bluuebunny/crossref_metadata_2025 huggingface dataset:
Short‐ and Long‐Term Outcomes of Laparoscopic Multivisceral Resection for Clinically Suspected T4 Colon Cancer
Authors: Kumamoto Tsutomu , Toda Shigeo , Matoba Shuichiro , Moriyama Jin , Hanaoka Yutaka , Tomizawa Kenji , Sawada Toshihito , Kuroyanagi Hiroya
Published: March 2017

Background

The use of laparoscopic surgery for colorectal cancer has become widespread recently. However, the safety and oncological outcomes of laparoscopic surgery for primary advanced colorectal cancer need extensive investigation. We analyzed the short‐ and long‐term outcomes after laparoscopic multivisceral resection for primary colon cancer with suspected invasion of other organs at a single institution.

Methods

Between January 2000 and December 2014, 118 patients underwent laparoscopic multivisceral resection for primary colon cancer invading or adhering to adjacent organs or structures; their short‐ and long‐term outcomes were retrospectively evaluated.

Results

The median operating time was 254 min (range 130–1051 min), and median blood loss was 48 ml (range 0–2777 ml). The overall conversion rate was 6.8%. The postoperative complication rate was 17.8%. The number of patients with R0 and R1 resection was 112 (94.9%) and 6 (5.1%), respectively. At a median follow‐up period of 32 months (range 0–157 months), the local recurrence rate in patients who underwent R0 resection was 1.8%, while for R1 resection it was 66.7%. In multivariate analysis, R1 resection and LN metastases were found to be predictors of poor prognosis. The cancer‐specific 5‐year survival was 87% when R0 resection was achieved; within these, the 5‐year survival rates for patients with stages II, III, and IV disease were 94, 81, and 40%, respectively.

Conclusions

Laparoscopic en bloc multivisceral resection for clinically suspected T4 colon cancer is a safe and feasible procedure for precisely selected patients, attaining satisfactory oncological outcomes when R0 resection is achieved.
Sweet and sour: an update on classic galactosemia
Authors: Coelho Ana I. , Rubio‐Gozalbo M. Estela , Vicente João B. , Rivera Isabel
Published: March 2017

Classic galactosemia is a rare inherited disorder of galactose metabolism caused by deficient activity of galactose‐1‐phosphate uridylyltransferase (GALT), the second enzyme of the Leloir pathway. It presents in the newborn period as a life‐threatening disease, whose clinical picture can be resolved by a galactose‐restricted diet. The dietary treatment proves, however, insufficient in preventing severe long‐term complications, such as cognitive, social and reproductive impairments. Classic galactosemia represents a heavy burden on patients’ and their families’ lives. After its first description in 1908 and despite intense research in the past century, the exact pathogenic mechanisms underlying galactosemia are still not fully understood. Recently, new important insights on molecular and cellular aspects of galactosemia have been gained, and should open new avenues for the development of novel therapeutic strategies. Moreover, an international galactosemia network has been established, which shall act as a platform for expertise and research in galactosemia. Herein are reviewed some of the latest developments in clinical practice and research findings on classic galactosemia, an enigmatic disorder with many unanswered questions warranting dedicated research.
Diffusive Interaction Between Ni-Cr-Al Alloys
Authors: Tkacz-Śmiech Katarzyna , Danielewski Marek , Bożek Bogusław , Berent Katarzyna , Zientara Dariusz , Zajusz Marek
Published: March 2017

In high-temperature coatings, welded parts, and a range of other applications, components in the contact zone interdiffuse at elevated temperatures and may react to change the phase composition. The diffusion zone can be complex and can consist of sequential layers of intermediate phases, solid solutions, and in the case of multicomponent systems also of multiphase layers. In this work, the interdiffusion in Ni-Cr-Al alloys is studied experimentally and modeled numerically. The diffusion multiples were prepared by hot isostatic pressing and post-annealing at 1473 K (1200 °C). The concentration profiles were measured with wide-line EDS technique which allowed obtaining high-accuracy diffusion paths. The experimental profiles and diffusion paths were compared with numerical results simulated with application of very recent model of interdiffusion in muticomponent–multiphase systems. The calculated and experimental data show good agreement.
Role of Organic Matter in Uranium Mineralisation in Vempalle Dolostone; Cuddapah Basin, India
Authors: Goswami Sukanta , Bhagat Sangeeta , Zakaulla Syed , Kumar Suresh , Rai A. K.
Published: March 2017

Dolostone of Vempalle Formation near Tummalapalle hosts large uranium deposit (>100,000 tonnes with an average grade of 0.045%U3O8). It is a unique type of uranium deposit because carbonate formations have been considered to be among the least uraniferous of all the rocks of the Earth’s crust due to mobility of uranium in aqueous fluid in the presence of carbonate and bicarbonate ions. Vempalle dolostone hosts syn-sedimentary uranium mineralization in the form of discrete uranium phases (pitchblende and coffinite) associated with collophane, and adsorbed uranium in organic matter. The organic matter has played dual role of concentrating uranium from solution and also chemically reducing it to pitchhblende and coffinite.
Ceding control: an experimental analysis of participatory management
Authors: Mellizo Philip , Carpenter Jeffrey , Matthews Peter Hans
Published: March 2017

