bluuebunny/crossref_metadata_2025_split huggingface dataset:
NMR‐monitored titration of acid‐stress bacterial chaperone HdeA reveals that Asp and Glu charge neutralization produces a loosened dimer structure in preparation for protein unfolding and chaperone activation
Authors: Garrison McKinzie A. , Crowhurst Karin A. 
Published: December 2013

AbstractHdeA is a periplasmic chaperone found in several gram‐negative pathogenic bacteria that are linked to millions of cases of dysentery per year worldwide. After the protein becomes activated at low pH, it can bind to other periplasmic proteins, protecting them from aggregation when the bacteria travel through the stomach on their way to colonize the intestines. It has been argued that one of the major driving forces for HdeA activation is the protonation of aspartate and glutamate side chains. The goal for this study, therefore, was to investigate, at the atomic level, the structural impact of this charge neutralization on HdeA during the transition from near‐neutral conditions to pH 3.0, in preparation for unfolding and activation of its chaperone capabilities. NMR spectroscopy was used to measure pKa values of Asp and Glu residues and monitor chemical shift changes. Measurements of R2/R1 ratios from relaxation experiments confirm that the protein maintains its dimer structure between pH 6.0 and 3.0. However, calculated correlation times and changes in amide protection from hydrogen/deuterium exchange experiments provide evidence for a loosening of the tertiary and quaternary structures of HdeA; in particular, the data indicate that the dimer structure becomes progressively weakened as the pH decreases. Taken together, these results provide insight into the process by which HdeA is primed to unfold and carry out its chaperone duties below pH 3.0, and it also demonstrates that neutralization of aspartate and glutamate residues is not likely to be the sole trigger for HdeA dissociation and unfolding.
Model‐based dose finding under model uncertainty using general parametric models
Authors: Pinheiro José , Bornkamp Björn , Glimm Ekkehard , Bretz Frank 
Published: December 2013

AbstractThe statistical methodology for the design and analysis of clinical Phase II dose‐response studies, with related software implementation, is well developed for the case of a normally distributed, homoscedastic response considered for a single timepoint in parallel group study designs. In practice, however, binary, count, or time‐to‐event endpoints are encountered, typically measured repeatedly over time and sometimes in more complex settings like crossover study designs. In this paper, we develop an overarching methodology to perform efficient multiple comparisons and modeling for dose finding, under uncertainty about the dose‐response shape, using general parametric models. The framework described here is quite broad and can be utilized in situations involving for example generalized nonlinear models, linear and nonlinear mixed effects models, Cox proportional hazards models, with the main restriction being that a univariate dose‐response relationship is modeled, that is, both dose and response correspond to univariate measurements. In addition to the core framework, we also develop a general purpose methodology to fit dose‐response data in a computationally and statistically efficient way. Several examples illustrate the breadth of applicability of the results. For the analyses, we developed the R add‐on package DoseFinding, which provides a convenient interface to the general approach adopted here. Copyright © 2013 John Wiley & Sons, Ltd.
Semiparametric varying‐coefficient model for interval censored data with a cured proportion
Authors: Shao Fang , Li Jialiang , Ma Shuangge , Lee Mei‐Ling Ting 
Published: December 2013

AbstractVarying‐coefficient models have claimed an increasing portion of statistical research and are now applied to censored data analysis in medical studies. We incorporate such flexible semiparametric regression tools for interval censored data with a cured proportion. We adopted a two‐part model to describe the overall survival experience for such complicated data. To fit the unknown functional components in the model, we take the local polynomial approach with bandwidth chosen by cross‐validation. We establish consistency and asymptotic distribution of the estimation and propose to use bootstrap for inference. We constructed a BIC‐type model selection method to recommend an appropriate specification of parametric and nonparametric components in the model. We conducted extensive simulations to assess the performance of our methods. An application on a decompression sickness data illustrates our methods. Copyright © 2013 John Wiley & Sons, Ltd.
CD13 Regulates Anchorage and Differentiation of the Skeletal Muscle Satellite Stem Cell Population in Ischemic Injury
Authors: Rahman M. Mamunur , Ghosh Mallika , Subramani Jaganathan , Fong Guo-Hua , Carlson Morgan E. , Shapiro Linda H. 
Published: December 2013

