bluuebunny/crossref_metadata_2025 huggingface dataset:
Facilitating the Evolution of Esterase Activity from a Promiscuous Enzyme (Mhg) with Catalytic Functions of Amide Hydrolysis and Carboxylic Acid Perhydrolysis by Engineering the Substrate Entrance Tunnel
Authors: Yan Xiaodan , Wang Jianjun , Sun Yu , Zhu Junge , Wu Sheng
Published: September 2016

Promiscuous enzymes are generally considered to be starting points in the evolution of offspring enzymes with more specific or even novel catalytic activities, which is the molecular basis of producing new biological functions. Mhg, a typical α/β fold hydrolase, was previously reported to have both γ-lactamase and perhydrolase activities. However, despite having high structural similarity to and sharing an identical catalytic triad with an extensively studied esterase from
Pseudomonas fluorescens
, this enzyme did not show any esterase activity. Molecular docking and sequence analysis suggested a possible role for the entry of the binding pocket in blocking the entrance tunnel, preventing the ester compounds from entering into the pocket. By engineering the entrance tunnel with only one or two amino acid substitutions, we successfully obtained five esterase variants of Mhg. The variants exhibited a very broad substrate acceptance, hydrolyzing not only the classical
p
-nitrophenol esters but also various types of chiral esters, which are widely used as drug intermediates. Site 233 at the entrance tunnel of Mhg was found to play a pivotal role in modulating the three catalytic activities by adjusting the size and shape of the tunnel, with different amino acid substitutions at this site facilitating different activities. Remarkably, the variant with the L233G mutation was a very specific esterase without any γ-lactamase and perhydrolase activities. Considering the amino acid conservation and differentiation, this site could be a key target for future protein engineering. In addition, we demonstrate that engineering the entrance tunnel is an efficient strategy to regulate enzyme catalytic capabilities.

IMPORTANCE
Promiscuous enzymes can act as starting points in the evolution of novel catalytic activities, thus providing a molecular basis for the production of new biological functions. In this study, we identified a critical amino acid residue (Leu233) at the entry of the substrate tunnel of a promiscuous enzyme, Mhg. We found that substitution of this residue with smaller amino acids such as Gly, Ala, Ser, or Pro endowed the enzyme with novel esterase activity. Different amino acids at this site can facilitate different catalytic activities. These findings exhibited universal significance in this subset of α/β fold hydrolases, including Mhg. Furthermore, we demonstrate that engineering the entrance tunnel is an efficient strategy to evolve new enzyme catalytic capabilities. Our study has important implications for the regulation of enzyme catalytic promiscuity and development of protein engineering methodologies.
The Escherichia coli
rhaSR-PrhaBAD
Inducible Promoter System Allows Tightly Controlled Gene Expression over a Wide Range in Pseudomonas aeruginosa
Authors: Meisner Jeffrey , Goldberg Joanna B.
Published: September 2016

The
araC-ParaBAD
inducible promoter system is tightly controlled and allows gene expression to be modulated over a wide range in
Escherichia coli
, which has led to its widespread use in other bacteria. Although anecdotal evidence suggests that
araC-ParaBAD
is leaky in
Pseudomonas aeruginosa
, neither a thorough analysis of this inducible promoter system in
P. aeruginosa
nor a concerted effort to identify alternatives with improved functionality has been reported. Here, we evaluated the functionality of the
araC-ParaBAD
system in
P. aeruginosa
. Using transcriptional fusions to a
lacZ
reporter gene, we determined that the noninduced expression from
araC-ParaBAD
is high and cannot be reduced by carbon catabolite repression as it can in
E. coli
. Modulating translational initiation by altering ribosome-binding site strength reduced the noninduced activity but also decreased the maximal induced activity and narrowed the induction range. Integrating the inducible promoter system into the posttranscriptional regulatory network that controls catabolite repression in
P. aeruginosa
significantly decreased the noninduced activity and increased the induction range. In addition to these improvements in the functionality of the
araC-ParaBAD
system, we found that the
lacI
q
-
Ptac
and
rhaSR-PrhaBAD
inducible promoter systems had significantly lower noninduced expression and were inducible over a broader range than
araC-ParaBAD
. We demonstrated that noninduced expression from the
araC-ParaBAD
system supported the function of genes involved in antibiotic resistance and tryptophan biosynthesis in
P. aeruginosa
, problems that were avoided with
rhaSR-PrhaBAD. rhaSR-PrhaBAD
is tightly controlled, allows gene expression over a wide range, and represents a significant improvement over
araC-ParaBAD
in
P. aeruginosa
.

IMPORTANCE
We report the shortcomings of the commonly used
Escherichia coli araC-ParaBAD
inducible promoter system in
Pseudomonas aeruginosa
, successfully reengineered it to improve its functionality, and show that the
E. coli
rhaSR-PrhaBAD
system is tightly controlled and allows inducible gene expression over a wide range in
P. aeruginosa
.
Silencing the Honey Bee (Apis mellifera) Naked Cuticle Gene (
nkd
) Improves Host Immune Function and Reduces Nosema ceranae Infections
Authors: Li Wenfeng , Evans Jay D. , Huang Qiang , Rodríguez-García Cristina , Liu Jie , Hamilton Michele , Grozinger Christina M. , Webster Thomas C. , Su Songkun , Chen Yan Ping
Published: September 2016