We use an experiment to evaluate the effects of participatory management on firm performance. Participants are randomly assigned roles as managers or workers in firms that generate output via real effort.
To identify the causal effect of participation on effort, workers are exogenously assigned to one of the two treatments: one in which the manager implements a compensation scheme unilaterally or another in which the manager cedes control over compensation to the workers who vote to implement a scheme. We find that output is between seven and twelve percentage points higher in participatory firms.
The satiating effect of pricing: The influence of price on enjoyment over time
Authors: Haws Kelly L. , McFerran Brent , Redden Joseph P.
Published: March 2017

Prices are typically critical to consumption decisions, but can the presence of price impact enjoyment over the course of an experience? We examine the effect of price on consumers' satisfaction over the course of consumption. We find that, compared to when no pricing information is available, the presence of prices accelerates satiation (i.e., enjoyment declines faster). Preliminary evidence suggests that price increases satiation by making the experience seem like less of a relaxing break and something to financially monitor. We rule out several alternative explanations for this effect and discuss important implications for marketers and consumer researchers.
HMOX1 Promoter Microsatellite Polymorphism Is Not Associated With High Altitude Pulmonary Edema in Han Chinese
Authors: Cao Xue-Feng , Ma Lan , Ma Shang , Xu Jin , Ge Ri-Li
Published: March 2017

Objective

To investigate the relationship between microsatellite polymorphism in the Heme oxygenase-1 ( HMOX1) gene promoter and high-altitude pulmonary edema (HAPE) in Han Chinese.

Methods

Eighty-three construction workers who developed HAPE 2 to 7 days after arrival at Yushu (3800 m) in Qinghai, China, and 145 matched healthy subjects were included in this study. The amplification and labeling of the polymerase chain reaction products for capillary electrophoresis were performed to identify HMOX1 genotype frequency. The alleles were classified as short (S: <25 [GT]n repeats) and long (L: ≥25 [GT]n repeats) alleles.

Results

Patients with HAPE have significantly higher white blood cell count, heart rate, and mean pulmonary artery pressure, but lower hemoglobin and arterial oxygen saturation than healthy subjects without HAPE. The numbers of (GT)n repeats in the HMOX1 gene promoter show a bimodal distribution. However, there is no significant difference in the genotype frequency and allele frequency between patients with HAPE and healthy subjects without HAPE. Chi-square test analysis reveals that the genotype frequency of (GT)n repeats is not associated with HAPE.

Conclusion

The microsatellite polymorphism in the HMOX1 gene promoter is not associated with HAPE in Han Chinese in Qinghai, China.
Tactical Combat Casualty Care: Beginnings
Authors: Butler Frank K.
Published: March 2017

Tactical Combat Casualty Care (TCCC) is a set of evidence-based, best-practice prehospital trauma care guidelines customized for use on the battlefield. The origins of TCCC were nontraditional. The TCCC program began as a Naval Special Warfare biomedical research effort launched after the realization that extremity hemorrhage, a leading cause of preventable death on the battlefield, was not being treated with a readily available and highly effective intervention: the tourniquet. This insight prompted a systematic reevaluation of all aspects of battlefield trauma care that was conducted from 1993 to 1996 as a joint effort by special operations medical personnel and the Uniformed Services University of the Health Sciences. The product of that 3-year research project was TCCC, the first-ever set of battlefield trauma care guidelines designed to combine good medicine with good small-unit tactics.
An audit of Cryptosporidium and Giardia detection in Scottish National Health Service Diagnostic Microbiology Laboratories
Authors: ALEXANDER C. L. , CURRIE S. , POLLOCK K. , SMITH-PALMER A. , JONES B. L.
Published: March 2017

Giardia duodenalis and Cryptosporidium species are protozoan parasites capable of causing gastrointestinal disease in humans and animals through the ingestion of infective faeces. Whereas Cryptosporidium species can be acquired locally or through foreign travel, there is the mis-conception that giardiasis is considered to be largely travel-associated, which results in differences in laboratory testing algorithms. In order to determine the level of variation in testing criteria and detection methods between diagnostic laboratories for both pathogens across Scotland, an audit was performed. Twenty Scottish diagnostic microbiology laboratories were invited to participate with questions on sample acceptance criteria, testing methods, testing rates and future plans for pathogen detection. Reponses were received from 19 of the 20 laboratories representing each of the 14 territorial Health Boards. Detection methods varied between laboratories with the majority performing microscopy, one using a lateral flow immunochromatographic antigen assay, another using a manually washed plate-based enzyme immunoassay (EIA) and one laboratory trialling a plate-based EIA automated with an EIA plate washer. Whereas all laboratories except one screened every stool for Cryptosporidium species, an important finding was that significant variation in the testing algorithm for detecting Giardia was noted with only four laboratories testing all diagnostic stools. The most common criteria were ‘travel history’ (11 laboratories) and/or ‘when requested’ (14 laboratories). Despite only a small proportion of stools being examined in 15 laboratories for Giardia (2%–18% of the total number of stools submitted), of interest is the finding that a higher positivity rate was observed for Giardia than Cryptosporidium in 10 of these 15 laboratories. These findings highlight that the underreporting of Giardia in Scotland is likely based on current selection and testing algorithms.
Bilateral coronary artery to left ventricular fistula: CT demonstration of drainage via a single, common channel
Authors: Lee Han Na , Kim Jung Im , Cho Jin-Man
Published: March 2017

We describe the case of a young man with bilateral coronary artery to left ventricular fistula, which was drained via a single, common channel. The anomaly was incidentally detected with coronary CT angiography.
Validierung eines Fragebogens zur umfassenden Operationalisierung von Wohlbefinden
Authors: Hausler Melanie , Huber Alexandra , Strecker Cornelia , Brenner Mirjam , Höge Thomas , Höfer Stefan
Published: March 2017

