgical treatment. A total of 55 statements graded according to different level of evidence and strength of recommendation were approved. However, if we consider the grade of recommendation, their strength remains suboptimal, with only 3 statements with grade of evidence A in the area of diagnosis. The Clinical guidelines by SICCR focus mainly on acute diverticulitis, and surgical treatment of complicated DD. One of the main topic analyzed, is represented by the management of the acute uncomplicated diverticulitis, in particular about the use of antibiotics and need of hospitalization. Despite the presence of many recent European and western country guidelines, there is a lack of robust data on epidemiology, risk factors, and medical and surgical management of DD, calling the need of further studies aimed to obtain an evidence-based approach in this condition.
Diverticular Disease in the Primary Care Setting
Authors: Wensaas Knut-Arne , Hungin Amrit Pali
Published: September 2016

Diverticular disease is a chronic and common condition, and yet the impact of diverticular disease in primary care is largely unknown. The diagnosis of diverticular disease relies on the demonstration of diverticula in the colon, and the necessary investigations are often not available in primary care. The specificity and sensitivity of symptoms, clinical signs and laboratory tests alone are generally low and consequently the diagnostic process will be characterized by uncertainty. Also, the criteria for symptomatic uncomplicated diverticular disease in the absence of macroscopic inflammation are not clearly defined. Therefore both the prevalence of diverticular disease and the incidence of diverticulitis in primary care are unknown. Current recommendations for treatment and follow-up of patients with acute diverticulitis are based on studies where the diagnosis has been verified by computerized tomography. The results cannot be directly transferred to primary care where the diagnosis has to rely on the interpretation of symptoms and signs. Therefore, one must allow for greater diagnostic uncertainty, and safety netting in the event of unexpected development of the condition is an important aspect of the management of diverticulitis in primary care. The highest prevalence of diverticular disease is found among older patients, where multimorbidity and polypharmacy is common. The challenge is to remember the possible contribution of diverticular disease to the patient’s overall condition and to foresee its implications in terms of advice and treatment in relation to other diseases.
Diverticular Disease of the Colon
Authors: Flor Nicola , Soldi Simone , Zanchetta Edoardo , Sbaraini Sara , Pesapane Filippo
Published: September 2016

Different scenarios embrace computed tomography imaging and diverticula, including asymptomatic (diverticulosis) and symptomatic patients (acute diverticulitis, follow-up of acute diverticulitis, chronic diverticulitis). If the role of computed tomography is validated and widely supported by evidence in case of acute diverticulitis, this is not the case of patients in their follow-up for acute diverticulitis or with symptoms related to diverticula, but without acute inflammation. In these settings, computed tomography colonography is gaining consensus as the preferred radiologic test.
Long-term Outcomes of Elective Surgery for Diverticular Disease
Authors: Biondi Alberto , Santullo Francesco , Fico Valeria , Persiani Roberto
Published: September 2016

To date, the appropriate management of diverticular disease is still controversial. The American Society of Colon and Rectal Surgeons declared that the decision between conservative or surgical approach should be taken by a case-by-case evaluation. There is still lack of evidence in literature about long-term outcomes after elective sigmoid resection for diverticular disease. Considering the potentially key role of the surgical technique in long-term outcomes, there is the need for surgeons to define strict rules to standardize the surgical technique. Currently there are 5 areas of debate in elective surgery for diverticular disease: laparoscopic versus open approach, the site of the proximal and distal colonic division, the vascular approach and the mobilization of the splenic flexure. The purpose of this paper is to review existing knowledge about technical aspects, which represent how the surgeon is able to affect the long-term results.
Peritoneal Lavage in Complicated Acute Diverticulitis
Authors: Escalante G Ricardo , Bustamante-Lopez Leonardo , Lizcano Ana , Acosta M Bernardo
Published: September 2016

Purpose:

The aim of this study was to assess laparoscopic lavage in patients with acute diverticulitis.

Background:

In recent times, laparoscopic peritoneal lavage has been considered a therapeutic alternative to standard resection procedures. In Hinchey III diverticulitis there is the possibility of avoiding ostomies or resection procedures.

Study:

This retrospective study was conducted in a single-care institution.