Nosema ceranae
is a new and emerging microsporidian parasite of European honey bees,
Apis mellifera
, that has been implicated in colony losses worldwide. RNA interference (RNAi), a posttranscriptional gene silencing mechanism, has emerged as a potent and specific strategy for controlling infections of parasites and pathogens in honey bees. While previous studies have focused on the silencing of parasite/pathogen virulence factors, we explore here the possibility of silencing a host factor as a mechanism for reducing parasite load. Specifically, we used an RNAi strategy to reduce the expression of a honey bee gene,
naked cuticle
(
nkd
), which is a negative regulator of host immune function. Our studies found that
nkd
mRNA levels in adult bees were upregulated by
N. ceranae
infection (and thus, the parasite may use this mechanism to suppress host immune function) and that ingestion of double-stranded RNA (dsRNA) specific to
nkd
efficiently silenced its expression. Furthermore, we found that RNAi-mediated knockdown of
nkd
transcripts in
Nosema
-infected bees resulted in upregulation of the expression of several immune genes (
Abaecin
,
Apidaecin
,
Defensin-1
, and
PGRP-S2
), reduction of
Nosema
spore loads, and extension of honey bee life span. The results of our studies clearly indicate that silencing the host
nkd
gene can activate honey bee immune responses, suppress the reproduction of
N. ceranae
, and improve the overall health of honey bees. This study represents a novel host-derived therapeutic for honey bee disease treatment that merits further exploration.

IMPORTANCE
Given the critical role of honey bees in the pollination of agricultural crops, it is urgent to develop strategies to prevent the colony decline induced by the infection of parasites/pathogens. Targeting parasites and pathogens directly by RNAi has been proven to be useful for controlling infections in honey bees, but little is known about the disease impacts of RNAi silencing of host factors. Here, we demonstrate that knocking down the honey bee immune repressor-encoding
nkd
gene can suppress the reproduction of
N. ceranae
and improve the overall health of honey bees, which highlights the potential role of host-derived and RNAi-based therapeutics in controlling the infections in honey bees. The information obtained from this study will have positive implications for honey bee disease management practices.
Immunotherapy in a rare case of primary pelvic retroperitoneal melanoma
Authors: Talag Maria Monica , Alsharedi Mohamed , Bou Zgheib Nadim , Lebowicz Yehuda
Published: September 2016

Recent advances in novel immunotherapeutic and targeted therapeutic agents have increased treatment options in patients with advanced metastatic melanoma. However, evidence in the literature on whether or not extracutaneous melanoma will acquire an equivalent advantage from these therapies is very scarce. In general, extracutaneous melanomas are rare and aggressive melanomas, which are clinically and biologically unique, with higher incidence of metastatic disease and poor prognosis. In this case report, we present a very rare case of a 54-year-old woman with primary pelvic retroperitoneal melanoma treated with an anti-PD-1 antibody, pembrolizumab. Furthermore, we explore the role of novel immunotherapies in the treatment of advanced melanoma.
Process quality of diabetes care under favorable access to healthcare: a 2-year longitudinal study using claims data in Japan
Authors: Tanaka Hirokazu , Tomio Jun , Sugiyama Takehiro , Kobayashi Yasuki
Published: September 2016

Objective

To investigate the process quality of diabetes care provided to patients under universal health insurance coverage.

Research design and methods

Using claim data for 570 363 beneficiaries aged 20–69 years who were covered by Health Insurance Societies between April 2010 and March 2012, we identified patients with type 2 diabetes who made follow-up visits at least every 3 months in the first year (subject-identification year). We assessed patient adherence to follow-up visits in the second year (quality-reporting year), calculated the proportion of patients that completed routine examinations for glycemic control and complications, and evaluated associations between characteristics of patients and quality indicators using multivariable logistic regression models.

Results

We identified 12 909 patients with diabetes; in the subject-identification year, 1415 (11.0%) had prescriptions for insulin injections, 6049 (46.9%) had prescriptions for oral antihyperglycemic agents, and 5445 (42.2%) had no diabetes-related prescriptions. Among patients using medication, 474 (6.4%) dropped out in the quality-reporting year. The adjusted percentages of quality indicators among patients using oral antihyperglycemic agents were 95.8% for glycated hemoglobin, 35.6% for eye examinations, 15.4% for urine microalbumin excretion, and 90.6% for serum lipids; the percentages among patients taking insulin were the same or higher. Annual testing for glycated hemoglobin was less frequent in patients aged 40–49 years than in patients aged 60–69 years (OR 0.77; 95% CI 0.66 to 0.91). Fewer men than women (OR 0.59; 95% CI 0.54 to 0.64), and fewer patients aged 40–49 years than those aged 60–69 years (OR 0.56; 95% CI 0.50 to 0.63) tended to complete routine eye examinations.

Conclusions

Screening for retinopathy and nephropathy was less frequent than required despite favorable conditions for access to healthcare in Japan. Suboptimal quality of care appeared to depend on provider factors as well as patient factors, such as limited access to retinopathy prevention among working-age men with diabetes.
Diagnostic accuracy of the APPY1 Test in patients aged 2–20 years with suspected acute appendicitis presenting to emergency departments
Authors: González del Castillo Juan , Ayuso Francisco Javier , Trenchs Victoria , Martinez Ortiz de Zarate Mikel , Navarro Carmen , Altali Kinda , Fernandez Cristina , Huckins David , Martín-Sánchez Francisco Javier ,   representing INFURG-SEMES group
Published: September 2016

Objective

Evaluate the diagnostic accuracy of the APPY1 Test alone and in combination with the Alvarado score (AS) to rule out acute appendicitis (AA) in patients presenting to EDs with abdominal pain suspicious for AA.

Methodology

Observational study in a prospective consecutive cohort including all patients from 2 to 20 years with abdominal pain suggestive of AA in four EDs. The APPY1 Test was performed and AS was calculated to determine risk stratification for each patient.