Zusammenfassung. Die Komponenten subjektives Wohlbefinden (SWB), Beziehungen, Sinn, Engagement, Können, Optimismus und Autonomie tragen zu umfassendem Wohlbefinden bei. Das Comprehensive Inventory of Thriving (CIT) und die Kurzversion Brief Inventory of Thriving (BIT) von Su, Tay und Diener (2014) messen dieses mit nur einem Instrument. Ziel der Studie war die Validierung des CIT und BIT in einer deutschsprachigen Stichprobe (N = 1 040). Gesundheits- und Wohlbefindensfragebögen wurden zur Bestimmung der Konstruktvalidität miterhoben. Verschiedene Faktorenmodelle des CIT wurden mittels konfirmatorischer Faktorenanalysen getestet und verglichen. Das Modell mit den 18 CIT-Skalen als Faktoren erster Ordnung sowie SWB und psychologischem Wohlbefinden (PWB) als Faktoren zweiter Ordnung wies die beste Modellgüte auf und bestätigte die traditionelle Differenzierung von Wohlbefinden in SWB und PWB. Zudem bestätigte sich das Einfaktorenmodell des BIT. Beide Fragebögen wiesen eine gute Reliabilität und Konstruktvalidität auf und können im deutschsprachigen Raum zur Messung des umfassenden Wohlbefindens empfohlen werden.
Epidermal Rac1 regulates the DNA damage response and protects from UV-light-induced keratinocyte apoptosis and skin carcinogenesis
Authors: Deshmukh Jayesh , Pofahl Ruth , Haase Ingo
Published: March 2017

Non-melanoma skin cancer (NMSC) is the most common type of cancer. Increased expression and activity of Rac1, a small Rho GTPase, has been shown previously in NMSC and other human cancers; suggesting that Rac1 may function as an oncogene in skin. DMBA/TPA skin carcinogenesis studies in mice have shown that Rac1 is required for chemically induced skin papilloma formation. However, UVB radiation by the sun, which causes DNA damage, is the most relevant cause for NMSC. A potential role of Rac1 in UV-light-induced skin carcinogenesis has not been investigated so far. To investigate this, we irradiated mice with epidermal Rac1 deficiency (Rac1-EKO) and their controls using a well-established protocol for long-term UV-irradiation. Most of the Rac1-EKO mice developed severe skin erosions upon long-term UV-irradiation, unlike their controls. These skin erosions in Rac1-EKO mice healed subsequently. Surprisingly, we observed development of squamous cell carcinomas (SCCs) within the UV-irradiation fields. This shows that the presence of Rac1 in the epidermis protects from UV-light-induced skin carcinogenesis. Short-term UV-irradiation experiments revealed increased UV-light-induced apoptosis of Rac1-deficient epidermal keratinocytesin vitroas well asin vivo. Further investigations using cyclobutane pyrimidine dimer photolyase transgenic mice revealed that the observed increase in UV-light-induced keratinocyte apoptosis in Rac1-EKO mice is DNA damage dependent and correlates with caspase-8 activation. Furthermore, Rac1-deficient keratinocytes showed reduced levels of p53,γ-H2AX and p-Chk1 suggesting an attenuated DNA damage response upon UV-irradiation. Taken together, our data provide direct evidence for a protective role of Rac1 in UV-light-induced skin carcinogenesis and keratinocyte apoptosis probably through regulating mechanisms of the DNA damage response and repair pathways.
MicroRNA-27a promotes podocyte injury via PPARγ-mediated β-catenin activation in diabetic nephropathy
Authors: Zhou Zhanmei , Wan Jiao , Hou Xiaoyan , Geng Jian , Li Xiao , Bai Xiaoyan
Published: March 2017

Podocyte injury has a pivotal role in the pathogenesis of diabetic nephropathy (DN). MicroRNA-27a (miR-27a), peroxisome proliferator-activated receptor γ (PPARγ) and β-catenin pathways have been involved in the pathogenesis of DN. Herein, we asked whether miR-27a mediates podocyte injury through PPARγ/β-catenin signaling in DN. The functional relevance of miR-27a, PPARγ and β-catenin were investigated in cultured podocytes and glomeruli of diabetic rats and patients using in vitro and in vivo approaches. Podocyte injury was assessed by migration, invasion and apoptosis assay. Biological parameters were analyzed using enzyme-linked immunosorbent assay. We found that high glucose stimulated miR-27a expression, which, by negatively targeting PPARγ, activated β-catenin signaling as evidenced by upregulation of β-catenin target genes, snail1 and α-smooth muscle actin (α-SMA) and downregulation of podocyte-specific markers podocin and synaptopodin. These changes caused podocyte injury as demonstrated by increased podocyte mesenchymal transition, disrupted podocyte architectural integrity and increased podocyte apoptosis. Furthermore, we provide evidence that miR-27a contributed to unfavorable renal function and increased podocyte injury in diabetic rats. Notably, miR-27a exhibited clinical and biological relevance as it was linked to elevated serum creatinine, proteinuria and reduced creatinine clearance rate. In addition, miR-27a upregulation and activation of PPARγ/β-catenin signaling were verified in renal biopsy samples from DN patients. We propose a novel role of the miR-27a/PPARγ/β-catenin axis in fostering the progression toward more deteriorated podocyte injury in DN. Targeting miR-27a could be a potential therapeutic approach for DN.
Optimal adaptive control for quantum metrology with time-dependent Hamiltonians
Authors: Pang Shengshi , Jordan Andrew N.
Published: March 2017

