bluuebunny/crossref_metadata_2025 huggingface dataset:
High‐Content Screening Identifies Src Family Kinases as Potential Regulators of AR‐V7 Expression and Androgen‐Independent Cell Growth
Authors: Szafran Adam T. , Stephan Cliff , Bolt Michael , Mancini Maureen G. , Marcelli Marco , Mancini Michael A.
Published: October 2016

BACKGROUND

AR‐V7 is an androgen receptor (AR) splice variant that lacks the ligand‐binding domain and is isolated from prostate cancer cell lines. Increased expression of AR‐V7 is associated with the transition from hormone‐sensitive prostate cancer to more advanced castration‐resistant prostate cancer (CRPC). Due to the loss of the ligand‐binding domain, AR‐V7 is not responsive to traditional AR‐targeted therapies, and the mechanisms that regulate AR‐V7 are still incompletely understood. Therefore, we aimed to explore existing classes of small molecules that may regulate AR‐V7 expression and intracellular localization and their potential therapeutic role in CRPC.

METHODS

We used AR high‐content analysis (AR‐HCA) to characterize the effects of a focused library of well‐characterized clinical compounds on AR‐V7 expression at the single‐cell level in PC3 prostate cancer cells stably expressing green fluorescent protein (GFP)‐AR‐V7 (GFP‐AR‐V7:PC3). In parallel, an orthogonal AR‐HCA screen of a small interfering (si)RNA library targeting 635 protein kinases was performed in GFP‐AR‐V7:PC3. The effect of the Src‐Abl inhibitor PD 180970 was further characterized using cell‐proliferation assays, quantitative PCR, and western blot analysis in multiple hormone‐sensitive and CRPC cell lines.

RESULTS

Compounds that tended to target Akt, Abl, and Src family kinases (SFKs) decreased overall AR‐V7 expression, nuclear translocation, absolute nuclear level, and/or altered nuclear distribution. We identified 20 protein kinases that, when knocked down, either decreased nuclear GFP‐AR‐V7 levels or altered AR‐V7 nuclear distribution, a set that included the SFKs Src and Fyn. The Src‐Abl dual kinase inhibitor PD180970 decreased expression of AR‐V7 by greater than 46% and decreased ligand‐independent transcription of AR target genes in the 22RV1 human prostate carcinoma cell line. Further, PD180970 inhibited androgen‐independent cell proliferation in endogenous—AR‐V7—expressing prostate cancer cell lines and also overcame bicalutamide resistance observed in the 22RV1 cell line.

CONCLUSIONS

SFKs, especially Src and Fyn, may be important upstream regulators of AR‐V7 expression and represent promising targets in a subset of CRPCs expressing high levels of AR‐V7. Prostate 77:82–93, 2017. © 2016 Wiley Periodicals, Inc.
Prostate Specific Antigen‐Growth Curve Model to Predict High‐Risk Prostate Cancer
Authors: Shoaibi Azza , Rao Gowtham A. , Cai Bo , Rawl John , Haddock Kathlyn Sue , Hébert James R.
Published: October 2016

PURPOSE

To investigate if a prostate specific antigen (PSA)‐derived growth curve can predict the occurrence of high‐risk prostate cancer (PrCA).

METHODS

Data from 38,340 men randomized to the PrCA screening arm in the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO) were used to develop a PSA growth curve model to estimate PSA rate of change. The model was then used to predict high‐risk PrCA in clinical data available from 680,390 veterans seeking routine care. The PSA growth curve was modeled using non‐linear mixed regression and the PSA rate was estimated by taking the 1st derivative of the growth curve equation at 1 year prior to diagnosis/exit.

RESULTS

In the PLCO, PrCA incidence was 8.1%; ≈19% of whom had high‐risk PrCA. Overall, a PSA rate threshold of 0.37 ng/ml/year had the best combination of sensitivity (97.2%) and specificity (97.3%) for detecting high‐risk PrCA. In the VA data; 7,347 men were diagnosed with PrCA; of these 4,315 (58.7%) were diagnosed with high‐risk PrCA. The PLCO optimal threshold of 0.37 ng/ml/year produced sensitivity = 95.5% and specificity = 85.2%. An optimal threshold of 0.99 ng/ml/year in AA produced sensitivity = 89.1% and specificity = 80.0%. PSA rate was a better predictor than the single last PSA value.

CONCLUSIONS

PSA growth curves predicted high‐risk PrCA in the PLCO data. Fitting the same algorithm in the VA data produced lower specificity. Although encouraging, this finding underlines the need for further research to prospectively test the algorithm, especially for African‐American men, the population group at highest risk of aggressive PrCA. Prostate 77:173–184, 2017. © 2016 Wiley Periodicals, Inc.
Anisotropic Elliott–Yafet theory and application to KC8 potassium intercalated graphite
Authors: Márkus Bence G. , Szolnoki Lénárd , Iván Dávid , Dóra Balázs , Szirmai Péter , Náfrádi Bálint , Forró László , Simon Ferenc
Published: October 2016

We report electron spin resonance (ESR) measurements on stage‐I potassium intercalated graphite (KC). Angular dependent measurements show that the spin–lattice relaxation time is longer when the magnetic field is perpendicular to the graphene layer as compared to when the magnetic field is in the plane. This anisotropy is analyzed in the framework of the Elliott–Yafet theory of spin‐relaxation in metals. The analysis considers an anisotropic spin–orbit Hamiltonian and the first order perturbative treatment of Elliott is reproduced for this model Hamiltonian. The result provides an experimental input for the first‐principles theories of spin–orbit interaction in layered carbon and thus to a better understanding of spin‐relaxation phenomena in graphene and in other layered materials as well.
Rapid detection of alteration of serum IgG in patients with schizophrenia after risperidone treatment by matrix‐assisted laser desorption ionization/time‐of‐flight mass spectrometry
Authors: Lo Li‐Hua , Shiea Jentaie , Huang Tiao‐Lai
Published: October 2016

Rationale

The aim of the study was to use a technique that combines acid hydrolysis and matrix‐assisted laser desorption ionization/time‐of‐flight mass spectrometry (MALDI‐TOF MS) in order to detect the serum biomarkers of patients diagnosed with schizophrenia both before and after four‐week antipsychotic treatment with risperidone.