Results

321 patients enrolled (mean age 11.8 (SD 3.8) years, 52.0% male), with 32.4% low risk, 23.7% intermediate risk and 43.9% high risk according to the AS. 111 (34.6%) had AA, of whom 1 (0.9%) had a false-negative APPY1 Test result. The APPY1 Test had a sensitivity (Se) of 99.1% (95% CI 94.4% to 99.9%), specificity (Sp) of 32.9% (95% CI 26.6% to 39.7%), negative predictive value (NPV) of 98.6% (95% CI 91.2% to 99.9%) and negative likelihood ratio (LHR−) of 0.03 (0.00 to 0.19) in this population. For patients at low risk by AS, the APPY1 Test had a Se of 100% (95% CI 62.9% to 100%), NPV of 100% (95% CI 91.1% to 100%) and LHR− of 0.0 (not calculable), and for patients at intermediate risk by AS, the APPY1 Test had a Se of 94.4% (95% CI 70.6% to 99.7%), NPV of 94.7% (95% CI 71.9% to 99.7%) and LHR− of 0.18 (0.0 to 1.2), respectively.

Conclusions

APPY1 Test is a potentially useful diagnostic tool to rule out AA in this population, with clinical utility primarily in those patients classified as having low clinical risk of appendicitis according to the AS.
Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers
Authors: Carotenuto Pietro , Fassan Matteo , Pandolfo Rosantony , Lampis Andrea , Vicentini Caterina , Cascione Luciano , Paulus-Hock Viola , Boulter Luke , Guest Rachel , Quagliata Luca , Hahne Jens Claus , Ridgway Rachel , Jamieson Tam , Athineos Dimitris , Veronese Angelo , Visone Rosa , Murgia Claudio , Ferrari Giulia , Guzzardo Vincenza , Evans Thomas Ronald Jeffry , MacLeod Martin , Feng Gui Ji , Dale Trevor , Negrini Massimo , Forbes Stuart J , Terracciano Luigi , Scarpa Aldo , Patel Tushar , Valeri Nicola , Workman Paul , Sansom Owen , Braconi Chiara
Published: September 2016

Objective

Transcribed-ultraconserved regions (T-UCR) are long non-coding RNAs which are conserved across species and are involved in carcinogenesis. We studied T-UCRs downstream of the Wnt/β-catenin pathway in liver cancer.

Design

Hypomorphic Apc mice (Apcfl/fl) and thiocetamide (TAA)-treated rats developed Wnt/β-catenin dependent hepatocarcinoma (HCC) and cholangiocarcinoma (CCA), respectively. T-UCR expression was assessed by microarray, real-time PCR and in situ hybridisation.

Results

Overexpression of the T-UCR uc.158− could differentiate Wnt/β-catenin dependent HCC from normal liver and from β-catenin negative diethylnitrosamine (DEN)-induced HCC. uc.158− was overexpressed in human HepG2 versus Huh7 cells in line with activation of the Wnt pathway. In vitro modulation of β-catenin altered uc.158− expression in human malignant hepatocytes. uc.158− expression was increased inCTNNB1-mutated human HCCs compared with non-mutated human HCCs, and in human HCC with nuclear localisation of β-catenin. uc.158− was increased in TAA rat CCA and reduced after treatment with Wnt/β-catenin inhibitors. uc.158− expression was negative in human normal liver and biliary epithelia, while it was increased in human CCA in two different cohorts. Locked nucleic acid-mediated inhibition of uc.158− reduced anchorage cell growth, 3D-spheroid formation and spheroid-based cell migration, and increased apoptosis in HepG2 and SW1 cells. miR-193b was predicted to have binding sites within the uc.158− sequence. Modulation of uc.158− changed miR-193b expression in human malignant hepatocytes. Co-transfection of uc.158− inhibitor and anti-miR-193b rescued the effect of uc.158− inhibition on cell viability.

Conclusions

We showed that uc.158− is activated by the Wnt pathway in liver cancers and drives their growth. Thus, it may represent a promising target for the development of novel therapeutics.
Expression pattern of miR-451 and its targetMIF(macrophage migration inhibitory factor) in colorectal cancer
Authors: Mamoori Afraa , Gopalan Vinod , Lu Cu-Tai , Chua Terence C , Morris David L , Smith Robert Anthony , Lam Alfred K-Y
Published: September 2016

Aims

To investigate the expression pattern of microRNA-451 (miR-451) in patients with colorectal carcinoma and correlate with the expression of its target geneMIF(macrophage migration inhibitory factor).

Methods

Matched cancer and non-cancer fresh frozen tissues were prospectively collected from 70 patients (35 men and 35 women) who underwent resection of colorectal adenocarcinoma. These tissues collected were extracted for miR and complementary DNA conversion. Then, miR-451 expressions in these tissues were measured by quantitative real-time PCR. The expression was correlated with clinical and pathological parameters of these patients. In addition, paraffin blocks of 10 colorectal carcinomas with lowest expression of miR-451 were used for the study of MIF protein expression by immunohistochemistry.

Results

miR-451 was downregulated in majority of the colorectal cancer tissues when compared with their matched normal tissues (84.3%, n=59/70). Downregulation of miR-451 correlates significantly with presence of coexisting adenoma (91.4%, p=0.025). In addition, persistence of cancer or cancer recurrence after surgery showed significant correlation with downregulation of miR-451 (80% vs 0%; p=0.028). There is no significant correlation between miR-451 expression and age, gender of the patients as well as size, grades, pathological stages, presence of lymphovascular permeation, perineural invasion and microsatellite instability status of the colorectal carcinoma (p>0.05). Majority of the cases (80%) with low expression of miR-451 showed high levels of MIF protein expression confirming the inverse relationship between miR-451 and MIF expressions.