AbstractCD13 is a multifunctional cell surface molecule that regulates inflammatory and angiogenic mechanisms in vitro, but its contribution to these processes in vivo or potential roles in stem cell biology remains unexplored. We investigated the impact of loss of CD13 on a model of ischemic skeletal muscle injury that involves angiogenesis, inflammation, and stem cell mobilization. Consistent with its role as an inflammatory adhesion molecule, lack of CD13 altered myeloid trafficking in the injured muscle, resulting in cytokine profiles skewed toward a prohealing environment. Despite this healing-favorable context, CD13KO animals showed significantly impaired limb perfusion with increased necrosis, fibrosis, and lipid accumulation. Capillary density was correspondingly decreased, implicating CD13 in skeletal muscle angiogenesis. The number of CD45−/Sca1−/α7-integrin+/β1-integrin+ satellite cells was markedly diminished in injured CD13KO muscles and adhesion of isolated CD13KO satellite cells was impaired while their differentiation was accelerated. Bone marrow transplantation studies showed contributions from both host and donor cells to wound healing. Importantly, CD13 was coexpressed with Pax7 on isolated muscle-resident satellite cells. Finally, phosphorylated-focal adhesion kinase and ERK levels were reduced in injured CD13KO muscles, consistent with CD13 regulating satellite cell adhesion, potentially contributing to the maintenance and renewal of the satellite stem cell pool and facilitating skeletal muscle regeneration. Stem Cells 2014;32:1564–1577
Intraoperative Neuromonitoring for Surgical Training in Thyroid Surgery: Its Routine Use Allows a Safe Operation Instead of Lack of Experienced Mentoring
Authors: Alesina P. F. , Hinrichs J. , Meier B. , Cho E. Y. , Bolli M. , Walz M. K. 
Published: December 2013

AbstractBackgroundThe aim of the present study was to evaluate the influence of intraoperative neuromonitoring (NM) on surgical training. The results of thyroidectomy performed by inexperienced surgeons under the supervision of a consultant surgeon without intraoperative neuromonitoring (ioNM) were compared to those of the operations performed without experienced assistance but under neuromonitoring control.Materials and methodsThe study included the thyroid operations performed in our Department between 2005 and 2012. Among them, residents or fellows performed 1,116 procedures. Seven hundred sixty‐five operations were conducted without neuromonitoring (NV group) and 351 with NM group. In the NV group 375 unilateral and 390 bilateral operations were performed. In the NM group 149 unilateral and 202 bilateral operations were performed. Primary end point of the study was the incidence of postoperative recurrent laryngeal nerve palsy. A secondary end point was the impact of ioNM on operating time and operative strategy.ResultsThe incidence of recurrent laryngeal nerve (RLN) palsy was 2.6 % in the NV group and 2.7 % in the NM group [p = ns]. One case of bilateral RLN palsy was observed in the NV group. The operative time was longer in the NM group for both lobectomy and total thyroidectomy (50 vs. 56 min and 76 vs. 81 min, respectively; p < 0.05).ConclusionsThe routine use of intermittent intraoperative neuromonitoring during thyroid operations does not reduce the incidence of RLN palsy. Nevertheless, it allows inexperienced surgeons to perform a safe operation with a complication rate comparable to that obtained under supervision of an experienced surgeon. Moreover, ioNM could avoid the unfortunate occurrence of a bilateral RLN palsy.
Prognostic Value of CEA and CK20 mRNA in the Peritoneal Lavage Fluid of Patients Undergoing Curative Surgery for Gastric Cancer
Authors: Takata Akihiro , Kurokawa Yukinori , Fujiwara Yoshiyuki , Nakamura Yurika , Takahashi Tsuyoshi , Yamasaki Makoto , Miyata Hiroshi , Nakajima Kiyokazu , Takiguchi Shuji , Mori Masaki , Doki Yuichiro 
Published: December 2013