Methods

During this study's two‐year period, inpatients were diagnosed with schizophrenia using the Structured Clinical Interview for DSM‐IV Axis I Disorders. Severity was then evaluated using the Positive and Negative Syndrome Scale both at baseline and at endpoint following four‐week treatment with risperidone. The patients' serum biomarkers were quickly measured using acid hydrolysis and MALDI‐TOF MS. The resulting peptides were then analyzed using MALDI‐TOF MS. We constructed a receiver operating characteristic (ROC) curve for the evaluated biomarkers.

Results

We recruited 20 pairs of participants for this study. The experimental group was treated with serum protein with HCl for 10 minutes to effectively hydrolyze abundant proteins. The target peptide, the immunoglobulin gamma chain (IgG), was then rapidly detected using this manner. A significant difference was found in the IgG levels of patients with schizophrenia before and after antipsychotic treatment. We constructed a ROC curve based on the IgG, and the area under said curve was 0.969. In comparison to conventional detection protocols, this method takes only minutes to complete and is also less costly.

Conclusions

This study found that applying acid hydrolysis with MALDI‐TOF MS technology could rapidly differentiate serum IgG levels in patients with schizophrenia before and after being treated with risperidone. This IgG difference may enhance the understanding of mechanism of antipsychotic treatment of schizophrenia. Copyright © 2016 John Wiley & Sons, Ltd.
A Robot System for Pruning Grape Vines
Authors: Botterill Tom , Paulin Scott , Green Richard , Williams Samuel , Lin Jessica , Saxton Valerie , Mills Steven , Chen XiaoQi , Corbett‐Davies Sam
Published: October 2016

This paper describes a robot system for the automatic pruning of grape vines. A mobile platform straddles the row of vines, and it images them with trinocular stereo cameras as it moves. A computer vision system builds a three‐dimensional (3D) model of the vines, an artificial intelligence (AI) system decides which canes to prune, and a six degree‐of‐freedom robot arm makes the required cuts. The system is demonstrated cutting vines in the vineyard. The main contributions of this paper are the computer vision system that builds 3D vine models, and the test of the complete‐integrated system. The vine models capture the structure of the plants so that the AI system can decide where to prune, and they are accurate enough that the robot arm can reach the required cuts. Vine models are reconstructed by matching features between images, triangulating feature matches to give a 3D model, then optimizing the model and the robot's trajectory jointly (incremental bundle adjustment). Trajectories are estimated online at 0.25 m/s, and they have errors below 1% when modeling a 96 m row of 59 vines. Pruning each vine requires the robot arm to cut an average of 8.4 canes. A collision‐free trajectory for the arm is planned in intervals of 1.5 s/vine with a rapidly exploring random tree motion planner. The total time to prune one vine is 2 min in field trials, which is similar to human pruners, and it could be greatly reduced with a faster arm. Trials also show that the long chain of interdependent components limits reliability. A commercially feasible pruning robot should stop and prune each vine in turn.
A CRT‐based verifiable secret sharing scheme secure against unbounded adversaries
Authors: Ersoy Oğuzhan , Pedersen Thomas Brochmann , Kaya Kamer , Selçuk Ali Aydın , Anarim Emin
Published: October 2016

For commitments on secrets, statistical hiding is a must when we are dealing with a long‐term secret or when the secret domain is small enough for a brute‐force attack by a powerful adversary. Unfortunately, all the Chinese Remainder Theorem‐based verifiable secret sharing schemes in the literature are either insecure or suffer from the vulnerability of computationally hiding commitments. To the best of our knowledge, there exist five such studies where two of them were already proven to be insecure. In this work, we first show that two of the remaining schemes are also insecure, that is, the schemes reveal information on the secret even when the adversary is passive. In addition, the remaining one is only secure against a computationally bounded adversary which can be a problem for secret sharing schemes requiring long‐term secret obscurity or using small secret domain. We propose a modification for the latter scheme and prove that the modified scheme is a secure verifiable secret sharing scheme against an unbounded adversary. Lastly, as an application, we show how to use the new scheme for joint random secret sharing and analyze the practicality and efficiency of the proposed schemes. Copyright © 2016 John Wiley & Sons, Ltd.
A novel approach for privacy homomorphism using attribute‐based encryption
Authors: Doshi Nishant , Jinwala Devesh C.
Published: October 2016