Conclusions

The results showed that miR-451 could play a role in development and progression of colorectal cancer and likely by targetingMIF.
Impact of a child stimulation intervention on early child development in rural Peru: a cluster randomised trial using a reciprocal control design
Authors: Hartinger Stella Maria , Lanata Claudio Franco , Hattendorf Jan , Wolf Jennyfer , Gil Ana Isabel , Obando Mariela Ortiz , Noblega Magaly , Verastegui Hector , Mäusezahl Daniel
Published: September 2016

Objective

Stimulation in early childhood can alleviate adverse effects of poverty. In a community-randomised trial, we implemented 2 home-based interventions, each serving as an attention control for the other. One group received an integrated household intervention package (IHIP), whereas the other group received an early child development (ECD) intervention. The primary objective of the study was to evaluate the effect of IHIP on diarrhoea and respiratory infections, the details of which are described elsewhere. Here, we present the impact of the ECD intervention on early childhood development indicators.

Methods

In this non-blinded community-randomised trial, an ECD intervention, adapted from the Peruvian government's National Wawa Wasi ECD programme, was implemented in 25 rural Peruvian Andean communities. We enrolled 534 children aged 6–35 months, from 50 communities randomised 1:1 into ECD and IHIP communities. In ECD communities, trained fieldworkers instructed mothers every 3 weeks over the 12 months study, to stimulate and interact with their children and to use standard programme toys. IHIP communities received an improved stove and hygiene promotion. Using a nationally validated ECD evaluation instrument, all children were assessed at baseline and 12 months later for overall performance on age-specific developmental milestones which fall into 7 developmental domains.

Findings

At baseline, ECD-group and IHIP-group children performed similarly in all domains. After 12 months, data from 258 ECD-group and 251 IHIP-group children could be analysed. The proportion of children scoring above the mean in their specific age group was significantly higher in the ECD group in all domains (range: 12–23%-points higher than IHIP group). We observed the biggest difference in fine motor skills (62% vs 39% scores above the mean, OR: 2.6, 95% CI 1.7 to 3.9).

Conclusions

The home-based ECD intervention effectively improved child development overall across domains and separately by investigated domain. Home-based strategies could be a promising component of poverty alleviation programmes seeking to improve developmental outcomes among rural Peruvian children.

Trial registration number

ISRCTN28191222; results.
Increase in avoidable hospital admissions after the Great East Japan Earthquake
Authors: Sasabuchi Yusuke , Matsui Hiroki , Yasunaga Hideo , Fushimi Kiyohide
Published: September 2016

Background

The Great East Japan Earthquake and subsequent tsunami and nuclear disaster on 11 March 2011 had a short-term influence on the increase in emergency department visits and hospital admissions due to various diseases. However, it remains unclear whether the earthquake and tsunami disaster affected the long-term health conditions of people in the affected areas.

Methods

Using a national inpatient database in Japan, we investigated people's ambulatory care sensitive conditions (ACSCs), which are defined as conditions for which effective management and treatment should prevent admission to a hospital. We compared the number of admissions for ACSCs before-quake (July 2010 to February 2011) with after-quake (July 2012 to February 2013) periods in the disaster area compared with other areas using a difference-in-differences design. Linear regression models with the interaction between periods and areas were used to estimate the impact of the earthquake on admissions for ACSCs.

Results

No significant difference in difference was seen in preventable ACSCs (where immunisation and other interventions can prevent illness) or chronic ACSCs (where effective care can prevent flare-ups), while acute ACSCs (where early intervention can prevent more serious progression) increased significantly (3.3 admissions per 100 000 population; 95% CI 0.4 to 6.3; p=0.028).

Conclusions

Preventable and chronic ACSCs may have increased just after the earthquake and then immediately decreased. However, avoidable admissions due to acute ACSCs remained high in the long term after the earthquake and tsunami disaster.
Two conceptions of conscience and the problem of conscientious objection
Authors: Symons Xavier
Published: September 2016

Schuklenk and Smalling argue that it is practically impossible for civic institutions to meet the conditions necessary to ensure that conscientious objection does not conflict with the core principles of liberal democracies. In this response, I propose an alternative definition of conscience to that offered by Schuklenk and Smalling. I discuss what I call the ‘traditional’ notion of conscience, and contrast this with the existentialist conception of conscience (which I take to be a close cousin of the view targeted by Schuklenk and Smalling). I argue that the traditional notion, grounded in an objective moral order, avoids the criticisms advanced by Schuklenk and Smalling; the existentialist conception, in contrast, does not. I conclude by discussing the benefits and risks of a ‘restricted view’ of respect for conscience.
One-year effects of glucocorticoids on bone density: a meta-analysis in cohorts on high and low-dose therapy
Authors: Lems Willem F , Baak Merel M E , van Tuyl Lilian H D , Lodder Mariëtte C , Dijkmans Ben A C , Boers Maarten
Published: September 2016

Background

Bone loss during glucocorticoid (GC) therapy is poorly quantified.

Objective

Quantification of bone loss in GC-treated patients with chronic inflammatory diseases (CID; low dose) and transplants (high dose).

Methods

Meta-analysis of cohorts: PubMed, Cochrane, EMBASE and bibliographic searches (1995–2012). Eligible studies prospectively included GC-treated patients with two dual X-ray absorptiometry measurements of spine or hip over a period of at least 12 months. Only supplementation with calcium or vitamin D3 was allowed. 5602 titles yielded 285 articles: 51 study arms in CID (N=1565), 18 study arms in transplantation (N=571). Prednisone-equivalent GC doses and inverse variance weighted mean bone changes were used in a random effects model.