Results:

Patients requiring emergency surgery for perforated diverticulitis and generalized peritonitis between March 2011 and May 2014 were identified from a prospective database. Seventy-two patients underwent surgery for diverticulitis. Forty-three patients presented with generalized peritonitis (Hinchey III) and 29 with gross fecal contamination (Hinchey IV). From the Hinchey III group, 17 patients (39.5%), with a median age of 56.8 years, were selected to undergo peritoneal lavage.

Postoperative length of stay was 4.2 days, the rate of minor complications was 35%, that of major complications was 0%, and mortality rate was 0%. Over a median follow-up of 24.6 months none required reoperation.

Conclusions:

The number of patients selected for laparoscopic lavage in the management of perforated diverticulitis is increasing as it provides an alternative to Hartmann’s procedure in emergency cases. This approach should be considered suitable for patients without important comorbidities, and only in centers experienced in laparoscopic surgery. It reduces the length of hospital stay. Morbidity and mortality are lower than in those in whom resection was considered necessary. Longer follow-up and results of other trials will be necessary to draw an adequate conclusion.
How to Differentiate Segmental Colitis Associated With Diverticulosis and Inflammatory Bowel Diseases
Authors: Cassieri Claudio , Brandimarte Giovanni , Elisei Walter , Lecca Giuseppina P. , Goni Elisabetta , Penna Antonio , Picchio Marcello , Tursi Antonio
Published: September 2016

The segmental colitis associated with diverticulosis,” better known by its acronym “SCAD,” is a chronic inflammatory process localized in the colonic area presenting diverticulosis, and therefore mainly in the sigmoid colon. By definition, both the rectum and the right colon are spared from any inflammation both endoscopically and from a histologic point of view. Recent data have hypothesized that SCAD may be an independent clinical entity within the inflammatory bowel disease set of diseases. Compared with inflammatory bowel disease, SCAD seems to have a more benign outcome, with low rate of complications.
Prevalence of Colonic Diverticulosis in Patients Affected by Ulcerative Colitis
Authors: Cassieri Claudio , Pica Roberta , Avallone Eleonora V. , Zippi Maddalena , Crispino Pietro , De Nitto Daniela , Paoluzi Paolo , Brandimarte Giovanni , Lecca Piera Giuseppina , Elisei Walter , Picchio Marcello , Tursi Antonio
Published: September 2016

Background:

Diverticulosis of the colon is an acquired condition that results from herniation of the mucosa and submucosa through defects in the muscular layer. The true prevalence of colonic diverticulosis is difficult to measure because most individuals are asymptomatic. In particularly, in literature, there are few studies about the prevalence of colonic diverticulosis in patients affected by ulcerative colitis (UC).

Goals:

To investigate the prevalence of colonic diverticulosis in UC and in adult patients referred in a single center.

Study:

Consecutive patients, referred to our institution to undergo a colonoscopy for colorectal cancer screening and/or for UC assessment, between January 1, 2014 and December 31, 2014, were studied.

Results:

Six hundred five consecutive patients were studied: 438 (72.4%) due to colorectal cancer screening (group A) and 167 (27.6%) for UC assessment (group B). Prevalence of colonic diverticulosis was higher in group A than group B (27.8% vs. 10.8%, P<0.0001). Female gender in patients with colonic diverticulosis was higher in group A than group B (55.7% vs. 22.2%, P=0.0106). Sigma and left colon was mainly involved in group A than group B (97.6% vs. 66.7%, P=0.0001), whereas in group B the right colon was mainly involved in group B versus group A (22.2% vs. 0.8%, P=0.0009).

Conclusions:

Prevalence of colonic diverticulosis was significantly lower in patients with UC than in control group. UC may, therefore, be a protective factor for colonic diverticulosis occurrence.
Probiotics for the Treatment of Symptomatic Uncomplicated Diverticular Disease
Authors: Scarpignato Carmelo , Bertelé Anna , Tursi Antonio
Published: September 2016