In CRYPTO'13, Gentry et al. proposed the first homomorphic encryption (HE) scheme for the attribute‐based encryption (ABE). However, Gentry's scheme requires the same index for encryption of each ciphertext and supports only the key‐policy ABE. Indeed, in SECRYPT'13, Clear et al. left an open problem in the Gentry et al. scheme viz. a scheme that requires different sets of index in HE using ABE and supports the ciphertext‐policy ABE (CP‐ABE), where the sender is assumed to be intelligent. In addition, in INDOCRYPT'12, Vaikuntanathan discussed an open problem viz. to work out the HE using cryptographic techniques other than lattice‐based cryptography. With an aim to propose the CP‐ABE scheme using HE, in this research attempt, we propose an approach that integrates the benefits of HE in CP‐ABE and yet uses pairing‐based cryptography. In our approach viz. attribute‐based HE (AB‐HE), a user is able to successfully decrypt the ciphertext only if the attributes in the policy match those in the secret key. However, in addition, our approach also allows multiple invocations of multiplication operation on the ciphertext as in a typical partially HE, coupling the advantages of the partial HE in the CP‐ABE. Further, we also propose an extension of the proposed scheme that serves as a pseudo‐fully HE, but requires the help of a key authority. The security of the proposed scheme is based on the decisional bilinear Diffie–Hellman problem. To the best of our knowledge, ours is a unique attempt in integrating HE into the attribute‐based cryptography with different indexes/policies. In addition, our AB‐HE scheme is pairing‐based, and by adding more ciphertexts, it does not blow the final ciphertext size because we use the constant length ciphertext approach for the encryption. Copyright © 2016 John Wiley & Sons, Ltd.
Visa and Immigration Trends: A Comparative Examination of International Student Mobility in Canada, Australia, the United Kingdom, and the United States
Authors: Gopal Anita
Published: October 2016

This comparative study examines visa and immigration regulations for international students and focuses on macro‐level policy trends during the past five to ten years in four English‐speaking countries: Canada, Australia, the United Kingdom, and the United States. The study highlights the trends and motivations to recruit international graduate students as valuable skilled labor and potential designer immigrants in order to compete in the global economic market. Based on the analysis of policy documents and secondary data, it was found that there is a weak connection between higher education institutions and national security or customs and border protection agencies and the role that they play on international education. Also, the ease and expense of obtaining a student visa greatly influences international student enrollment trends.
A new taxon of cistecephalid dicynodont from the upper Permian Kundaram Formation of India
Authors: Kammerer Christian F. , Bandyopadhyay Saswati , Ray Sanghamitra
Published: October 2016

A new cistecephalid dicynodont,Sauroscaptor tharavatigen. et sp. nov., is described from the upper Permian Kundaram Formation of India. This taxon is represented by specimens formerly referred to the African dicynodont generaCistecephalusandEmydops.Sauroscaptorcan be distinguished from other cistecephalids by the extremely posterior position of the pineal foramen (overhanging the edge of the occiput), bipartite nuchal crest, and relatively narrow skull roof. The recognition ofSauroscaptoras a distinct cistecephalid taxon adds to the increasing evidence for high levels of basinal endemism in this family. However, dicynodont biogeographical patterns are complex, and there is no simple relationship between inferred dispersal ability based on body size and levels of endemicity within clades.
Longitudinal functional additive model with continuous proportional outcomes for physical activity data
Authors: Li Haocheng , Keadle Sarah Kozey , Kipnis Victor , Carroll Raymond J.
Published: October 2016

Motivated by physical activity data obtained from the BodyMedia FIT device (http://www.bodymedia.com), we take a functional data approach for longitudinal studies with continuous proportional outcomes. The functional structure depends on three factors. In our three‐factor model, the regression structures are specified as curves measured at various factor points with random effects that have a correlation structure. The random curve for the continuous factor is summarized using a few important principal components. The difficulties in handling the continuous proportion variables are solved by using a quasilikelihood‐type approximation. We develop an efficient algorithm to fit the model, which involves the selection of the number of principal components. The method is evaluated empirically by a simulation study. This approach is applied to the BodyMedia data with 935 males and 84 consecutive days of observation, for a total of 78,540 observations. We show that sleep efficiency increases with increasing physical activity, while its variance decreases at the same time. Copyright © 2016 John Wiley & Sons, Ltd.
Bürogebäude mit städtebaulicher Funktion
Authors: Seidel Marc
Published: October 2016

Zentral gelegen im Bonner Bundesviertel befindet sich seit dem Jahr 2013 die moderne Unternehmenszentrale der Beratungsgesellschaft DHPG. Das fünfgeschossige Bürogebäude zeichnet sich in seiner Außenwirkung durch die elegante Kombination aus Glas und Beton mit markanter Rippenstruktur und einem Stahlverbundtragwerk aus. Das Bauunternehmen Goldbeck war von der Planungsberatung an über die gesamte Ausführung bis zur schlüsselfertigen Übergabe für das Bauvorhaben verantwortlich. Im Rahmen eines vorgeschalteten Architektenwettbewerbs wurde das Büro Prof. Schmitz Architekten mit der architektonischen Gestaltung beauftragt. Errichtet wurde das Gebäude innerhalb von nur 16 Monaten. Der Rohbau besteht komplett aus Systembauteilen mit einem hohen Vorfertigungsgrad, die gestapelte Fassade entwickelten Goldbeck und die Architekten aus Betonfertigteilen mit individueller Rezeptur. Beim Innenausbau standen der Komfortgedanke und ein kommunikatives Arbeitsumfeld unter Nutzung einer einheitlichen Designsprache im Mittelpunkt. Der Beitrag beleuchtet am Beispiel DHPG die Vielseitigkeit und die Vorteile der elementierten Systembauweise.

