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Find video protocols related to scientific articles indexed in Pubmed.
Justifying One's Transgressions: How Rationalizations Based on Equity, Equality, and Need Affect Trust After Its Violation.
J Exp Psychol Appl
PUBLISHED: 11-04-2014
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We investigate how efforts to justify a transgression as an attempt to address matters of equity, equality, or need would affect the implications of an apology for trust after its violation, and how this would depend on the intended beneficiary. To do so, we conducted 2 studies, including a new research design that supplements the rigor of experiments with far greater realism. Although combining a justification with an apology tended to elicit higher trust relative to an apology alone when the violation benefited another party, doing so was ineffective or harmful when the violation benefited the violator. Finer-grained analyses comparing the 3 types of justifications, furthermore, revealed that the addition of equity-based justifications elicited higher trust than the addition of equality- or need-based justifications in general, and that the addition of need-based justifications was particularly harmful when the violation benefited the self. Perceived fairness mediated these effects. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
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Incorporating Three-dimensional Printing into a Simulation-based Congenital Heart Disease and Critical Care Training Curriculum for Resident Physicians.
Congenit Heart Dis
PUBLISHED: 10-14-2014
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Although simulation-based education is now commonly utilized in medicine, its use in the instruction of congenital heart disease remains limited. The objective of this study is to evaluate whether heart models created with three-dimensional printing technology can be effectively incorporated into a simulation-based congenital heart disease and critical care training curriculum for pediatric resident physicians.
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Modelling the impact of marine reserves on a population with depensatory dynamics.
Bull. Math. Biol.
PUBLISHED: 08-15-2014
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In this study, we use a spatially implicit, stage-structured model to evaluate marine reserve effectiveness for a fish population exhibiting depensatory (strong Allee) effects in its dynamics. We examine the stability and sensitivity of the equilibria of the modelled system with regards to key system parameters and find that for a reasonable set of parameters, populations can be protected from a collapse if a small percentage of the total area is set aside in reserves. Furthermore, the overall abundance of the population is predicted to achieve a maximum at a certain ratio A of reserve area to fished area, which depends heavily on the other system parameters such as the net export rate of fish from the marine reserves to the fished areas. This finding runs contrary to the contested "equivalence at best" result when comparing fishery management through traditional catch or effort control and management through marine reserves. Lastly, we analyse the problem from a bioeconomics perspective by computing the optimal harvesting policy using Pontryagin's Maximum Principle, which suggests that the value for A which maximizes the optimal equilibrium fishery yield also maximizes population abundance when the cost per unit harvest is constant, but can increase substantially when the cost per unit harvest increases with the area being harvested.
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Improved Long-Term Outcomes After Resection of Pancreatic Adenocarcinoma: A Comparison Between Two Time Periods.
Ann. Surg. Oncol.
PUBLISHED: 07-25-2014
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Despite reduced perioperative mortality and routine use of adjuvant therapy following pancreatectomy for pancreatic ductal adenocarcinoma (PDAC), improvement in long-term outcome has been difficult to ascertain. This study compares outcomes in patients undergoing resection for PDAC within a single, high-volume academic institution over two sequential time periods.
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Heterogeneous photodynamics of the pfr state in the cyanobacterial phytochrome Cph1.
Biochemistry
PUBLISHED: 07-08-2014
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Femtosecond photodynamics of the Pfr form of the red/far-red phytochrome N-terminal PAS-GAF-PHY photosensory core module of the cyanobacterial phytochrome Cph1 (termed Cph1?) from Synechocystis were resolved with visible broadband transient absorption spectroscopy. Multiphasic generation dynamics via global target analysis revealed parallel evolution of two pathways with distinct excited- and ground-state kinetics. These measurements resolved two subpopulations: a majority subpopulation with fast excited-state decay and slower ground-state dynamics, corresponding to previous descriptions of Pfr dynamics, and a minority subpopulation with slower excited-state decay and faster ground-state primary dynamics. Both excited-state subpopulations generated the isomerized, red-shifted Lumi-Ff photoproduct (715 nm); subsequent ground-state evolution to a blue-shifted Meta-Fr population (635 nm) proceeded on 3 ps and 1.5 ns time scales for the two subpopulations. Meta-Fr was spectrally similar to a recently described photoinactive fluorescent subpopulation of Pr ((Fluor)Pr). Thus, the reverse Pfr to Pr photoconversion of Cph1? involves minor structural deformation of Meta-Fr to generate the fluorescent, photochemically refractory form of Pr, with slower subsequent equilibration with the photoactive Pr subpopulation ((Photo)Pr).