Quantum metrology has been studied for a wide range of systems with time-independent Hamiltonians. For systems with time-dependent Hamiltonians, however, due to the complexity of dynamics, little has been known about quantum metrology. Here we investigate quantum metrology with time-dependent Hamiltonians to bridge this gap. We obtain the optimal quantum Fisher information for parameters in time-dependent Hamiltonians, and show proper Hamiltonian control is generally necessary to optimize the Fisher information. We derive the optimal Hamiltonian control, which is generally adaptive, and the measurement scheme to attain the optimal Fisher information. In a minimal example of a qubit in a rotating magnetic field, we find a surprising result that the fundamental limit of T2 time scaling of quantum Fisher information can be broken with time-dependent Hamiltonians, which reaches T4 in estimating the rotation frequency of the field. We conclude by considering level crossings in the derivatives of the Hamiltonians, and point out additional control is necessary for that case.
CD40-signalling abrogates induction of RORγt+ Treg cells by intestinal CD103+ DCs and causes fatal colitis
Authors: Barthels Christian , Ogrinc Ana , Steyer Verena , Meier Stefanie , Simon Ferdinand , Wimmer Maria , Blutke Andreas , Straub Tobias , Zimber-Strobl Ursula , Lutgens Esther , Marconi Peggy , Ohnmacht Caspar , Garzetti Debora , Stecher Bärbel , Brocker Thomas
Published: March 2017

Immune homeostasis in intestinal tissues depends on the generation of regulatory T (Treg) cells. CD103+dendritic cells (DCs) acquire microbiota-derived material from the gut lumen for transport to draining lymph nodes and generation of receptor-related orphan γt+(RORγt+) Helios−-induced Treg (iTreg) cells. Here we show CD40-signalling as a microbe-independent signal that can induce migration of CD103+DCs from the lamina propria (LP) to the mesenteric lymph nodes. Transgenic mice with constitutive CD11c-specific CD40-signalling have reduced numbers of CD103+DCs in LP and a low frequency of RORγt+Helios−iTreg cells, exacerbated inflammatory Th1/Th17 responses, high titres of microbiota-specific immunoglobulins, dysbiosis and fatal colitis, but no pathology is detected in other tissues. Our data demonstrate a CD40-dependent mechanism capable of abrogating iTreg cell induction by DCs, and suggest that the CD40L/CD40-signalling axis might be able to intervene in the generation of new iTreg cells in order to counter-regulate immune suppression to enhance immunity.
Observation of stable Néel skyrmions in cobalt/palladium multilayers with Lorentz transmission electron microscopy
Authors: Pollard Shawn D. , Garlow Joseph A. , Yu Jiawei , Wang Zhen , Zhu Yimei , Yang Hyunsoo
Published: March 2017

Néel skyrmions are of high interest due to their potential applications in a variety of spintronic devices, currently accessible in ultrathin heavy metal/ferromagnetic bilayers and multilayers with a strong Dzyaloshinskii–Moriya interaction. Here we report on the direct imaging of chiral spin structures including skyrmions in an exchange-coupled cobalt/palladium multilayer at room temperature with Lorentz transmission electron microscopy, a high-resolution technique previously suggested to exhibit no Néel skyrmion contrast. Phase retrieval methods allow us to map the internal spin structure of the skyrmion core, identifying a 25 nm central region of uniform magnetization followed by a larger region characterized by rotation from in- to out-of-plane. The formation and resolution of the internal spin structure of room temperature skyrmions without a stabilizing out-of-plane field in thick magnetic multilayers opens up a new set of tools and materials to study the physics and device applications associated with chiral ordering and skyrmions.
Triamidoamine thorium-arsenic complexes with parent arsenide, arsinidiide and arsenido structural motifs
Authors: Wildman Elizabeth P. , Balázs Gábor , Wooles Ashley J. , Scheer Manfred , Liddle Stephen T.
Published: March 2017

Despite a major expansion of uranium–ligand multiple bond chemistry in recent years, analogous complexes involving other actinides (An) remain scarce. For thorium, under ambient conditions only a few multiple bonds to carbon, nitrogen, phosphorus and chalcogenides are reported, and none to arsenic are known; indeed only two complexes with thorium–arsenic single bonds have been structurally authenticated, reflecting the challenges of stabilizing polar linkages at the large thorium ion. Here, we report thorium parent–arsenide (ThAsH2), –arsinidiides (ThAs(H)K and ThAs(H)Th) and arsenido (ThAsTh) linkages stabilized by a bulky triamidoamine ligand. The ThAs(H)K and ThAsTh linkages exhibit polarized-covalent thorium–arsenic multiple bonding interactions, hitherto restricted to cryogenic matrix isolation experiments, and the AnAs(H)An and AnAsAn linkages reported here have no precedent in f-block chemistry. 7s, 6d and 5f orbital contributions to the Th–As bonds are suggested by quantum chemical calculations, and their compositions unexpectedly appear to be tensioned differently compared to phosphorus congeners.
Clinical characteristics of anti-SAE antibodies in Chinese patients with dermatomyositis in comparison with different patient cohorts
Authors: Ge Yongpeng , Lu Xin , Shu Xiaoming , Peng Qinglin , Wang Guochun
Published: March 2017