Office building with an impact on urban architecture – DHPG Head Office in Bonn. The modern head office of the advisory firm DHPG has been centrally located in Bonn's Federal Quarter (Bundesviertel) since 2013. Due to its elegant combination of glass and concrete featuring prominent ribbing and a composite steel structure, the five‐storey office building stands out from its surroundings. Goldbeck consulted on planning and design, and oversaw the entire construction project from the beginning to turnkey handover. Prof. Schmitz Architekten won an architectural competition prior to the project and was commissioned to design the building's architecture. Construction took just 16 months. The shell is made entirely of system components, many of which were pre‐fabricated. Goldbeck and the architects developed the graduated facade from customised precast concrete elements. Interior design and construction centred on comfort and a communicative working environment with a uniform design language. The article highlights the diversity and advantages of system construction based on the example of DHPG.
Ersatzneubau der Talbrücke Heidingsfeld
Authors: Langer Stephan
Published: October 2016

50 Jahre nach ihrer Erbauung weicht die 665 m lange Talbrücke Heidingsfeld einem Ersatzneubau. Dabei kommt für den Stahlverbundüberbau aus dem Jahr 1964 erneut ein Stahlverbundquerschnitt zum Zuge, der je Fahrtrichtung durch einen modernen einzelligen Stahlhohlkasten mit außenliegenden Kragarmen und aufbetonierter Fahrbahnplatte gebildet wird. Aufgrund der topographischen Verhältnisse und der Bedingungen zur Aufrechterhaltung eines 4+0‐Verkehrs erfolgt die Montage durch Längseinschub der Stahlkonstruktion mit Stützweiten bis zu 120 m.

Replacement of the viaduct Heidingsfeld. 50 years after its construction the 665 m long viaduct Heidingsfeld will be totally replaced. Hereby the steel composite superstructure from 1964 is constructed again as a steel composite section, which is formed in every roadway by a modern unicellular steel box with external cantilevers and concreted slab. Due to the topographical conditions and the conditions for maintaining a 4+0 traffic the steel construction will be installed by longitudinal launching with spans up to 120 m.
Rio 2016 – Ein Rückblick
Authors: Stockhusen Knut
Published: October 2016

Wenn man schon nicht als Sportler bei den Olympischen Spielen teilnehmen kann, dann bietet der Beruf des Ingenieurs wider Erwarten eine Alternative. Es gibt garantiert keine Medaillen zu gewinnen, aber auch hier gilt “Dabeisein ist alles”. Dass “unser” Maracanã‐Stadion eine Hauptrolle bei der Olympiade spielen würde, war zu erwarten. Dass wir Teil des Teams zur Planung der Eröffnungs‐ und Schlusszeremonie werden würden, und somit ein ganz ungewöhnliches Betätigungsfeld für Ingenieure erschließen würden, war nicht vorherzusehen. Auch die restlichen Planungsaufgaben für die größtenteils temporären Tennis‐ und Schwimmanlagen und die Live Site eröffneten neue Perspektiven und Herausforderungen. Alles in allem waren es sehr spannende Jahre mit einem tollen Finale.

Rio 2016. If you can't make it to the Olympics as an athlete, then maybe you should try engineering. There's no medals to be won, but the most important thing is to take part. That “our” Maracanã Stadium would play a major role at the Olympics goes without saying, but the fact that we would end up being part of the team to plan the opening and closing ceremonies went well beyond our expectations, opening up a very different field of engineering. Even the planning for the (in large parts) temporary tennis and swimming facilities revealed a host of new perspectives and challenges. Altogether, it was a very exciting time with beautiful games.
Note on a Noetherian conservation law and its corresponding general class of nonlinear second‐order ordinary differential equations
Authors: Casetta Leonardo
Published: October 2016

By virtue of their fundamental nature and intrinsic elegance, there has long been a great interest in searching for the conservation laws of the problem at hand. In such field of research, the famous Noether's theorem has been recognized as a highlight. The objective of our note is to provide the reader with an original contribution to the study of Noetherian conservation laws. Namely, we aim at connecting a general class of nonlinear second‐order ordinary differential equations with a Noetherian conservation law. Our analysis will be considered within the known structure of Noether's theorem. An aspect to be here emphasized is that, particularly, we will use the following simplifying assumptions: the invariance condition holds absolutely, the transformation generators do not depend on the derivative of the generalized coordinate with respect to the independent variable. We will present our contribution via a theorem and a corollary. First, our theorem will establish a general condition to obtain Noetherian conservation law for a certain type of variational problem. Then, the corollary will demonstrate that such Noetherian conservation law is a first integral for a general class of nonlinear second‐order ordinary differential equations. This class of differential equations means the Lagrange's equation directly resulting from that type of variational problem. Last, a case of the Emden‐Fowler equation will be presented as a testing example.
Surgical Strategy and Outcome in Patients Undergoing Pancreaticoduodenectomy After Gastric Resection: A Three‐Center Experience with 39 Patients
Authors: Lee Dooin , Lee Jae Hoon , Choi Dongho , Kang Chang Moo , Chong Jae Uk , Kim Song‐Chul , Lee Kyeong Geun
Published: October 2016

Background

Stomach cancer is the second most commonly diagnosed cancer in Korea. Although the long‐term survival outcome has improved, secondary primary tumors from periampullary regions are increasing inevitably and pancreaticoduodenectomy (PD) following gastrectomy is challenging. This study evaluates the surgical outcomes of PD following gastrectomy and suggests the optimum method for reconstruction.

Methods

Patients who underwent curative PD with a history of gastric resection between 2005 and 2015 were assessed retrospectively. PD was performed according to the standard fashion, with the aim of creating a new pancreaticobiliary limb with sufficient length (40–50 cm). Different reconstructive methods were employed during PD according to the previous gastrectomy type.