AbstractBackground
Peritoneal recurrence is the most common type of recurrence in gastric cancer. Although cytological examination of peritoneal lavage fluid has been used to predict peritoneal spread, peritoneal recurrences often occur even in patients with negative cytology. Our previous retrospective study suggested that reverse transcriptase‐polymerase chain reaction (RT‐PCR) using peritoneal lavage fluid may be useful for predicting peritoneal recurrence in patients with negative cytology. This prospective study was conducted to validate the clinical impact of this RT‐PCR method.MethodsFrom July 2009 to June 2012, a total of 118 cT2‐4 gastric cancer patients underwent surgery. Since 14 patients were ineligible because they had incurable factors, the remaining 104 eligible patients were evaluated for carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20) messenger RNA (mRNA) using RT‐PCR. If either CEA or CK20 mRNA was detected by RT‐PCR, the patient was defined as PCR‐positive as in our previous study. The association between recurrence‐free survival (RFS) and background factors was analyzed using Cox proportional hazards models.ResultsOf 104 patients, 16 (15.4 %) were positive for either CEA or CK20. PCR‐positive patients had significantly worse RFS than PCR‐negative patients (log‐rank p = 0.007). Regarding the pattern of recurrence, 4 of 16 (25 %) PCR‐positive patients and 2 of 88 (2 %) PCR‐negative patients had peritoneal recurrence (p < 0.001), but there were no significant differences in recurrence at other sites. Cox multivariate analysis indicated only PCR‐positivity as a significant predictor of poor RFS (p = 0.029).ConclusionThis prospective study demonstrated that CEA and CK20 PCR results could predict peritoneal recurrence after curative surgery.
A Simple Risk Score to Predict the Presence of Non‐Sentinel Lymph Node Metastases in Breast Cancer Patients with a Positive Sentinel Node
Authors: van la Parra Raquel F. D. , Peer Petronella G. M. , de Roos Wilfred K. , Ernst Miranda F. , de Wilt Johannes H. W. , Bosscha Koop 
Published: December 2013

AbstractBackgroundHistorically, completion axillary lymph node dissection (cALND) is recommended in sentinel lymph node (SLN)‐positive patients. However, the high rate of negative non‐sentinel nodes (NSNs) in cALND and the reported low axillary recurrence rates have led to a more conservative approach. A risk score was developed to identify a patient’s individual risk for NSN metastases.MethodsData of 182 SLN‐positive patients who underwent cALND were used for risk score development. The risk score, consisting of pathological tumor size (≤20/>20 mm), lymphovascular invasion (no/yes), extracapsular extension (no/yes), size of metastases (≤2/>2 mm), and number of positive SLNs (1/>1), was subsequently validated on an external population (n = 180).ResultsThe area under the receiver operating characteristic curve was 0.78 (95 % CI 0.71–0.85) in the original population and 0.78 (95 % CI 0.70–0.85) in the validation population. Based on the predicted risk for positive NSNs, three groups were defined: low risk (≤20 %), intermediate risk (21–50 %), and high risk (>50 %). In total, 88 patients met the Z0011 inclusion criteria and none of them had a high predicted risk. Of the 199 non‐Z0011 patients, 67 (33.7 %) had low risk, 96 (48.2 %) had intermediate risk, and 36 (18.1 %) had high risk.ConclusionA simple risk score, integrating just five clinicopathological variables, was developed that may assist in individual decision making regarding ALND in SLN‐positive patients outside of the Z0011 trial.
Decision science for effective management of populations subject to stochasticity and imperfect knowledge
Authors: Yokomizo Hiroyuki , Coutts Shaun R. , Possingham Hugh P. 
Published: December 2013

AbstractMany species are threatened by human activity through processes such as habitat modification, water management, hunting, and introduction of invasive species. These anthropogenic threats must be mitigated as efficiently as possible because both time and money available for mitigation are limited. For example, it is essential to address the type and degree of uncertainties present to derive effective management strategies for managed populations. Decision science provides the tools required to produce effective management strategies that can maximize or minimize the desired objective(s) based on imperfect knowledge, taking into account stochasticity. Of particular importance are questions such as how much of available budgets should be invested in reducing uncertainty and which uncertainties should be reduced. In such instances, decision science can help select efficient environmental management actions that may be subject to stochasticity and imperfect knowledge. Here, we review the use of decision science in environmental management to demonstrate the utility of the decision science framework. Our points are illustrated using examples from the literature. We conclude that collaboration between theoreticians and practitioners is crucial to maximize the benefits of decision science's rational approach to dealing with uncertainty.
Meta‐models as a straightforward approach to the sensitivity analysis of complex models
Authors: Coutts Shaun R. , Yokomizo Hiroyuki 
Published: December 2013