This study aimed to analyze the clinical features of anti-SAE antibodies in Chinese myositis patients in comparison with different cohorts. The anti-SAE antibodies were tested in myositis patients and in control subjects. Long-term follow-up was conducted on the antibody-positive patients. Anti-SAE antibodies were exclusively present in 12 out of 394 (3.0%) adult dermatomyositis (DM) patients. Of the anti-SAE-positive DM patients, 75% had distinctive diffuse dark-red or pigment-like skin rashes, and 67% of these patients experienced mild muscle weakness. Muscular biopsies showed mild pathological manifestations. Compared with the antibody-negative group, the average age of dermatomyositis onset in the antibody-positive group was higher, and dysphagia occurred more frequently noted (p = 0.012). Only 9 patients received follow-up, 7 experienced improvement after treatment. The anti-SAE antibody levels correlated with improved disease condition. The anti-SAE antibody was found exclusively in adult DM patients, occurring infrequently in Chinese patients. In addition to a diffuse dark-red or pigment-like skin rash and mild muscular weakness, common symptoms included propensity for developing dysphagia. Serum levels of the anti-SAE antibody correlated with myositis disease activity, and anti-SAE-positive patients were responsive to treatment.
Strong antibiotic production is correlated with highly active oxidative metabolism in Streptomyces coelicolor M145
Authors: Esnault Catherine , Dulermo Thierry , Smirnov Aleksey , Askora Ahmed , David Michelle , Deniset-Besseau Ariane , Holland Ian-Barry , Virolle Marie-Joelle
Published: March 2017

The Streptomyces genus is well known for its ability to produce bio-active secondary metabolites of great medical interest. However, the metabolic features accompanying these bio-productions remain to be defined. In this study, the comparison of related model strains producing differing levels of actinorhoddin (ACT), showed that S. lividans, a weak producer, had high TriAcylGlycerol (TAG) content indicative of a glycolytic metabolism. In contrast, the strong producer, S. coelicolor, was characterized by low TAG content, active consumption of its polyphosphate (PolyP) stores and extremely high ATP/ADP ratios. This indicated highly active oxidative metabolism that was correlated with induction of ACT biosynthesis. Interestingly, in conditions of phosphate limitation, the ppk mutant had TAG content and ACT production levels intermediary between those of S. lividans and S. coelicolor. This strain was characterized by high ADP levels indicating that Ppk was acting as an Adenosine Di Phosphate Kinase. Its absence resulted in energetic stress that is proposed to trigger an activation of oxidative metabolism to restore its energetic balance. This process, which is correlated with ACT biosynthesis, requires acetylCoA to fuel the Krebs cycle and phosphate for ATP generation by the ATP synthase coupled to the respiratory chain, resulting in low TAG and polyP content of the ACT producing strains.
Hybrid Magnetic-DNA Directed Immobilisation Approach for Efficient Protein Capture and Detection on Microfluidic Platforms
Authors: Esmaeili Elaheh , Ghiass Mohammad Adel , Vossoughi Manouchehr , Soleimani Masoud
Published: March 2017

In this study, a hybrid magnetic-DNA directed immobilisation approach is presented to enhance protein capture and detection on a microfluidic platform. DNA-modified magnetic nanoparticles are added in a solution to capture fluorescently labelled immunocomplexes to be detected optically. A magnetic set-up composed of cubic permanent magnets and a microchannel was designed and implemented based on finite element analysis results to efficiently concentrate the nanoparticles only over a defined area of the microchannel as the sensing zone. This in turn, led to the fluorescence emission localisation and the searching area reduction. Also, compared to processes in which the immunocomplex is formed directly on the surface, the proposed approach provides a lower steric hindrance, higher mass transfer, lower equilibrium time, and more surface concentration of the captured targets leading to a faster and more sensitive detection. As a proof-of-concept, the set-up is capable of detecting prostate-specific membrane antigen with concentrations down to 0.7 nM. Our findings suggest that the approach holds a great promise for applications in clinical assays and disease diagnosis.
Novel mutations in CRYGC are associated with congenital cataracts in Chinese families
Authors: Zhong Zilin , Wu Zehua , Han Liyun , Chen Jianjun
Published: March 2017

Congenital cataract (CC), responsible for about one-third of blindness in infants, is a major cause of vision loss in children worldwide. 10–25% of CC cases are attributed to genetic causes and CC is a clinically and genetically highly heterogeneous lens disorder in children. Autosomal dominant (AD) inheritance is the most commonly pattern. 195 unrelated non-syndromic ADCC families in this study are recruited from 15 provinces of China. Sanger sequencing approach followed by intra-familial co-segregation, in Silico analyses and interpretation of the variations according to the published guidelines of American College of Medical Genetics (ACMG), were employed to determine the genetic defects. Two mutations (p.Tyr139X and p.Ser166Phe) identified in two unrelated families were associated with their congenital nuclear cataracts and microcornea respectively, which are also reported previously. Six novel CRYGC mutations (p.Asp65ThrfsX38, p.Arg142GlyfsX5, p.Arg142AlafsX22, p.Tyr144X, p.Arg169X, and p.Tyr46Asp) were identified in other six families with congenital nuclear cataracts, respectively. Mutations in the CRYGC were responsible for 4.1% Chinese ADCC families in our cohort. Our results expand the spectrum of CRYGC mutations as well as their associated phenotypes.
Human pressures and ecological status of European rivers
Authors: Grizzetti B. , Pistocchi A. , Liquete C. , Udias A. , Bouraoui F. , van de Bund W.
Published: March 2017