Results

In CID, the mean GC dose was 8.7 mg/day (range 1.2–16.4). The mean 1-year bone loss in the lumbar spine was −1.7% (95% CI –2.2% to –1.2%); in the femoral neck: –1.3 (–1.8 to –0.7). In transplantation, the mean GC dose was 18.9 mg/day (range 6.0–52.7). Bone loss in the lumbar spine was −3.6% (–5.2% to –2.0%); in the femoral neck: –3.1% (–5.1% to –1.1%). Within the two groups, bone loss was not related to GC dose.

Conclusion

In CID, GC-related bone loss appears limited and manageable if current anti-osteoporotic strategies are fully implemented. In transplantation, and probably also other high-dose settings, bone loss is considerable and represents unmet need. The heterogeneity probably reflects the important influence of other factors, most notably the underlying disease and the efficacy of GC treatment.
Tests of quark–hadron duality in τ-decays
Authors: Dominguez C. A. , Hernandez L. A. , Schilcher K. , Spiesberger H.
Published: September 2016

An exhaustive number of QCD finite energy sum rules for [Formula: see text]-decay together with the latest updated ALEPH data is used to test the assumption of global duality. Typical checks are the absence of the dimension d = 2 condensate, the equality of the gluon condensate extracted from vector or axial vector spectral functions, the Weinberg sum rules, the chiral condensates of dimensions d = 6 and d = 8, as well as the extraction of some low-energy parameters of chiral perturbation theory. Suitable pinched linear integration kernels are introduced in the sum rules in order to suppress potential quark–hadron duality violations and experimental errors. We find no compelling indications of duality violations in hadronic [Formula: see text]-decay in the kinematic region above s [Formula: see text] 2.2 GeV2 for these kernels.
Role of Wigner function in studying quantum correlations
Authors: Siyouri F. , El Baz M. , Hassouni Y.
Published: September 2016

In this paper, we investigate the possibility to use the Wigner function to detect and quantify quantum correlations in general. We study these quantum correlations for two quasi-Werner states formed with two general bipartite superposed squeezed states. We find then that the Wigner function is not sensitive to all kinds of quantum correlations but it only witnesses entanglement.
Accelerated and Airy–Bloch oscillations
Authors: Longhi Stefano
Published: September 2016

A quantum particle subjected to a constant force undergoes an accelerated motion following a parabolic path, which differs from the classical motion just because of wave packet spreading (quantum diffusion). However, when a periodic potential is added (such as in a crystal) the particle undergoes Bragg scattering and an oscillatory (rather than accelerated) motion is found, corresponding to the famous Bloch oscillations (BOs). Here, we introduce an exactly-solvable quantum Hamiltonian model, corresponding to a generalized Wannier–Stark Hamiltonian [Formula: see text], in which a quantum particle shows an intermediate dynamical behavior, namely an oscillatory motion superimposed to an accelerated one. Such a novel dynamical behavior is referred to as accelerated BOs. Analytical expressions of the spectrum, improper eigenfunctions and propagator of the generalized Wannier–Stark Hamiltonian [Formula: see text] are derived. Finally, it is shown that acceleration and quantum diffusion in the generalized Wannier–Stark Hamiltonian are prevented for Airy wave packets, which undergo a periodic breathing dynamics that can be referred to as Airy–Bloch oscillations.
Investigated electronic structure and magnetic ordering of rare earth impurities (Eu, Gd) in ZnO
Authors: Benosman F. , Dridi Z. , Al-Douri Y. , Bouhafs B.
Published: September 2016

First-principles calculations of the electronic structure of substitutional rare earth (RE) impurity (Eu and Gd) in wurtzite ZnO have been performed using density functional theory within a Hubbard potential correction to the RE 4f states. For Eu-doped ZnO, the magnetic coupling between Eu ions in the nearest neighbor sites is ferromagnetic (FM). The room temperature (RT) ferromagnetism (FM) can be enhanced by an appropriate hole doping into the sample. The ZnO:Gd is found to favor the antiferromagnetic (AFM) phase. The FM can be achieved by high electron doping. The native defects effect (V[Formula: see text], V[Formula: see text]) on the FM is also studied. The oxygen vacancies seem to play an important role in the generation of the FM in both ZnO:Eu and ZnO:Gd, which is in good agreement with recent experimental results.
A Fault-Tolerant Deflection Routing for Network-on-Chip
Authors: Zhou Xiaofeng , Liu Lu , Zhu Zhangming
Published: September 2016

Network-on-Chip (NoC) has become a promising design methodology for the modern on-chip communication infrastructure of many-core system. To guarantee the reliability of traffic, effective fault-tolerant scheme is critical to NoC systems. In this paper, we propose a fault-tolerant deflection routing (FTDR) to address faults on links and router by redundancy technique. The proposed FTDR employs backup links and a redundant fault-tolerant unit (FTU) at router-level to sustain the traffic reliability of NoC. Experimental results show that the proposed FTDR yields an improvement of routing performance and fault-tolerant capability over the reported fault-tolerant routing schemes in average flit deflection rate, average packet latency, saturation throughput and reliability by up to 13.5%, 9.8%, 10.6% and 17.5%, respectively. The layout area and power consumption are increased merely 3.5% and 2.6%.
Free skew Boolean algebras
Authors: Kudryavtseva Ganna , Leech Jonathan
Published: September 2016

We study the structure and properties of free skew Boolean algebras (SBAs). For finite generating sets, these free algebras are finite and we give their representation as a product of primitive algebras and provide formulas for calculating their cardinality. We also characterize atomic elements and central elements, and calculate the number of such elements. These results are used to study minimal generating sets of finite SBAs. We also prove that the center of the free infinitely generated algebra is trivial and show that all free algebras have intersections.
EFFECTIVENESS OF BOTULINUM TOXIN TYPE A IN CARPAL TUNNEL SYNDROME
Authors: Juan-García Francisco J. , Formigo-Couceiro Jacobo , Barrio-Alonso Manuela , Ouviña-Arribas Rubén
Published: September 2016