AbstractComplex simulation models are important tools in applied ecological and conservation research. However sensitivity analysis of this important class of models can be difficult to conduct. High level interactions and non‐linear responses are common in complex simulations, and this necessitates a global sensitivity analysis, where each parameter is tested at a range of values, and in combination with changes in many other parameters. We reviewed the literature, searching for population viability analyses that used simulation models. We found only 9 out of the 122 simulation population viability analysis used global sensitivity analysis. This result is typical of other simulation models in applied ecology, where global sensitivity analysis is rare. We then demonstrate how to conduct a meta‐modeling sensitivity analysis, where a simpler statistically fit function (the meta‐model, also known as the surrogate model or emulator) is used to approximate the behavior of the complicated simulation. This simpler meta‐model is interrogated to inform on the behavior of simulation model. We fit two example meta‐models, a generalized linear model and a boosted regression tree, to exemplify the approach. Our hope is that by going through these techniques thoroughly they will become more widely adopted.
Update on transcobalamin deficiency: clinical presentation, treatment and outcome
Authors: Trakadis Y. J. , Alfares A. , Bodamer O. A. , Buyukavci M. , Christodoulou J. , Connor P. , Glamuzina E. , Gonzalez‐Fernandez F. , Bibi H. , Echenne B. , Manoli I. , Mitchell J. , Nordwall M. , Prasad C. , Scaglia F. , Schiff M. , Schrewe B. , Touati G. , Tchan M. C. , Varet B. , Venditti C. P. , Zafeiriou D. , Rupar C. A. , Rosenblatt D. S. , Watkins D. , Braverman N. 
Published: December 2013

AbstractTranscobalamin (TC) transports cobalamin from blood into cells. TC deficiency is a rare autosomal recessive disorder usually presenting in early infancy with failure to thrive, weakness, diarrhoea, pallor, anemia, and pancytopenia or agammaglobulinemia. It can sometimes resemble neonatal leukemia or severe combined immunodeficiency disease. Diagnosis of TC deficiency is suspected based on megaloblastic anemia, elevation of total plasma homocysteine, and blood or urine methylmalonic acid. It is confirmed by studying the synthesis of TC in cultured fibroblasts, or by molecular analysis of the TCN2 gene. TC deficiency is treatable with supplemental cobalamin, but the optimal type, route and frequency of cobalamin administration and long term patient outcomes are unknown. Here we present a series of 30 patients with TC deficiency, including an update on multiple previously published patients, in order to evaluate the different treatment strategies and provide information about long term outcome. Based on the data presented, current practice appears to favour treatment of individuals with TC deficiency by intramuscular injections of hydroxy‐ or cyanocobalamin. In most cases presented, at least weekly injections (1 mg IM) were necessary to ensure optimal treatment. Most centres adjusted the treatment regimen based on monitoring CBC, total plasma homocysteine, plasma and urine methylmalonic acid, as well as, clinical status. Finally, continuing IM treatment into adulthood appears to be beneficial.
Muscle MRI in patients with long‐chain fatty acid oxidation disorders
Authors: Diekman Eugene F. , van der Pol W. Ludo , Nievelstein Rutger A. J. , Houten Sander M. , Wijburg Frits A. , Visser Gepke 
Published: December 2013

AbstractIntroductionMuscle magnetic resonance imaging (MRI) is a useful tool for visualizing abnormalities in neuromuscular disorders. The value of muscle MRI has not been studied in long‐chain fatty acid oxidation (lcFAO) disorders. LcFAO disorders may present with metabolic myopathy including episodic rhabdomyolysis.ObjectiveTo investigate whether lcFAO disorders are associated with muscle MRI abnormalities.MethodsLower body MRI was performed in 20 patients with lcFAO disorders, i.e. three carnitine palmitoyltransferase 2 deficiency (CPT2D), 12 very long‐chain acyl‐CoA dehydrogenase deficiency (VLCADD), three mitochondrial trifunctional protein deficiency (MTPD) and two isolated long‐chain hydroxyacyl‐CoA dehydrogenase deficiency (LCHADD).ResultsAt the time of MRI, four patients had muscle weakness, 14 had muscle pain and 13 were exercise intolerant. Median creatine kinase (CK) level of patients at the day of MRI was 398 U/L (range 35‐12,483). T1W and STIR signal intensity (SI) were markedly increased in MTPD patients from girdle to lower leg. VLCADD patients showed predominantly proximal T1W SI changes, whereas LCHADD patients mostly showed distal T1W SI changes. Prominent STIR weighted signal intensity increases of almost all muscle groups were observed in patients with VLCADD and LCHADD with very high CK (>11.000) levels.Conclusions and relevancelcFAO disorders are associated with specific patterns of increased T1W and STIR signal intensity. These patterns may reflect lipid accumulation and inflammation secondary to lcFAO defects and progressive muscle damage. Future studies are needed to investigate whether muscle MRI might be a useful tool to monitor disease course and to study pathogenesis of lcFAO related myopathy.
Enzamin ameliorates adipose tissue inflammation with impaired adipocytokine expression and insulin resistance in db/db mice
Authors: Tamura Yukinori , Yano Masato , Kawao Naoyuki , Okumoto Katsumi , Ueshima Shigeru , Kaji Hiroshi , Matsuo Osamu 
Published: December 2013