Humans have increased the discharge of pollution, altered water flow regime and modified the morphology of rivers. All these actions have resulted in multiple pressures on freshwater ecosystems, undermining their biodiversity and ecological functioning. The European Union has adopted an ambitious water policy to reduce pressures and achieve a good ecological status for all water bodies. However, assessing multiple pressures on aquatic ecosystems and understanding their combined impact on the ecological status is challenging, especially at the large scale, though crucial to the planning of effective policies. Here, for the first time, we quantify multiple human pressures and their relationship with the ecological status for all European rivers. We considered ecological data collected across Europe and pressures assessed by pan-European models, including pollution, hydrological and hydromorphological alterations. We estimated that in one third of EU’s territory rivers are in good ecological status. We found that better ecological status is associated with the presence of natural areas in floodplains, while urbanisation and nutrient pollution are important predictors of ecological degradation. We explored scenarios of improvement of rivers ecological status for Europe. Our results strengthen the need to halt urban land take, curb nitrogen pollution and maintain and restore nature along rivers.
Genomic Analyses of Breast Cancer Progression Reveal Distinct Routes of Metastasis Emergence
Authors: Krøigård Anne Bruun , Larsen Martin Jakob , Brasch-Andersen Charlotte , Lænkholm Anne-Vibeke , Knoop Ann S. , Jensen Jeanette Dupont , Bak Martin , Mollenhauer Jan , Thomassen Mads , Kruse Torben A.
Published: March 2017

A main controversy in cancer research is whether metastatic abilities are present in the most advanced clone of the primary tumor or result from independently acquired aberrations in early disseminated cancer cells as suggested by the linear and the parallel progression models, respectively. The genetic concordance between different steps of malignant progression is mostly unexplored as very few studies have included cancer samples separated by both space and time. We applied whole exome sequencing and targeted deep sequencing to 26 successive samples from six patients with metastatic estrogen receptor (ER)-positive breast cancer. Our data provide support for both linear and parallel progression towards metastasis. We report for the first time evidence of metastasis-to-metastasis seeding in breast cancer. Our results point to three distinct routes of metastasis emergence. This may have profound clinical implications and provides substantial novel molecular insights into the timing and mutational evolution of breast cancer metastasis.
IGF-1 potentiates sensory innervation signalling by modulating the mitochondrial fission/fusion balance
Authors: Ding Yuan , Li Jianmin , Liu Zhen , Liu Huaxiang , Li Hao , Li Zhenzhong
Published: March 2017

Restoring the contractile function of long-term denervated skeletal muscle (SKM) cells is difficult due to the long period of denervation, which causes a loss of contractility. Although sensory innervation is considered a promising protective approach, its effect is still restricted. In this study, we introduced insulin-like growth factor-1 (IGF-1) as an efficient protective agent and observed that IGF-1 potentiated the effects of sensory protection by preventing denervated muscle atrophy and improving the condition of denervated muscle cells in vivo and in vitro. IGF-1-induced Akt phosphorylation suppressed the mitochondrial outer-membrane protein Mul1 expression, which is a key step on preserving contractile property of sensory innervated SKM cells. Mul1 overexpression interfered with the balance between mitochondrial fusion and fission and was a key node for blocking the effects of IGF-1 that preserved the contractility of sensory-innervated SKM cells. Activation of AMP-activated protein kinase α (AMPKα), a mitochondrial downstream target, could block the effects of IGF-1. These data provide novel evidence that might be applied when searching for new approaches to improve the functional condition of long-term denervated SKM cells by increasing sensory protection using the IGF-1 signalling system to modulate the balance between mitochondrial fusion and fission.
MRI Assessment of Cardiomyopathy Induced by β1-Adrenoreceptor Autoantibodies and Protection Through β3-Adrenoreceptor Overexpression
Authors: Vanhoutte Laetitia , Guilbaud Céline , Martherus Ruben , Bouzin Caroline , Gallez Bernard , Dessy Chantal , Balligand Jean-Luc , Moniotte Stéphane , Feron Olivier
Published: March 2017

The cardiopathogenic role of autoantibodies (aabs) directed against β1-adrenoreceptors (β1-AR) is well established. In mouse models, they cause progressive dilated cardiomyopathy (DCM) whose characterization with echocardiography requires prolonged protocols with numerous animals, complicating the evaluation of new treatments. Here, we report on the characterization of β1-aabs-induced DCM in mice using 11.7T MRI. C57BL/6J mice (n = 10 per group) were immunized against the β1-AR and left ventricular (LV) systolic function was assessed at 10, 18 and 27 weeks. Increase in LV mass/tibial length ratio was detected as the first modification at 10 weeks together with dilation of cavities, thereby outperforming echocardiography. Significant impairment in diastolic index was also observed in immunized animals before the onset of systolic dysfunction. Morphometric and histological measurements confirmed these observations. The same protocol performed on β3-AR-overexpressing mice and wild-type littermates (n = 8–12 per group) showed that transgenic animals were protected with reduced LV/TL ratio compared to wild-type animals and maintenance of the diastolic index. This study demonstrates that MRI allows a precocious detection of the subtle myocardial dysfunction induced by β1-aabs and that β3-AR stimulation blunts the development of β1-aabs-induced DCM, thereby paving the way for the use of β3AR-stimulating drugs to treat this autoimmune cardiomyopathy.
Correction: Corrigendum: Evidence of genotypic adaptation to the exposure to volcanic risk at the dopamine receptor DRD4 locus
Authors: Faurie Charlotte , Mettling Clement , Bchir Mohamed Ali , Hadmoko Danang Sri , Heitz Carine , Lestari Evi Dwi , Raymond Michel , Willinger Marc
Published: March 2017