Background and objectives: Carpal tunnel syndrome (CTS) is caused by compression of the median nerve as it passes through the wrist. It can be treated with both surgical and non-surgical methods. Botulinum toxin type A has been used in the treatment of spasms, dystonia, migraine relief and myofascial pain. This study is aimed at evaluating the safety and tolerability of botulinum toxin type A in carpal tunnel syndrome. Methods: We conducted an open-label, prospective study using 30 units of onabotulinum Toxin A (Botox[Formula: see text]), injected into the carpal tunnel using the in-plane ultrasound-guided ulnar approach. We used the verbal numeric rating scale (VNRS) to assess changes in pain and paraesthesias both 4 and 12 weeks following the injection. All adverse effects were recorded. Results: A total of 18 patients with 22 mild-moderate idiopathic CTS were included in the study. A total of 14 women and 4 men with a mean of age [Formula: see text] years. Botulinum toxin A was well tolerated and only one patient reported temporary subjective weakness in his/her hand muscles. Both at 4 weeks and 3 months following the injection we observed a 63.6% subjective improvement in the patients’ level of pain and paraesthesias, with no statistical significance ([Formula: see text]). Conclusion: Our study shows the effects of botulinum toxin in relieving pain and paraesthesias in carpal tunnel syndrome with moderate symptoms. The use of an in-plane ultrasound approach for its injection into the carpal tunnel adds value and safety to the procedure, and, based on our experience, is well tolerated and safe. Further studies are required to confirm these results and define optimal doses of botulinum toxin.
Wave Number-Based Technique for Detecting Slope Discontinuity in Simple Beams Using Moving Test Vehicle
Authors: Yau J. D. , Yang Judy P. , Yang Y. B.
Published: September 2016

The wavelength characteristic is a useful clue for locating and assessing the severity of slope discontinuity in beams. In this study, the slope discontinuity of a beam is represented by an internal hinge restrained by elastic springs, and the wavelength of the beam is calculated indirectly from the vertical response of a test vehicle during its travel over the beam. The key parameters of the problem at hand are first unveiled using an approximate, closed-form solution for the response of the vehicle moving at low speeds over the bridge. Then a two-beam element model with slope discontinuity is formulated for the vehicle–bridge interaction (VBI) system for use in numerical simulation. In the examples, the wavenumber-based response of the test vehicle is used to identify the location and severity of the discontinuity in the beam. It is demonstrated that the wavelength-based technique presented herein by using the moving test vehicle as a moving sensor system offers a promising, alternative approach for damage detection in girder type bridges.
13th Five-Year Plan Reorientates China’s Housing Policy
Authors: ZHOU Zhihua
Published: September 2016

The 13th Guideline has created a friendly policy atmosphere for a moderately prosperous and stable housing development to attain a 6.5% gross domestic product growth rate and ensure a harmonious society. However, the overall impact remains unclear as details have yet to be rolled out. As the role of housing development in overall development changes, the contribution of housing development to future economic growth is expected to be lower.
China’s Military Reform: In Search of Centrality and Joint Capability
Authors: LIU Bojian , CHEN Gang
Published: September 2016

In a new wave of reform, China’s Central Military Commission remains a party-state organ of the highest military control. Politically, the reorganisation enhances intra-People’s Liberation Army (PLA) supervision and inter-section checks, and paves the way for the personnel reshuffle before the 19th Party Congress scheduled in 2017. Strategically, the military reshuffle is to advance the PLA’s joint operational capability, facilitate modernisation of weapon systems, accelerate China’s transition towards maritime power and improve the PLA’s systemic commanding efficiency.
William Labov: An Appreciation
Authors: Chambers Jack
Published: September 2016

William Labov launched the branch of language studies known as language variation and change or (more vaguely) sociolinguistics with several influential studies in the 1960s and seminal publications in the early 1970s. As the discipline spread to universities and research institutes in North America and, with remarkable rapidity, to Europe, Asia, the Antipodes, and ultimately all corners of the globe, Professor Labov has remained at or near the forefront of its various movements, including historical sociolinguistics, narrative analysis, sociometrics, subjective evaluation testing, educational and forensic applications, and sociophonetics, as well as mainstream variation studies. His breadth and depth as a scholar have influenced countless linguists and policy makers, and his enthusiasm and boundless optimism have inspired numerous colleagues, collaborators, and students. Several of them relate their personal experiences with the man and his ideas here.
Adoptive Transfer of Tumor-Specific Th2 Cells Eradicates Tumors by Triggering anIn SituInflammatory Immune Response
Authors: Lorvik Kristina Berg , Hammarström Clara , Fauskanger Marte , Haabeth Ole Audun Werner , Zangani Michael , Haraldsen Guttorm , Bogen Bjarne , Corthay Alexandre
Published: September 2016