Changes in the colonic microbiota are critical to the pathogenesis of diverticular complications such as diverticulitis and peridiverticular abscesses. However, more subtle changes in microbiota composition may well be important to the more chronic manifestations of diverticulosis. Some studies have shown the presence of bacterial overgrowth in subgroups of patients with diverticular disease and recent studies, using molecular biology techniques, found an increase of proteobacteria and actinobacteria in patients with symptomatic uncomplicated diverticular disease (SUDD), compared with healthy controls. The use of probiotics to modulate intestinal microecology in SUDD appears therefore rational. Although several investigations evaluating the clinical efficacy of probiotics have been performed, no definitive results have yet been achieved, mainly due to the heterogeneity of the available studies. Most of the studies used probiotics in combination with poorly absorbed antimicrobials or anti-inflammatory drugs. In only 4 studies, there was a harm using probiotics alone, but only 1 was a placebo-controlled, double-blind trial. The analysis of the available evidence reveals a poor quality of the published studies, whose design was heterogeneous, with only 2 out of 11 trials being double-blind and randomized. Therefore, available data can only suggest a benefit of probiotics in SUDD, but do not allow any evidence-based definite conclusion. As a consequence, current guidelines state that there is insufficient evidence to recommend probiotics for symptom relief in patients with diverticular disease.
Management of Diverticular Disease in Scandinavia
Authors: Schultz Johannes K. , Yaqub Sheraz , Øresland Tom
Published: September 2016

Throughout the last century, the incidence of diverticular disease of the colon has increased tremendously in industrialized countries; nevertheless, the management of this condition is still controversial. Although several international guidelines for the management of diverticular disease are based on the same evidence, the recommendations differ greatly, emphasizing the lack of high-quality prospective studies. In Scandinavia, official guidelines for the management of diverticular disease exist only in Denmark. However, the treatment policies are quite similar in all Scandinavian countries. Computed tomography is the first choice for imaging of acute diverticulitis and its complications. Furthermore, the use of antibiotics in uncomplicated diverticulitis is nearly abandoned in Scandinavia, whereas several international guidelines still recommend their use. There is a broad consensus that abscesses secondary to acute diverticulitis can safely be managed with percutaneous drainage, which is in line with international recommendations. The surgical management of perforated diverticulitis with peritonitis is still as controversial in Scandinavia as elsewhere. Common surgical options are laparoscopic peritoneal lavage, primary resection with anastomosis, and primary resection with terminal colostomy (Hartmann’s procedure). Elective sigmoid resection in patients with diverticular disease seems to be performed less frequently in Scandinavia than in other European countries; the right indications are a current matter of debate. Symptomatic uncomplicated diverticular disease in the absence of diverticulitis has not gained great attention in Scandinavia.
Management of Patients With Diverticulosis and Diverticular Disease
Authors: Tursi Antonio , Picchio Marcello , Elisei Walter , Di Mario Francesco , Scarpignato Carmelo , Brandimarte Giovanni
Published: September 2016

The statements produced by the Chairmen of the 2nd International Symposium on Diverticular Disease, held in Rome on April 8th to 9th, 2016, are reported. Topics such as epidemiology, risk factors, diagnosis, medical and surgical treatment of diverticular disease in patients with uncomplicated and complicated diverticular disease were reviewed by the Chairmen who proposed 41 statements graded according to level of evidence and strength of recommendation. Each topic was explored focusing on the more relevant clinical questions. The vote was conducted on a 6-point scale and consensus was defined a priori as 67% agreement of the participants. The voting group consisted of 80 physicians from 6 countries, and agreement with all statements was provided. Comments were added explaining some controversial areas.
When Should We Operate for Recurrent Diverticulitis?
Authors: Papagrigoriadis Savvas
Published: September 2016

Recent guidelines on elective surgery for recurrent diverticulitis have removed generalized recommendations for elective preventive surgery and advice individualized decision per patient. We discuss the clinical evidence and potential use of risk factors to help with decision-making for patient selection for elective surgery in the presence of a history of diverticulitis.
United States Guidelines for Diverticulitis Treatment
Authors: Floch Martin H. , Longo Walter E.
Published: September 2016

Guidelines for diverticular disease management were last supported and published by the American Gastroenterology Association and the American College of Gastroenterology 2 decades ago. Guidelines have been published in other countries and by some societies. These guidelines are suggested as United States of America guidelines. In reality, they are what is practiced in Connecticut at Yale New Haven hospitals. The epidemiology and pathophysiology is described. This is still considered a dietary fiber-deficiency disease that results in high intracolonic pressure with resultant outpocketing of diverticula in the weakest point of the colon at the sites of vascular penetration with developing elastin deposition in the colon wall. The age and gender distribution is described. They are most common in the sigmoid. The guidelines of management are described according to accepted classification of the disease at all stages from onset, to early formation, to mild disease, to complicated disease, to rare specific states. The outcomes and mortality are discussed.
Rifaximin and midodrine improve clinical outcome in refractory ascites including renal function, weight loss, and short-term survival
Authors: Hanafy Amr S. , Hassaneen Ahmad M.
Published: September 2016

Backgrounds and aims

The occurrence of refractory ascites in nearly 17% of patients with decompensated cirrhosis is an unresolved issue. Advanced liver disease, functional renal impairment, and vascular insensitivity to vasopressors are the main causes of its refractoriness. Therefore, the aim of this study was to evaluate the impact on diuresis, weight loss, and short-term survival if midodrine and rifaximin were added to the diuretic therapy (DT).