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PEX16 contributes to peroxisome maintenance by constantly trafficking PEX3 via the ER.
J. Cell. Sci.
PUBLISHED: 07-07-2014
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The endoplasmic reticulum (ER) is required for the de novo biogenesis of peroxisomes in mammalian cells. However, its role in peroxisome maintenance is unclear. To explore ER involvement in the maintenance of peroxisomes, we redirect a peroxisomal membrane protein (PMP), PEX3, to directly target to the ER using the N-terminal ER signal sequence from preprolactin. Using biochemical techniques and fluorescent imaging, we find that ER-targeting PEX3 (ssPEX3) is continuously imported into pre-existing peroxisomes. This suggests that the ER constitutively provides membrane proteins and associated lipids to pre-existing peroxisomes. Using quantitative time-lapse live-cell fluorescence microscopy applied to cells that were either depleted of or exogenously expressing PEX16, we find that PEX16 mediates the peroxisomal trafficking of two distinct peroxisomal membrane proteins, PEX3 and PMP34, via the ER. These results not only provide insight into peroxisome maintenance and PMP trafficking in mammalian cells but also highlight important similarities and differences in the mechanisms of PMP import between the mammalian and yeast systems.
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Maternal mortality in Bangladesh: a Countdown to 2015 country case study.
Lancet
PUBLISHED: 06-29-2014
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Bangladesh is one of the only nine Countdown countries that are on track to achieve the primary target of Millennium Development Goal (MDG) 5 by 2015. It is also the only low-income or middle-income country with two large, nationally-representative, high-quality household surveys focused on the measurement of maternal mortality and service use.
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Utilizing Three-Dimensional Printing Technology to Assess the Feasibility of High-Fidelity Synthetic Ventricular Septal Defect Models for Simulation in Medical Education.
World J Pediatr Congenit Heart Surg
PUBLISHED: 06-25-2014
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The current educational approach for teaching congenital heart disease (CHD) anatomy to students involves instructional tools and techniques that have significant limitations. This study sought to assess the feasibility of utilizing present-day three-dimensional (3D) printing technology to create high-fidelity synthetic heart models with ventricular septal defect (VSD) lesions and applying these models to a novel, simulation-based educational curriculum for premedical and medical students.
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Nuclear imaging: A powerful novel approach for tuberculosis.
Nucl. Med. Biol.
PUBLISHED: 05-29-2014
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Nearly 20years after the World Health Organization declared tuberculosis (TB) a global public health emergency, TB still remains a major global threat with 8.6 million new cases and 1.3 million deaths annually. Mycobacterium tuberculosis adapts to a quiescent physiological state, and is notable for complex interaction with the host, producing poorly-understood disease states ranging from latent infection to fully active disease. Of the approximately 2.5 billion people latently infected with M. tuberculosis, many will develop reactivation disease (relapse), years after the initial infection. While progress has been made on some fronts, the alarming spread of multidrug-resistant, extensively drug-resistant, and more recently totally-drug resistant strains is of grave concern. New tools are urgently needed for rapidly diagnosing TB, monitoring TB treatments and to allow unique insights into disease pathogenesis. Nuclear bioimaging is a powerful, noninvasive tool that can rapidly provide three-dimensional views of disease processes deep within the body and conduct noninvasive longitudinal assessments of the same patient. In this review, we discuss the application of nuclear bioimaging to TB, including the current state of the field, considerations for radioprobe development, study of TB drug pharmacokinetics in infected tissues, and areas of research and clinical needs that could be addressed by nuclear bioimaging. These technologies are an emerging field of research, overcome several fundamental limitations of current tools, and will have a broad impact on both basic research and patient care. Beyond diagnosis and monitoring disease, these technologies will also allow unique insights into understanding disease pathogenesis; and expedite bench-to-bedside translation of new therapeutics. Finally, since molecular imaging is readily available for humans, validated tracers will become valuable tools for clinical applications.