Adoptive cell therapy (ACT) trials to date have focused on transfer of autologous tumor-specific cytotoxic CD8+ T cells; however, the potential of CD4+ T helper (Th) cells for ACT is gaining interest. While encouraging results have been reported with IFNγ-producing Th1 cells, tumor-specific Th2 cells have been largely neglected for ACT due to their reported tumor-promoting properties. In this study, we tested the efficacy of idiotype-specific Th2 cells for the treatment of mice with MHC class II-negative myeloma. Th2 ACT efficiently eradicated subcutaneous myeloma in an antigen-specific fashion. Transferred Th2 cells persisted in vivo and conferred long-lasting immunity. Cancer eradication mediated by tumor-specific Th2 cells did not require B cells, natural killer T cells, CD8+ T cells, or IFNγ. Th2 ACT was also curative against B-cell lymphoma. Upon transfer, Th2 cells induced a type II inflammation at the tumor site with massive infiltration of M2-type macrophages producing arginase. In vivo blockade of arginase strongly inhibited Th2 ACT, consistent with a key role of arginase and M2 macrophages in myeloma elimination by Th2 cells. These results illustrate that cancer eradication may be achieved by induction of a tumor-specific Th2 inflammatory immune response at the tumor site. Thus, ACT with tumor-specific Th2 cells may represent a highly efficient immunotherapy protocol against cancer. Cancer Res; 76(23); 6864–76. ©2016 AACR.
Acquired Resistance Mechanisms to Combination Met-TKI/EGFR-TKI Exposure in Met-Amplified EGFR-TKI–Resistant Lung Adenocarcinoma Harboring an Activating EGFR Mutation
Authors: Yamaoka Toshimitsu , Ohmori Tohru , Ohba Motoi , Arata Satoru , Kishino Yasunari , Murata Yasunori , Kusumoto Sojiro , Ishida Hiroo , Shirai Takao , Hirose Takashi , Ohnishi Tsukasa , Sasaki Yasutsuna
Published: September 2016

Met-amplified EGFR-tyrosine kinase inhibitor (TKI)-resistant non–small cell lung cancer (NSCLC) harboring an activating EGFR mutation is responsive to concurrent EGFR-TKI and Met-TKI treatment in a preclinical model. Here, we determined that Met-amplified gefitinib-resistant cells acquire dual resistance to inhibition of EGFR and Met tyrosine kinase activities. PC-9 lung adenocarcinoma cells harboring 15-bp deletions (Del E746_A750) in EGFR exon 19 were treated with increasing concentrations of the Met-TKI PHA665752 and 1 μmol/L gefitinib for 1 year; three resistant clones were established via Met amplification. The three dual-resistance cell lines (PC-9DR2, PC-9DR4, and PC-9DR6, designated as DR2, DR4, and DR6, respectively) exhibited different mechanisms for evading both EGFR and Met inhibition. None of the clones harbored a secondary mutation of EGFR T790M or a Met mutation. Insulin-like growth factor (IGF)/IGF1 receptor activation in DR2 and DR4 cells acted as a bypass signaling pathway. Met expression was attenuated to a greater extent in DR2 than in PC-9 cells, but was maintained in DR4 cells by overexpression of IGF-binding protein 3. In DR6 cells, Met was further amplified by association with HSP90, which protected Met from degradation and induced SET and MYND domain-containing 3 (SMYD3)-mediated Met transcription. This is the first report describing the acquisition of dual resistance mechanisms in NSCLC harboring an activating EGFR mutation to Met-TKI and EGFR-TKI following previous EGFR-TKI treatment. These results might inform the development of more effective therapeutic strategies for NSCLC treatment. Mol Cancer Ther; 15(12); 3040–54. ©2016 AACR.
PDGF-Inhibition als potenzieller Behandlungsansatz bei okularer Neovaskularisation
Authors: Sadiq Mohammad Ali , Hanout Mostafa , Sarwar Salman , Hassan Muhammad , Agarwal Aniruddha , Sepah Yasir Jamal , Do Diana V. , Nguyen Quan Dong
Published: September 2016

Retinochoroidale Gefäßerkrankungen sind die häufigste Ursache für Erblindung in den Industrieländern. Zur Gruppe dieser Erkrankungen zählen neben vielen anderen die diabetische Retinopathie, der retinale Venenverschluss, Frühgeborenen-Retinopathie, die altersbedingte Makuladegeneration (AMD) und die pathologische Myopie. Verschiedene Therapien werden derzeit in der Behandlung dieser Erkrankungen erprobt. Im vorliegenden Artikel werden gegen den Wachstumsfaktor PDGF (Platelet-Derived Growth Factor) gerichtete Wirkstoffe als potenzielle neue Behandlungsoptionen bei Gefäßerkrankungen der Netz- und Aderhaut vorgestellt. PDGF spielt eine wichtige Rolle in der Angiogenese-Kaskade, die bei retinochoroidalen Gefäßerkrankungen aktiviert wird. Nachstehend wird auf den Wirkmechanismus, die Nebenwirkungen, die Wirksamkeit und die potenzielle synergistische Rolle dieser Wirkstoffe in Kombination mit anderen Behandlungsansätzen eingegangen. Wirkstoffe wie PDGF-Antagonisten bieten spannende Perspektiven für die zukünftige Behandlung retinochoroidaler Gefäßerkrankungen, insbesondere der neovaskulären AMD.
Langzeitbehandlung von RAP-Läsionen
Authors: Treder Maximilian
Published: September 2016