Materials and methods

The study evaluated the eligibility of 650 patients with cirrhosis and refractory ascites who were selected during the period from November 2011 to May 2015. A total of 50 patients were excluded and finally 600 were selected and divided into the following groups: patients exposed to DT (n=200) as a control group, or DT with midodrine and rifaximin group (n=400). Body weight, mean arterial pressure, and glomerular filtration rate were determined. Plasma renin and aldosterone were also determined. Follow-up was performed after 2, 6, and 12 weeks, and then every 2 months for 24 months.

Results

The mean arterial pressure was significantly higher in the midodrine and rifaximin group (P=0.000), and there was a highly significant weight loss after 12 weeks (12.5 kg) (P=0.000), a highly significant increase in serum sodium, urine output, and urinary sodium excretion (P=0.000), and creatinine clearance was more reduced in the control group. With rifaximin and midodrine, a complete response occurred in 310 (78%) patients, a partial response in 72 (18%), and no response in 18 (4%) versus 30 (15%), 110 (55%), and 60 (30%) in the control group, respectively (P=0.000). Midodrine and rifaximin significantly reduced paracentesis needs when compared with the controls (18 study patients vs. 75 DT-only patients, P=0.000).

Conclusion

Adding rifaximin and midodrine to DT enhanced diuresis in refractory ascites with improved systemic, renal hemodynamics and short-term survival.
The Economic Burden of Prescription Opioid Overdose, Abuse, and Dependence in the United States, 2013
Authors: Florence Curtis S. , Zhou Chao , Luo Feijun , Xu Likang
Published: September 2016

Importance:

It is important to understand the magnitude and distribution of the economic burden of prescription opioid overdose, abuse, and dependence to inform clinical practice, research, and other decision makers. Decision makers choosing approaches to address this epidemic need cost information to evaluate the cost effectiveness of their choices.

Objective:

To estimate the economic burden of prescription opioid overdose, abuse, and dependence from a societal perspective.

Design, Setting, and Participants:

Incidence of fatal prescription opioid overdose from the National Vital Statistics System, prevalence of abuse and dependence from the National Survey of Drug Use and Health. Fatal data are for the US population, nonfatal data are a nationally representative sample of the US civilian noninstitutionalized population ages 12 and older. Cost data are from various sources including health care claims data from the Truven Health MarketScan Research Databases, and cost of fatal cases from the WISQARS (Web-based Injury Statistics Query and Reporting System) cost module. Criminal justice costs were derived from the Justice Expenditure and Employment Extracts published by the Department of Justice. Estimates of lost productivity were based on a previously published study.

Exposure:

Calendar year 2013.

Main Outcomes and Measures:

Monetized burden of fatal overdose and abuse and dependence of prescription opioids.

Results:

The total economic burden is estimated to be $78.5 billion. Over one third of this amount is due to increased health care and substance abuse treatment costs ($28.9 billion). Approximately one quarter of the cost is borne by the public sector in health care, substance abuse treatment, and criminal justice costs.

Conclusions and Relevance:

These estimates can assist decision makers in understanding the magnitude of adverse health outcomes associated with prescription opioid use such as overdose, abuse, and dependence.
Diapause and maintenance of facultative sexual reproductive strategies
Authors: Stelzer Claus-Peter , Lehtonen Jussi
Published: September 2016