Results

A total of 3064 patients underwent PD, 39 of whom had previous gastrectomies including 12 with Billroth I gastrectomy, 20 with Billroth II gastrectomy, and seven patients with total gastrectomy (TG). In patients with Billroth I gastrectomy, all of the previous gastroduodenostomy site was resected for specimen retrieval. All previous esophagojejunostomy site was preserved in seven patients who had TG. In the Billroth II patients, the gastrojejunostomy site was preserved in 17 patients. Re‐operation after PD was required in two patients, and 14 patients (36 %) developed pancreatic fistula and five (13 %) of grade B or higher.

Conclusions

Our study has been the largest report so far of PD following gastric resection, and we were able to confirm the safety and the feasibility of PD procedure. We therefore suggest standardizing the reconstruction method for PD following gastrectomy based on the type of previous gastrectomy.
Stanniocalcin 1 Enhances Carbon Flux from Glucose to Lipids in White Retroperitoneal Adipose Tissue in the Fed Rat
Authors: Cozer Aline G. , Trapp Márcia , Vieira Marques Claudia , Martins Tiago L. , Model Jorge Felipe A. , Schein Vanessa , Kucharski Luiz Carlos , Da Silva Roselis S. M.
Published: October 2016

The present work assesses in vitro the role of human Stanniocalcin 1 (hSTC‐1) in glucose metabolism in white retroperitoneal adipose tissue (WRAT) from fed rat. In the fed state, hSTC1 increases the incorporation of 14C from glucose into lipids in the rat WRAT. The increase in lipogenesis capacity supports the hypothesis that the activity of the glycerol‐3‐phosphate‐generating pathway (glycolysis) from glucose is regulated by hSTC‐1. The effect of hSTC‐1 on de novo fatty acid synthesis and on glucose oxidation in WRAT is supported by an 85 % increase in 14CO2 production from 14C‐glucose. The incubation of WRAT in the presence of hSTC‐1 maintained the ADP/ATP ratio close to the control group. The presence of hSTC‐1 in the incubation medium did not inhibit the lipolytic effect of epinephrine. In conclusion, hSTC‐1 is one of the hormonal factors that control glucose metabolism in WRAT in the fed state.
Histological and adhesiogenic characterization of the Zenapro Hybrid Hernia Repair Device
Authors: Hodde Jason P. , Suckow Mark D. , Johnson Chad , Rodenberg Eric , Ritchie Rae D.
Published: October 2016

Abstract

Background

A major clinical problem relating to hernia repair is the formation of intra-abdominal, post-surgical adhesions when mesh products are used to reinforce the abdominal wall. To achieve better outcomes, more technologically-advanced products designed to achieve permanence of repair while eliminating serious complications such as adhesion formation are needed. This study was designed to assess the histological remodeling and adhesiogenic properties of the Zenapro™ Hybrid Hernia Repair Device as compared to uncoated and coated polypropylene.

Materials and Methods

Zenapro™, Prolene® and Ventralight® ST Mesh were implanted to repair full-thickness abdominal wall defects in rabbits and rats and were allowed to survive for various lengths of time. Animals were euthanized, the implants were identified, and the extent and tenacity of adhesions were evaluated. Tissue samples were collected and evaluated for inflammation, integration of the mesh with the abdominal wall, and collagen deposition.

Results

A significant difference was found in the extent of adhesions in the Prolene group as compared to the Zenapro group (p = 0.021) and the Ventralight ST group (p = 0.04) in the rat study. The tenacity of the adhesions in the Prolene mesh group trended higher than in the other groups but failed to reach statistical significance. Histological evaluation demonstrated that collagen accumulation was greatest for the Zenapro implants as compared to either the Ventralight ST or Prolene samples. At the conclusion of 6-months in the rabbit model, the Zenapro sites showed signs of a thicker repair composed of more organized mature collagen than was seen in the Ventralight ST samples. Neither device was found to elicit any sort of detrimental inflammatory tissue reaction.

Conclusion

A combination hernia device composed of a complete extracellular matrix with a synthetic mesh can result in enhanced tissue ingrowth and neovascularization while maintaining high tensile strength and mitigating adhesiogenic effects.

Highlights
Lamivudine switch therapy in chronic hepatitis B patients achieving undetectable hepatitis B virus DNA after 3 years of entecavir therapy: A prospective, open‐label, multicenter study
Authors: Yeh Ming‐Lun , Huang Ching‐I. , Hsieh Ming‐Yen , Huang Chung‐Feng , Hsieh Meng‐Hsuan , Huang Jee‐Fu , Dai Chia‐Yen , Lin Zu‐Yau , Chen Shinn‐Chern , Yu Ming‐Lung , Chuang Wan‐Long
Published: October 2016

The subsequent maintenance therapy in chronic hepatitis B (CHB) patients after long‐term viral replication suppression is still uncertain. We aim to evaluate the efficacy of lamivudine (LAM) maintenance therapy in CHB patients achieving undetectable hepatitis B virus (HBV) DNA after 3 years of entecavir (ETV) therapy. Consecutive CHB patients who received at least 3 years of ETV and achieved HBV DNA negativity were allocated either LAM switch therapy or stopped ETV therapy in a prospective, open‐label study. Another group of sex‐ and age‐matched patients with continuous ETV therapy for at least 4 years served as historical control group. The primary outcome measurement of the study was relapse of HBV DNA (defined as serum HBV DNA level ≥ 2000 IU/mL). A total of 74 patients, including 42 of LAM switch and 32 of the nonswitch group, were enrolled. There were no significant differences in demographics, except a higher proportion of patients with positive hepatitis B envelope antigen in the nonswitch group at the initiation of ETV therapy. The LAM switch group had significantly lower 1‐year relapse rate of HBV within 1 year compared to the nonswitch group (14.3% vs. 75%, p < 0.001). However, none of the 48 historical control patients developed relapse of HBV, which was significantly lower than the rate in LAM switch group (p < 0.001). LAM switch was the only factor associated with HBV DNA relapse. In conclusion, continuous long‐term potent nucleot(s)ide analogue therapy is mandatory for prevention of viral relapse in CHB patients.
Epigenetic determinants of metastasis
Authors: Patel Saroor A. , Vanharanta Sakari
Published: October 2016