Ziel: Beurteilung der langfristigen Wirksamkeit von Ranibizumab in der Behandlung der retinalen angiomatösen Proliferation (RAP) und Identifikation von Prädiktoren für das funktionelle Behandlungsergebnis. Methoden: Retrospektive Fallserie mit 79 Augen von 68 konsekutiven Patienten mit RAP, die über ≥36 Monate nachbeobachtet wurden. Primäre Endpunkte waren die Veränderung der besten korrigierten Sehschärfe (Visus c. c.) und der zentralen Netzhautdicke nach 36 Monaten und beim letzten Termin. Ergebnisse: Die mittlere Nachbeobachtungsdauer betrug 59,8 ± 16,0 Monate. Alle Augen wurden mit Ranibizumab pro re nata behandelt; mit (n = 33) oder ohne (n = 46) begleitende photodynamische Therapie (PDT). Eine Stabilisierung oder Verbesserung des Visus c. c. lag nach 36 Monaten bei 50,6% der Patienten vor und am Ende der Nachbeobachtung bei 40,5%, wobei bei 20,3% das Lesevermögen erhalten blieb. Eine signifikante Abnahme der zentralen Netzhautdicke war nach 36 Monaten festzustellen (p < 0,001), nicht jedoch am Ende des Nachbeobachtungszeitraums. Eine geographische Atrophie (GA) lag beim letzten Termin in 59,5% der Augen vor. Subretinale Flüssigkeit zu Studienbeginn war mit einem besseren visuellen Outcome assoziiert (p = 0,001). Die Ergebnisse der Kombinationstherapie mit intravitrealem Ranibizumab und PDT unterschieden sich nicht signifikant von denen der Ranibizumab-Monotherapie. Schlussfolgerung: Von der Langzeittherapie bei RAP-Läsionen sind in der klinischen Praxis bescheidene Erfolge zu erwarten, was vermutlich auf das Auftreten von GA zurückzuführen ist. Subretinale Flüssigkeit zu Studienbeginn korrelierte positiv mit dem Visus c. c. am Ende der Studie. Übersetzung aus Ophthalmologica 2016;55:119-125 (DOI:10.1159/000441797)
Mediastinal Gray Zone Lymphoma with Features Intermediate between Classical Hodgkin Lymphoma and Primary Mediastinal B-Cell Lymphoma
Authors: Song Haa-Na , Kim Seok Jin , Ko Young Hyeh , Kim Won Seog
Published: September 2016

Background: Mediastinal gray zone lymphoma (MGZL) shares clinical characteristics with primary mediastinal B-cell lymphoma (PMBCL) and nodular sclerosing Hodgkin lymphoma (NSHL). However, MGZL is extremely rare, and an appropriate treatment for it has not yet been established. Methods: We retrospectively analyzed 8 patients who were treated with systemic chemotherapy for MGZL between 2007 and 2014. Results: The patients with MGZL were predominantly young and male (median age 26 years), and 62.5% of patients had bulky disease. The overall response rate (ORR) and complete remission (CR) rate were both 75% (6/8) for all treated patients The median overall survival (OS) and progression-free survival (PFS) was 40.7 and 3.9 months, respectively. Most responders (4/6, 66.7%) were treated with R-CHOP (rituximab + cyclophosphamide, hydroxydaunorubicin, Oncovin and prednisolone) as the frontline therapy. The CR rate of patients who received R-CHOP and those who did not was 100% (4/4) and 50% (2/4), respectively. Particularly striking was the finding that the median PFS of patients who received R-CHOP frontline chemotherapy was 11.4 months, which was superior to the median PFS of patients who did not receive R-CHOP. Conclusions: Of the 8 patients with MGZL who were treated with systemic chemotherapy, superior treatment responses were observed in patients who received R-CHOP as the frontline therapy.
Fallbericht über anhaltende Erhöhung des Augeninnendrucks nach multiplen intravitrealen Injektionen mit Ranibizumab und Aflibercept zur Behandlung der neovaskulären altersbedingten Makuladegeneration
Authors: Matsubara Hisashi , Miyata Ryohei , Kobayashi Maki , Tsukitome Hideyuki , Ikesugi Kengo , Kondo Mineo
Published: September 2016

Intravitreale Injektionen mit Wirkstoffen gegen den vaskulären endothelialen Wachstumsfaktor (VEGF) sind eine gängige Behandlungsmaßnahme bei neovaskulärer altersbedingter Makuladegeneration (nAMD). Obwohl diese Behandlungen sehr effektiv sind, sind in jüngster Zeit multiple Injektionen empfohlen worden, um auch langfristig für eine günstige Prognose zu sorgen. Es liegen jedoch Berichte über einen Anstieg des Augeninnendrucks (AID) nach multiplen Injektionen mit Anti-VEGF-Wirkstoffen vor. Wir präsentieren hier einen Fall von unkontrollierter persistierender AID-Erhöhung nach der Umstellung von intravitrealen Ranibizumab- auf Aflibercept-Injektionen. Bei einem 74-jährigen japanischen Mann ohne Glaukom in der Vorgeschichte, der zur Behandlung einer nAMD 22 Ranibizumab-Injektionen erhalten hatte, stieg nach der 22. Injektion der AID unvermittelt an. Die daraufhin eingeleitete medikamentöse Therapie führte zwar zur Normalisierung des AID, doch unterhalb der Fovea centralis lag auch nach der 25. Ranibizumab-Injektion noch subretinale Flüssigkeit vor. Daher erfolgte eine Umstellung der Therapie von Ranibizumab auf 2-monatliche intravitreale Injektionen mit Aflibercept, begleitet von Glaukom-Medikamenten. Der AID kehrte daraufhin in den Normalbereich zurück. Nach der 11. Aflibercept-Injektion kam es trotz der weiterhin angewandten Glaukom-Medikamente wiederum zu einem plötzlichen AID-Anstieg. Aufgrund dieser anhaltenden AID-Erhöhung wurden die Aflibercept-Injektionen für 16 Wochen ausgesetzt. Da es auch mit einem umfassenden Glaukom-Medikationsschema nicht gelang, den AID zu normalisieren, unterzog sich der Patient einer Trabekulotomie, die zur Rückkehr des AID in den Normalbereich führte. Wir gelangen zu der Schlussfolgerung, dass Patienten, die serielle intravitreale Injektionen eines Anti-VEGF-Wirkstoffs erhalten, aufmerksam überwacht werden müssen, da sich eine schwere und anhaltende okuläre Hypertension entwickeln kann.