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The practice of jhum cultivation and its relationship to Plasmodium falciparum infection in the Chittagong Hill Districts of Bangladesh.
Am. J. Trop. Med. Hyg.
PUBLISHED: 05-12-2014
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Malaria is endemic in the Chittagong Hill Districts of southeastern Bangladesh. Previous epidemiological analyses identified the agricultural practice of jhum cultivation as a potential risk factor for malaria infection. We conducted qualitative interviews with jhum cultivators and surveillance workers to describe jhum cultivation and used demographic and malaria surveillance in two study unions from May of 2010 to August of 2012 to better understand the relationship between jhum cultivation and malaria infection. Qualitative interviews revealed that jhum cultivation is conducted on remote, steep hillsides by ethnic tribal groups. Quantitative analyses found that adult jhum cultivators and individuals who live in the same residence had significantly higher incidence rates of symptomatic Plasmodium falciparum infection compared with non-cultivators. These results confirm that jhum cultivation is an independent risk factor for malaria infection and underscore the need for malaria testing and treatment services to reach remote populations in the Chittagong Hill Districts.
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Impact of viral hepatitis on outcomes after liver resection for hepatocellular carcinoma: results from a north american center.
Ann. Surg. Oncol.
PUBLISHED: 05-08-2014
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Hepatitis B (HBV) and hepatitis C (HCV) are well-recognized risk factors for hepatocellular carcinoma (HCC). The characteristics and clinical outcomes of HCC arising from these conditions may differ. This study was conducted to compare the outcomes of HCC associated with HBV and HCV after liver resection.
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Dynamic inhomogeneity in the photodynamics of cyanobacterial phytochrome Cph1.
Biochemistry
PUBLISHED: 04-21-2014
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Phytochromes are widespread red/far-red photosensory proteins well known as critical regulators of photomorphogenesis in plants. It is often assumed that natural selection would have optimized the light sensing efficiency of phytochromes to minimize nonproductive photochemical deexcitation pathways. Surprisingly, the quantum efficiency for the forward Pr-to-Pfr photoconversion of phytochromes seldom exceeds 15%, a value very much lower than that of animal rhodopsins. Exploiting ultrafast excitation wavelength- and temperature-dependent transient absorption spectroscopy, we resolve multiple pathways within the ultrafast photodynamics of the N-terminal PAS-GAF-PHY photosensory core module of cyanobacterial phytochrome Cph1 (termed Cph1?) that are primarily responsible for the overall low quantum efficiency. This inhomogeneity primarily reflects a long-lived fluorescent subpopulation that exists in equilibrium with a spectrally distinct, photoactive subpopulation. The fluorescent subpopulation is favored at elevated temperatures, resulting in anomalous excited-state dynamics (slower kinetics at higher temperatures). The spectral and kinetic behavior of the fluorescent subpopulation strongly resembles that of the photochemically compromised and highly fluorescent Y176H variant of Cph1?. We present an integrated, heterogeneous model for Cph1? that is based on the observed transient and static spectroscopic signals. Understanding the molecular basis for this dynamic inhomogeneity holds potential for rational design of efficient phytochrome-based fluorescent and photoswitchable probes.
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Fabrication of poly(ethylene glycol): gelatin methacrylate composite nanostructures with tunable stiffness and degradation for vascular tissue engineering.