Scientific Reports 6: Article number: 37745; published online: 01 December 2016; updated: 09 March 2017 The Acknowledgements section in this Article is incomplete. “Genotyping Data used in this work were produced through the technical facilities of ISEM (Institut des Sciences de l’Evolution-Montpellier) and Labex Centre Méditerranéen Environnement Biodiversité.
Isolation mediates persistent founder effects on zooplankton colonisation in new temporary ponds
Authors: Badosa Anna , Frisch Dagmar , Green Andy J. , Rico Ciro , Gómez Africa
Published: March 2017

Understanding the colonisation process in zooplankton is crucial for successful restoration of aquatic ecosystems. Here, we analyzed the clonal and genetic structure of the cyclical parthenogenetic rotifer Brachionus plicatilis by following populations established in new temporary ponds during the first three hydroperiods. Rotifer populations established rapidly after first flooding, although colonisation was ongoing throughout the study. Multilocus genotypes from 7 microsatellite loci suggested that most populations (10 of 14) were founded by few clones. The exception was one of the four populations that persisted throughout the studied hydroperiods, where high genetic diversity in the first hydroperiod suggested colonisation from a historical egg bank, and no increase in allelic diversity was detected with time. In contrast, in another of these four populations, we observed a progressive increase of allelic diversity. This population became less differentiated from the other populations suggesting effective gene flow soon after its foundation. Allelic diversity and richness remained low in the remaining two, more isolated, populations, suggesting little gene flow. Our results highlight the complexity of colonisation dynamics, with evidence for persistent founder effects in some ponds, but not in others, and with early immigration both from external source populations, and from residual, historical diapausing egg banks.
Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors
Authors: Chen Yunching , Liu Ya-Chi , Sung Yun-Chieh , Ramjiawan Rakesh R. , Lin Ts-Ting , Chang Chih-Chun , Jeng Kuo-Shyang , Chang Chiung-Fang , Liu Chun-Hung , Gao Dong-Yu , Hsu Fu-Fei , Duyverman Annique M. , Kitahara Shuji , Huang Peigen , Dima Simona , Popescu Irinel , Flaherty Keith T. , Zhu Andrew X. , Bardeesy Nabeel , Jain Rakesh K. , Benes Cyril H. , Duda Dan G.
Published: March 2017

Sorafenib is a RAF inhibitor approved for several cancers, including hepatocellular carcinoma (HCC). Inhibition of RAF kinases can induce a dose-dependent “paradoxical” upregulation of the downstream mitogen-activated protein kinase (MAPK) pathway in cancer cells. It is unknown whether “paradoxical” ERK activation occurs after sorafenib therapy in HCC, and if so, if it impacts the therapeutic efficacy. Here, we demonstrate that RAF inhibition by sorafenib rapidly leads to RAF dimerization and ERK activation in HCCs, which contributes to treatment evasion. The transactivation of RAF dimers and ERK signaling promotes HCC cell survival, prevents apoptosis via downregulation of BIM and achieves immunosuppression by MAPK/NF-kB-dependent activation of PD-L1 gene expression. To overcome treatment evasion and reduce systemic effects, we developed CXCR4-targeted nanoparticles to co-deliver sorafenib with the MEK inhibitor AZD6244 in HCC. Using this approach, we preferentially and efficiently inactivated RAF/ERK, upregulated BIM and down-regulated PD-L1 expression in HCC, and facilitated intra-tumoral infiltration of cytotoxic CD8+ T cells. These effects resulted in a profound delay in tumor growth. Thus, this nano-delivery strategy to selectively target tumors and prevent the paradoxical ERK activation could increase the feasibility of dual RAF/MEK inhibition to overcome sorafenib treatment escape in HCC.
The efficacy and safety of SGLT2 inhibitors for adjunctive treatment of type 1 diabetes: a systematic review and meta-analysis
Authors: Chen Jiao , Fan Fang , Wang J. Y. , Long Yang , Gao C. L. , Stanton R. C. , Xu Yong
Published: March 2017

To assess the efficacy and safety of the SGLT-2 inhibitors as adjunct therapy to insulin in T1DM, clinical trials indexed in PubMed, Cochrane Library, EMbase from inception through April 5, 2016. A meta-analysis was conducted on trials of SGLT-2 inhibitors in patients with T1DM on insulin therapy using RevMan 5.3 software. Of the 371 articles identified, ten met eligibility criteria. Seven clinical trials including four randomized controlled trials and 581 patients were included. Compared with the control group, SGLT-2 inhibitors group had significantly reduced fasting plasma glucose by 0.69 mmol/L [1.32; 0.07], glycosylated hemoglobin A1C by 0.37% [0.54; 0.20], body weight by 2.54 kg [3.48; 1.60] and total daily insulin dose by 6.22 IU [8.04; 4.40]. The total incidence of adverse events (AEs), hypoglycemia, and genital and urinary infections were also similar to placebo, while an increased incidence of diabetic ketoacidosis (DKA) (n = 16) was seen in SGLT-2 inhibitors group. The present study demonstrates that SGLT-2 inhibitors are effective as adjunct therapy to insulin in T1DM, heralding improved glycemic control, reduced body weight and total daily insulin dose without an increase in total AEs, hypoglycemia, or genital and urinary infections. However, the risk of DKA should be carefully monitored in future clinical trials.
Electrochemical tuning of the optical properties of nanoporous gold
Authors: Jalas D. , Shao L.-H. , Canchi R. , Okuma T. , Lang S. , Petrov A. , Weissmüller J. , Eich M.
Published: March 2017