Genetic analyses of cancer progression in patient samples and model systems have thus far failed to identify specific mutational drivers of metastasis. Yet, at least in experimental systems, metastatic cancer clones display stable traits that can facilitate progression through the many steps of metastasis. How cancer cells establish and maintain the transcriptional programmes required for metastasis remains mostly unknown. Emerging evidence suggests that metastatic traits may arise from epigenetically altered transcriptional output of the oncogenic signals that drive tumour initiation and early progression. Molecular dissection of such mechanisms remains a central challenge for a comprehensive understanding of the origins of metastasis.
Tumor cell dormancy
Authors: Gomis Roger R. , Gawrzak Sylwia
Published: October 2016

Metastasis is the primary cause of death in cancer patients and current treatments fail to provide durable responses. Efforts to treat metastatic disease are hindered by the fact that metastatic cells often remain dormant for prolonged intervals of years, or even decades. Tumor dormancy reflects the capability of disseminated tumor cells (DTCs), or micrometastases, to evade treatment and remain at low numbers after primary tumor resection. Unfortunately, dormant cells will eventually produce overt metastasis. Innovations are needed to understand metastatic dormancy and improve cancer detection and treatment. Currently, few models exist that faithfully recapitulate metastatic dormancy and metastasis to clinically relevant tissues, such as the bone. Herein, we discuss recent advances describing genetic cell‐autonomous and systemic or local changes in the microenvironment that have been shown to endow DTCs with properties to survive and eventually colonize distant organs.
Trump Touts "Clean Coal" in Second Debate
Authors: Showstack Randy
Published: October 2016

The Republican presidential candidate also attacked regulation of energy production by the Environmental Protection Agency.
DNA N6-methyladenine demethylase ALKBH1 enhances osteogenic differentiation of human MSCs
Authors: Zhou Chenchen , Liu Yuting , Li Xiaobing , Zou Jing , Zou Shujuan
Published: October 2016

ALKBH1 was recently discovered as a demethylase for DNA N6-methyladenine (N6-mA), a new epigenetic modification, and interacts with the core transcriptional pluripotency network of embryonic stem cells. However, the role of ALKBH1 and DNA N6-mA in regulating osteogenic differentiation is largely unknown. In this study, we demonstrated that the expression of ALKBH1 in human mesenchymal stem cells (MSCs) was upregulated during osteogenic induction. Knockdown of ALKBH1 increased the genomic DNA N6-mA levels and significantly reduced the expression of osteogenic-related genes, alkaline phosphatase activity, and mineralization. ALKBH1-depleted MSCs also exhibited a restricted capacity for bone formation in vivo. By contrast, the ectopic overexpression of ALKBH1 enhanced osteoblastic differentiation. Mechanically, we found that the depletion of ALKBH1 resulted in the accumulation of N6-mA on the promoter region of ATF4, which subsequently silenced ATF4 transcription. In addition, restoring the expression of ATP by adenovirus-mediated transduction successfully rescued osteogenic differentiation. Taken together, our results demonstrate that ALKBH1 is indispensable for the osteogenic differentiation of MSCs and indicate that DNA N6-mA modifications area new mechanism for the epigenetic regulation of stem cell differentiation.
Protein tyrosine phosphatase PTPN22 has dual roles in promoting pathogen versus homeostatic‐driven CD8 T‐cell responses
Authors: Jofra Tatiana , Di Fonte Roberta , Hutchinson Tarun Edgar , Dastmalchi Farhad , Galvani Giuseppe , Battaglia Manuela , Salek‐Ardakani Shahram , Fousteri Georgia
Published: October 2016

PTPN22 (protein tyrosine phosphatase non receptor 22) encodes a tyrosine phosphatase that functions as a key regulator of immune homeostasis. In particular, PTPN22 inhibits T‐cell receptor signaling and selectively promotes type I interferon responses in myeloid cells. To date, there is little information on the CD8 T‐cell‐intrinsic role of PTPN22 in response to a viral pathogen. We unexpectedly found that PTPN22‐deficient virus‐specific CD8 T cells failed to accumulate in wild‐type hosts after lymphocytic choriomeningitis virus infection. Lack of PTPN22 expression altered CD8 T‐cell activation and antiviral cytokine production, but did not significantly affect the composition of effector and memory cell precursors. Most significantly, in vivo, PTPN22‐deficient CD8 T cells showed a profound defect in upregulating STAT‐1 after lymphocytic choriomeningitis virus infection and considerably less phosphorylation of STAT‐1 in response to IFN‐α treatment in vitro compared with their wild‐type counterparts. In stark contrast, following transfer into lymphopenic mice, CD8 T‐cell expansion and central‐like phenotype, was considerably increased in the absence of PTPN22. Collectively, our results suggest that PTPN22 has dual roles in T‐cell clonal expansion and effector function; whereas it promotes antigen‐driven responses during acute infection by positively regulating interferon signaling in T cells, PTPN22 inhibits homeostatic‐driven proliferation.
A quantum spin-probe molecular microscope
Authors: Perunicic V. S. , Hill C. D. , Hall L. T. , Hollenberg L.C.L.
Published: October 2016