AbstractThe effects of Enzamin on obesity-related metabolic disorders in obese db/db mice were examined to explore a novel agent for the prevention of insulin resistance. Db/db mice were treated with water containing Enzamin (0·1 and 1·0 %) for 8 weeks from 6 weeks of age. Enzamin treatment at 1·0 %, but not at 0·1 %, significantly decreased the fasting plasma glucose, serum total cholesterol and TAG levels in db/db mice, without affecting body weight gain and body fat composition. Furthermore, insulin sensitivity and glucose tolerance were improved by the treatment of db/db mice with 1·0 % Enzamin. Immunohistochemical studies and gene expression analysis showed that 1·0 % Enzamin treatment suppressed macrophage accumulation and inflammation in the adipose tissue. In addition, 1·0 % Enzamin treatment increased serum adiponectin in db/db mice. Treatment with 1·0 % Enzamin also significantly suppressed the expression of NADPH oxidase subunits, suggesting an antioxidative effect for Enzamin in the adipose tissue. Furthermore, in vitro experiments demonstrated that the lipopolysaccharide-induced inflammatory reaction was significantly suppressed by Enzamin treatment in macrophages. Enzamin treatment increased the expression of GLUT4 mRNA in muscle, but not GLUT2 mRNA in the liver of db/db mice. Enzamin also increased the mRNA expression of carnitine palmitoyltransferase 1a (CPT1a, muscle isoform) in db/db mice, whereas Enzamin treatment did not affect the mRNA expression of CPT1b (liver isoform) in db/db mice. In conclusion, our data indicate that Enzamin can improve insulin resistance by ameliorating impaired adipocytokine expression, presumably through its anti-inflammatory action, and that Enzamin possesses a potential for preventing the metabolic syndrome.
Fabrication methods for performance improvement of Cu(In,Ga)Se2 thin film solar cells
Authors: Choi P.H. , Baek D.H. , Kim H.J. , Kim K.S. , Park H.S. , Kim S.S. , Choi B.D. 
Published: December 2013

Two advanced fabrication methods are introduced: the hydrogen peroxide (H2O2)‐added chemical bath deposition technique and molybdenum (Mo) back‐contact formation under 3 kW sputter power. The parameters of the short circuit current density (JSC) and conversion efficiency (η) were improved over standard cells when the ZnS buffer layer was deposited in the H2O2‐added chemical solution. Otherwise, the fill‐factor and η were best at 3 kW Mo sputtering power conditions. Advanced fabrication methods are realised to improve cell performance without modifying the chemical composition of the Cu(In,Ga)Se2 absorption layer.
Multiplierless approximate 4‐point DCT VLSI architectures for transform block coding
Authors: Bayer F.M. , Cintra R.J. , Madanayake A. , Potluri U.S. 
Published: December 2013

Two multiplierless algorithms are proposed for 4 × 4 approximate‐discrete cosine transform (DCT) for transform coding in digital video. Computational architectures for one‐dimensional (1D)/2D realisations are implemented using Xilinx field programmable gate array devices. CMOS synthesis at the 45 nm node indicates real‐time operation at 1 GHz yielding 4 × 4 block rates of 125 MHz at < 120 mW of dynamic power consumption.
9.5 dB relative intensity noise reduction in quantum cascade laser by detuned loading
Authors: Juretzka C. , Breuer S. , Drzewietzki L. , Schad F. , Carras M. , Elsäßer W. 
Published: December 2013

The possibility of reducing the relative intensity noise (RIN) of a quantum cascade laser is demonstrated. By phase‐dependent optical feedback from a short, piezo‐controlled external cavity configuration, it is possible to achieve up to 9.5 dB of RIN reduction. These findings are consistently explained by a detuned loading approach based on modifying the alpha parameter.