Using optical in-situ measurements in an electrochemical environment, we study the electrochemical tuning of the transmission spectrum of films from the nanoporous gold (NPG) based optical metamaterial, including the effect of the ligament size. The long wavelength part of the transmission spectrum around 800 nm can be reversibly tuned via the applied electrode potential. The NPG behaves as diluted metal with its transition from dielectric to metallic response shifted to longer wavelengths. We find that the applied potential alters the charge carrier density to a comparable extent as in experiments on gold nanoparticles. However, compared to nanoparticles, a NPG optical metamaterial, due to its connected structure, shows a much stronger and more broadband change in optical transmission for the same change in charge carrier density. We were able to tune the transmission through an only 200 nm thin sample by 30%. In combination with an electrolyte the tunable NPG based optical metamaterial, which employs a very large surface-to-volume ratio is expected to play an important role in sensor applications, for photoelectrochemical water splitting into hydrogen and oxygen and for solar water purification.
Biotic and abiotic factors predicting the global distribution and population density of an invasive large mammal
Authors: Lewis Jesse S. , Farnsworth Matthew L. , Burdett Chris L. , Theobald David M. , Gray Miranda , Miller Ryan S.
Published: March 2017

Biotic and abiotic factors are increasingly acknowledged to synergistically shape broad-scale species distributions. However, the relative importance of biotic and abiotic factors in predicting species distributions is unclear. In particular, biotic factors, such as predation and vegetation, including those resulting from anthropogenic land-use change, are underrepresented in species distribution modeling, but could improve model predictions. Using generalized linear models and model selection techniques, we used 129 estimates of population density of wild pigs (Sus scrofa) from 5 continents to evaluate the relative importance, magnitude, and direction of biotic and abiotic factors in predicting population density of an invasive large mammal with a global distribution. Incorporating diverse biotic factors, including agriculture, vegetation cover, and large carnivore richness, into species distribution modeling substantially improved model fit and predictions. Abiotic factors, including precipitation and potential evapotranspiration, were also important predictors. The predictive map of population density revealed wide-ranging potential for an invasive large mammal to expand its distribution globally. This information can be used to proactively create conservation/management plans to control future invasions. Our study demonstrates that the ongoing paradigm shift, which recognizes that both biotic and abiotic factors shape species distributions across broad scales, can be advanced by incorporating diverse biotic factors.
Regulation of molecular clock oscillations and phagocytic activity via muscarinic Ca2+ signaling in human retinal pigment epithelial cells
Authors: Ikarashi Rina , Akechi Honami , Kanda Yuzuki , Ahmad Alsawaf , Takeuchi Kouhei , Morioka Eri , Sugiyama Takashi , Ebisawa Takashi , Ikeda Masaaki , Ikeda Masayuki
Published: March 2017

Vertebrate eyes are known to contain circadian clocks, however, the intracellular mechanisms regulating the retinal clockwork remain largely unknown. To address this, we generated a cell line (hRPE-YC) from human retinal pigmental epithelium, which stably co-expressed reporters for molecular clock oscillations (Bmal1-luciferase) and intracellular Ca2+ concentrations (YC3.6). The hRPE-YC cells demonstrated circadian rhythms in Bmal1 transcription. Also, these cells represented circadian rhythms in Ca2+-spiking frequencies, which were canceled by dominant-negative Bmal1 transfections. The muscarinic agonist carbachol, but not photic stimulation, phase-shifted Bmal1 transcriptional rhythms with a type-1 phase response curve. This is consistent with significant M3 muscarinic receptor expression and little photo-sensor (Cry2 and Opn4) expression in these cells. Moreover, forskolin phase-shifted Bmal1 transcriptional rhythm with a type-0 phase response curve, in accordance with long-lasting CREB phosphorylation levels after forskolin exposure. Interestingly, the hRPE-YC cells demonstrated apparent circadian rhythms in phagocytic activities, which were abolished by carbachol or dominant-negative Bmal1 transfection. Because phagocytosis in RPE cells determines photoreceptor disc shedding, molecular clock oscillations and cytosolic Ca2+ signaling may be the driving forces for disc-shedding rhythms known in various vertebrates. In conclusion, the present study provides a cellular model to understand molecular and intracellular signaling mechanisms underlying human retinal circadian clocks.
Microwave Study of Field-Effect Devices Based on Graphene/Aluminum Nitride/Graphene Structures
Authors: Adabi Mohammad , Lischner Johannes , Hanham Stephen M. , Mihai Andrei P. , Shaforost Olena , Wang Rui , Hao Ling , Petrov Peter K. , Klein Norbert
Published: March 2017

Metallic gate electrodes are often employed to control the conductivity of graphene based field effect devices. The lack of transparency of such electrodes in many optical applications is a key limiting factor. We demonstrate a working concept of a double layer graphene field effect device that utilizes a thin film of sputtered aluminum nitride as dielectric gate material. For this system, we show that the graphene resistance can be modified by a voltage between the two graphene layers. We study how a second gate voltage applied to the silicon back gate modifies the measured microwave transport data at around 8.7 GHz. As confirmed by numerical simulations based on the Boltzmann equation, this system resembles a parallel circuit of two graphene layers with different intrinsic doping levels. The obtained experimental results indicate that the graphene-aluminum nitride-graphene device concept presents a promising technology platform for terahertz- to- optical devices as well as radio-frequency acoustic devices where piezoelectricity in aluminum nitride can also be exploited.