Facultative sex combines sexual and asexual reproduction in the same individual (or clone) and allows for a large diversity of life-history patterns regarding the timing, frequency and intensity of sexual episodes. In addition, other life-history traits such as a diapause stage may become linked to sex. Here, we develop a matrix modelling framework for addressing the cost of sex in facultative sexuals, in constant, periodic and stochastically fluctuating environments. The model is parametrized using life-history data from
Brachionus calyciflorus
, a facultative sexual rotifer in which sex and diapause are linked. Sexual propensity was an important driver of costs in constant environments, in which high costs (always > onefold, and sometimes > twofold) indicated that asexuals should outcompete facultative sexuals. By contrast, stochastic environments with high temporal autocorrelation favoured facultative sex over obligate asex, in particular, if the penalty to fecundity in ‘bad’ environments was large. In such environments, obligate asexuals were constrained by their life cycle length (i.e. time from birth to last reproductive adult age class), which determined an upper limit to the number of consecutive bad periods they could tolerate. Nevertheless, when facultative asexuals with different sexual propensities competed simultaneously against each other and asex, the lowest sex propensity was the most successful in stochastic environments with positive autocorrelation. Our results suggest that a highly specific mechanism (i.e. diapause linked to sex) can alone stabilize facultative sex in these animals, and protect it from invasion of both asexual and pure sexual strategies.

This article is part of the themed issue ‘Weird sex: the underappreciated diversity of sexual reproduction’.
Condition-dependent sex: who does it, when and why?
Authors: Ram Yoav , Hadany Lilach
Published: September 2016

We review the phenomenon of condition-dependent sex—where individuals' condition affects the likelihood that they will reproduce sexually rather than asexually. In recent years, condition-dependent sex has been studied both theoretically and empirically. Empirical results in microbes, fungi and plants support the theoretical prediction that negative condition-dependent sex, in which individuals in poor condition are more likely to reproduce sexually, can be evolutionarily advantageous under a wide range of settings. Here, we review the evidence for condition-dependent sex and its potential implications for the long-term survival and adaptability of populations. We conclude by asking why condition-dependent sex is not more commonly observed, and by considering generalizations of condition-dependent sex that might apply even for obligate sexuals.

This article is part of the themed issue ‘Weird sex: the underappreciated diversity of sexual reproduction’.
Directed Network Discovery with Dynamic Network Modeling
Authors: Anzellotti Stefano , Kliemann Dorit , Jacoby Nir , Saxe Rebecca
Published: September 2016

Cognitive tasks recruit multiple brain regions. Understanding how these regions influence each other (the network structure) is an important step to characterize the neural basis of cognitive processes. Often, limited evidence is available to restrict the range of hypotheses a priori, and techniques that sift efficiently through a large number of possible network structures are needed (network discovery). This article introduces a novel modeling technique for network discovery (Dynamic Network Modeling or DNM) that builds on ideas from Granger Causality and Dynamic Causal Modeling introducing three key changes: 1) regularization is exploited for efficient network discovery, 2) the magnitude and sign of each influence are tested with a random effects model across participants, and 3) variance explained in independent data is used as an absolute (rather than relative) measure of the quality of the network model. In this article, we outline the functioning of DNM and we report an example of its application to the investigation of influences between regions during emotion recognition. Across two experiments, DNM individuates a stable set of influences between face-selective regions during emotion recognition.

New and Noteworthy

In this article we introduce a new analysis method (Dynamic Network Mod- elling or DNM) which exploitsℓ1regularization to perform efficient for network discovery. DNM provides information about the direction and sign (inhibitory vs excitatory) of influences between brain regions, and generates measures of variance explained in independent data to evaluate quality of fit. The method is applied to brain regions engaged in emotion recognition, individuating a similar network structure across two separate experiments.
Single-cell transcriptome analysis of fish immune cells provides insight into the evolution of vertebrate immunity
Authors: Carmona Santiago J. , Teichmann Sarah A. , Ferreira Lauren , Macaulay Iain C. , Stubbington Michael J.T. , Cvejic Ana , Gfeller David
Published: September 2016

The immune system of vertebrate species consists of many different cell types that have distinct functional roles and are subject to different evolutionary pressures. Here, we first analysed gene conservation of all major immune cell types in human and mouse. Our results revealed higher gene turnover and faster evolution of trans-membrane proteins in NK cells compared to other immune cell populations, and especially T cells, but similar conservation of nuclear and cytoplasmic protein coding genes. To validate these findings in a distant vertebrate species, we used single-cell RNA-Sequencing oflck:GFPcells in zebrafish to obtain the first transcriptome of specific immune cell types in a non-mammalian species. Unsupervised clustering and single-cell TCR locus reconstruction identified three cell populations, T-cells, a novel type of NK-like cells and a smaller population of myeloid-like cells. Differential expression analysis uncovered new immune cell specific genes, including novel immunoglobulin-like receptors, and neofunctionalization of recently duplicated paralogs. Evolutionary analyses confirmed a higher gene turnover and lower conservation of trans-membrane proteins in NK cells compared to T cells in fish species, suggesting that this is a general property of immune cell types across all vertebrates.
A note on detecting statistical outliers in psychophysical data
Authors: Jones Pete R.
Published: September 2016