Imaging the atomic structure of a single biomolecule is an important challenge in the physical biosciences. Whilst existing techniques all rely on averaging over large ensembles of molecules, the single-molecule realm remains unsolved. Here we present a protocol for 3D magnetic resonance imaging of a single molecule using a quantum spin probe acting simultaneously as the magnetic resonance sensor and source of magnetic field gradient. Signals corresponding to specific regions of the molecule’s nuclear spin density are encoded on the quantum state of the probe, which is used to produce a 3D image of the molecular structure. Quantum simulations of the protocol applied to the rapamycin molecule (C51H79NO13) show that the hydrogen and carbon substructure can be imaged at the angstrom level using current spin-probe technology. With prospects for scaling to large molecules and/or fast dynamic conformation mapping using spin labels, this method provides a realistic pathway for single-molecule microscopy.
Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors
Authors: Zuhl Andrea M. , Nolan Charles E. , Brodney Michael A. , Niessen Sherry , Atchison Kevin , Houle Christopher , Karanian David A. , Ambroise Claude , Brulet Jeffrey W. , Beck Elizabeth M. , Doran Shawn D. , O’Neill Brian T. , am Ende Christopher W. , Chang Cheng , Geoghegan Kieran F. , West Graham M. , Judkins Joshua C. , Hou Xinjun , Riddell David R. , Johnson Douglas S.
Published: October 2016

Inhibition of β-secretase BACE1 is considered one of the most promising approaches for treating Alzheimer’s disease. Several structurally distinct BACE1 inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but the target mediating this toxicity has not been identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as a principal off-target of BACE1 inhibitors in human cells. We find that several BACE1 inhibitors blocked CatD activity in cells with much greater potency than that displayed in cell-free assays with purified protein. Through a series of exploratory toxicology studies, we show that quantifying CatD target engagement in cells with the probe is predictive of ocular toxicity in vivo. Taken together, our findings designate off-target inhibition of CatD as a principal driver of ocular toxicity for BACE1 inhibitors and more generally underscore the power of chemical proteomics for discerning mechanisms of drug action.
Circumpolar distribution and carbon storage of thermokarst landscapes
Authors: Olefeldt D. , Goswami S. , Grosse G. , Hayes D. , Hugelius G. , Kuhry P. , McGuire A. D. , Romanovsky V. E. , Sannel A.B.K. , Schuur E.A.G. , Turetsky M. R.
Published: October 2016

Thermokarst is the process whereby the thawing of ice-rich permafrost ground causes land subsidence, resulting in development of distinctive landforms. Accelerated thermokarst due to climate change will damage infrastructure, but also impact hydrology, ecology and biogeochemistry. Here, we present a circumpolar assessment of the distribution of thermokarst landscapes, defined as landscapes comprised of current thermokarst landforms and areas susceptible to future thermokarst development. At 3.6 × 106 km2, thermokarst landscapes are estimated to cover ∼20% of the northern permafrost region, with approximately equal contributions from three landscape types where characteristic wetland, lake and hillslope thermokarst landforms occur. We estimate that approximately half of the below-ground organic carbon within the study region is stored in thermokarst landscapes. Our results highlight the importance of explicitly considering thermokarst when assessing impacts of climate change, including future landscape greenhouse gas emissions, and provide a means for assessing such impacts at the circumpolar scale.
Tiam1/Rac1 complex controls Il17a transcription and autoimmunity
Authors: Kurdi Ahmed T. , Bassil Ribal , Olah Marta , Wu Chuan , Xiao Sheng , Taga Mariko , Frangieh Michael , Buttrick Thomas , Orent William , Bradshaw Elizabeth M. , Khoury Samia J. , Elyaman Wassim
Published: October 2016

RORγt is a master transcription factor of Th17 cells and considered as a promising drug target for the treatment of autoimmune diseases. Here, we show the guanine nucleotide exchange factor, Tiam1, and its cognate Rho-family G protein, Rac1, regulate interleukin (IL)17A transcription and autoimmunity. Whereas Tiam1 genetic deficiency weakens IL-17A expression partially and inhibits the development of experimental autoimmune encephalomyelitis (EAE), deletion of Rac1 in T cells exhibits more robust effects on Th17 cells and EAE. We demonstrate Tiam1 and Rac1 form a complex with RORγt in the nuclear compartment of Th17 cells, and together bind and activate the Il17 promoter. The clinical relevance of these findings is emphasized by pharmacological targeting of Rac1 that suppresses both murine and human Th17 cells as well as EAE. Thus, our findings highlight a regulatory pathway of Tiam1/Rac1 in Th17 cells and suggest that it may be a therapeutic target in multiple sclerosis.
Giant piezoelectric voltage coefficient in grain-oriented modified PbTiO3 material
Authors: Yan Yongke , Zhou Jie E. , Maurya Deepam , Wang Yu U. , Priya Shashank
Published: October 2016

A rapid surge in the research on piezoelectric sensors is occurring with the arrival of the Internet of Things. Single-phase oxide piezoelectric materials with giant piezoelectric voltage coefficient (g, induced voltage under applied stress) and high Curie temperature (Tc) are crucial towards providing desired performance for sensing, especially under harsh environmental conditions. Here, we report a grain-oriented (with 95% <001> texture) modified PbTiO3 ceramic that has a high Tc (364 °C) and an extremely large g33 (115 × 10−3 Vm N−1) in comparison with other known single-phase oxide materials. Our results reveal that self-polarization due to grain orientation along the spontaneous polarization direction plays an important role in achieving large piezoelectric response in a domain motion-confined material. The phase field simulations confirm that the large piezoelectric voltage coefficient g33 originates from maximized piezoelectric strain coefficient d33 and minimized dielectric permittivity ɛ33 in [001]-textured PbTiO3 ceramics where domain wall motions are absent.
Salicylic acid receptors activate jasmonic acid signalling through a non-canonical pathway to promote effector-triggered immunity
Authors: Liu Lijing , Sonbol Fathi-Mohamed , Huot Bethany , Gu Yangnan , Withers John , Mwimba Musoki , Yao Jian , He Sheng Yang , Dong Xinnian
Published: October 2016

It is an apparent conundrum how plants evolved effector-triggered immunity (ETI), involving programmed cell death (PCD), as a major defence mechanism against biotrophic pathogens, because ETI-associated PCD could leave them vulnerable to necrotrophic pathogens that thrive on dead host cells. Interestingly, during ETI, the normally antagonistic defence hormones, salicylic acid (SA) and jasmonic acid (JA) associated with defence against biotrophs and necrotrophs respectively, both accumulate to high levels. In this study, we made the surprising finding that JA is a positive regulator of RPS2-mediated ETI. Early induction of JA-responsive genes and de novo JA synthesis following SA accumulation is activated through the SA receptors NPR3 and NPR4, instead of the JA receptor COI1. We provide evidence that NPR3 and NPR4 may mediate this effect by promoting degradation of the JA transcriptional repressor JAZs. This unique interplay between SA and JA offers a possible explanation of how plants can mount defence against a biotrophic pathogen without becoming vulnerable to necrotrophic pathogens.
NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells
Authors: Ratajczak Joanna , Joffraud Magali , Trammell Samuel A. J. , Ras Rosa , Canela Núria , Boutant Marie , Kulkarni Sameer S. , Rodrigues Marcelo , Redpath Philip , Migaud Marie E. , Auwerx Johan , Yanes Oscar , Brenner Charles , Cantó Carles
Published: October 2016

NAD+ is a vital redox cofactor and a substrate required for activity of various enzyme families, including sirtuins and poly(ADP-ribose) polymerases. Supplementation with NAD+ precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), protects against metabolic disease, neurodegenerative disorders and age-related physiological decline in mammals. Here we show that nicotinamide riboside kinase 1 (NRK1) is necessary and rate-limiting for the use of exogenous NR and NMN for NAD+ synthesis. Using genetic gain- and loss-of-function models, we further demonstrate that the role of NRK1 in driving NAD+ synthesis from other NAD+ precursors, such as nicotinamide or nicotinic acid, is dispensable. Using stable isotope-labelled compounds, we confirm NMN is metabolized extracellularly to NR that is then taken up by the cell and converted into NAD+. Our results indicate that mammalian cells require conversion of extracellular NMN to NR for cellular uptake and NAD+ synthesis, explaining the overlapping metabolic effects observed with the two compounds.
The solution structure of an anti-CRISPR protein
Authors: Maxwell Karen L. , Garcia Bianca , Bondy-Denomy Joseph , Bona Diane , Hidalgo-Reyes Yurima , Davidson Alan R.
Published: October 2016

Bacterial CRISPR–Cas adaptive immune systems use small guide RNAs to protect against phage infection and invasion by foreign genetic elements. We previously demonstrated that a group of Pseudomonas aeruginosa phages encode anti-CRISPR proteins that inactivate the type I-F and I-E CRISPR–Cas systems using distinct mechanisms. Here, we present the three-dimensional structure of an anti-CRISPR protein and map a functional surface that is critical for its potent inhibitory activity. The interaction of the anti-CRISPR protein with the CRISPR–Cas complex through this functional surface is proposed to prevent the binding of target DNA.
Land-use choices follow profitability at the expense of ecological functions in Indonesian smallholder landscapes
Authors: Clough Yann , Krishna Vijesh V. , Corre Marife D. , Darras Kevin , Denmead Lisa H. , Meijide Ana , Moser Stefan , Musshoff Oliver , Steinebach Stefanie , Veldkamp Edzo , Allen Kara , Barnes Andrew D. , Breidenbach Natalie , Brose Ulrich , Buchori Damayanti , Daniel Rolf , Finkeldey Reiner , Harahap Idham , Hertel Dietrich , Holtkamp A. Mareike , Hörandl Elvira , Irawan Bambang , Jaya I. Nengah Surati , Jochum Malte , Klarner Bernhard , Knohl Alexander , Kotowska Martyna M. , Krashevska Valentyna , Kreft Holger , Kurniawan Syahrul , Leuschner Christoph , Maraun Mark , Melati Dian Nuraini , Opfermann Nicole , Pérez-Cruzado César , Prabowo Walesa Edho , Rembold Katja , Rizali Akhmad , Rubiana Ratna , Schneider Dominik , Tjitrosoedirdjo Sri Sudarmiyati , Tjoa Aiyen , Tscharntke Teja , Scheu Stefan
Published: October 2016

Smallholder-dominated agricultural mosaic landscapes are highlighted as model production systems that deliver both economic and ecological goods in tropical agricultural landscapes, but trade-offs underlying current land-use dynamics are poorly known. Here, using the most comprehensive quantification of land-use change and associated bundles of ecosystem functions, services and economic benefits to date, we show that Indonesian smallholders predominantly choose farm portfolios with high economic productivity but low ecological value. The more profitable oil palm and rubber monocultures replace forests and agroforests critical for maintaining above- and below-ground ecological functions and the diversity of most taxa. Between the monocultures, the higher economic performance of oil palm over rubber comes with the reliance on fertilizer inputs and with increased nutrient leaching losses. Strategies to achieve an ecological-economic balance and a sustainable management of tropical smallholder landscapes must be prioritized to avoid further environmental degradation.