This paper considers how best to identify statistical outliers in psychophysical datasets, where the underlying sampling distributions are unknown. Eight methods are described, and each is evaluated using Monte Carlo simulations of a typical psychophysical experiment. The best method is shown to be one based on a measure of absolute-deviation known asSn. This method is shown to be more accurate than popular heuristics based on standard deviations from the mean, and more robust than non-parametric methods based on interquartile range. Matlab code for computingSnis included.
Universal attenuators and their interactions with feedback loops in gene regulatory networks
Authors: Liu Dianbo , Albergante Luca , Newman Timothy J
Published: September 2016

Using a combination of mathematical modelling, statistical simulation and large-scale data analysis we study the properties of linear regulatory chains (LRCs) within gene regulatory networks (GRNs). Our modelling indicates that downstream genes embedded within LRCs are highly insulated from the variation in expression of upstream genes, and thus LRCs act as attenuators. This observation implies a progressively weaker functionality of LRCs as their length increases. When analysing the preponderance of LRCs in the GRNs ofE. coliK12 and several other organisms, we find that very long LRCs are essentially absent. In bothE. coliandM. tuberculosiswe find that four-gene LRCs are intimately linked to identical feedback loops that are involved in potentially chaotic stress response, indicating that the dynamics of these potentially destabilising motifs are strongly restrained under homeostatic conditions. The same relationship is observed in a human cancer cell line (K562), and we postulate that four-gene LRCs act as “universal attenuators”. These findings suggest a role for long LRCs in dampening variation in gene expression, thereby protecting cell identity, and in controlling dramatic shifts in cell-wide gene expression through inhibiting chaos-generating motifs.

In brief

We present a general principle that linear regulatory chains exponentially attenuate the range of expression in gene regulatory networks. The discovery of a universal interplay between linear regulatory chains and genetic feedback loops in microorganisms and a human cancer cell line is analysed and discussed.

Highlights

Within gene networks, linear regulatory chains act as exponentially strong attenuators of upstream variation

Because of their exponential behaviour, linear regulatory chains beyond a few genes provide no additional functionality and are rarely observed in gene networks across a range of different organisms

Novel interactions between four-gene linear regulatory chains and feedback loops were discovered inE. coli, M. tuberculosisand human cancer cells, suggesting a universal mechanism of control.
Chromatin marks govern mutation landscape of cancer at early stage of progression
Authors: Ha Kyungsik , Kim Hong-Gee , Lee Hwajin
Published: September 2016

Accumulation of somatic mutations over time leads to tissue abnormalities, such as cancer. Somatic mutation rates vary across the genome in a cell-type specific manner, depending on the types of mutation processes1–7. Although recent studies have identified several determinants relevant to the establishment of the cancer mutation landscape8–13, these studies have yet to propose the major time point at which these factors come into play during cancer progression. Here, we analyzed whole genome sequencing data from two different types of precancerous tissues, monoclonal B-cell lymphocytosis and Barrett’s esophagus, and their matching cancer types along with 423 epigenetic features from normal tissues to determine the critical time point when chromatin features contribute to the formation of the somatic mutation landscape. Our analyses revealed that a subset of cell-of-origin associated chromatin features can explain more than 80% of the regional mutation variance for both types of precancerous tissues, comparable to the variance explained level for the genomes of matching cancer types. In particular, major significant chromatin features explaining the mutation landscape of Barrett’s esophagus and esophageal adenocarcinoma were derived from stomach tissues, indicating that mutation landscape establishment occurs mostly after environment-mediated epigenetic changes during gastric metaplasia. Analyses of the genome of esophageal squamous cell carcinoma tissues demonstrated that the proposed time point for mutation landscape establishment of Barrett’s esophagus and esophageal adenocarcinoma were specific to the occurrence of cell-type shift. Thus, our data suggest that the major time point for the mutation landscape establishment dictated by chromatin features is early in the process of cancer progression, and epigenetic changes due to environmental conditions at early stages can dramatically impact the somatic mutation landscape of cancer.