Biofabrication
PUBLISHED: 04-10-2014
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Although synthetic polymers are desirable in tissue engineering applications for the reproducibility and tunability of their properties, synthetic small diameter vascular grafts lack the capability to endothelialize in vivo. Thus, synthetically fabricated biodegradable tissue scaffolds that reproduce important aspects of the extracellular environment are required to meet the urgent need for improved vascular grafting materials. In this study, we have successfully fabricated well-defined nanopatterned cell culture substrates made of a biodegradable composite hydrogel consisting of poly(ethylene glycol) dimethacrylate (PEGDMA) and gelatin methacrylate (GelMA) by using UV-assisted capillary force lithography. The elasticity and degradation rate of the composite PEG-GelMA nanostructures were tuned by varying the ratios of PEGDMA and GelMA. Human umbilical vein endothelial cells (HUVECs) cultured on nanopatterned PEG-GelMA substrates exhibited enhanced cell attachment compared with those cultured on unpatterned PEG-GelMA substrates. Additionally, HUVECs cultured on nanopatterned PEG-GelM substrates displayed well-aligned, elongated morphology similar to that of native vascular endothelial cells and demonstrated rapid and directionally persistent migration. The ability to alter both substrate stiffness and degradation rate and culture endothelial cells with increased elongation and alignment is a promising next step in recapitulating the properties of native human vascular tissue for tissue engineering applications.
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A dynamical model of tumour immunotherapy.
Math Biosci
PUBLISHED: 04-08-2014
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A coupled ordinary differential equation model of tumour-immune dynamics is presented and analysed. The model accounts for biological and clinical factors which regulate the interaction rates of cytotoxic T lymphocytes on the surface of the tumour mass. A phase plane analysis demonstrates that competition between tumour cells and lymphocytes can result in tumour eradication, perpetual oscillations, or unbounded solutions. To investigate the dependence of the dynamic behaviour on model parameters, the equations are solved analytically and conditions for unbounded versus bounded solutions are discussed. An analytic characterisation of the basin of attraction for oscillatory orbits is given. It is also shown that the tumour shape, characterised by a surface area to volume scaling factor, influences the size of the basin, with significant consequences for therapy design. The findings reveal that the tumour volume must surpass a threshold size that depends on lymphocyte parameters for the cancer to be completely eliminated. A semi-analytic procedure to calculate oscillation periods and determine their sensitivity to model parameters is also presented. Numerical results show that the period of oscillations exhibits notable nonlinear dependence on biologically relevant conditions.
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Synergistic effects of matrix nanotopography and stiffness on vascular smooth muscle cell function.
Tissue Eng Part A
PUBLISHED: 04-02-2014
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Vascular smooth muscle cells (vSMCs) retain the ability to undergo modulation in their phenotypic continuum, ranging from a mature contractile state to a proliferative, secretory state. vSMC differentiation is modulated by a complex array of microenvironmental cues, which include the biochemical milieu of the cells and the architecture and stiffness of the extracellular matrix. In this study, we demonstrate that by using UV-assisted capillary force lithography (CFL) to engineer a polyurethane substratum of defined nanotopography and stiffness, we can facilitate the differentiation of cultured vSMCs, reduce their inflammatory signature, and potentially promote the optimal functioning of the vSMC contractile and cytoskeletal machinery. Specifically, we found that the combination of medial tissue-like stiffness (11?MPa) and anisotropic nanotopography (ridge width_groove width_ridge height of 800_800_600?nm) resulted in significant upregulation of calponin, desmin, and smoothelin, in addition to the downregulation of intercellular adhesion molecule-1, tissue factor, interleukin-6, and monocyte chemoattractant protein-1. Further, our results allude to the mechanistic role of the RhoA/ROCK pathway and caveolin-1 in altered cellular mechanotransduction pathways via differential matrix nanotopography and stiffness. Notably, the nanopatterning of the stiffer substrata (1.1?GPa) resulted in the significant upregulation of RhoA, ROCK1, and ROCK2. This indicates that nanopatterning an 800_800_600?nm pattern on a stiff substratum may trigger the mechanical plasticity of vSMCs resulting in a hypercontractile vSMC phenotype, as observed in diabetes or hypertension. Given that matrix stiffness is an independent risk factor for cardiovascular disease and that CFL can create different matrix nanotopographic patterns with high pattern fidelity, we are poised to create a combinatorial library of arterial test beds, whether they are healthy, diseased, injured, or aged. Such high-throughput testing environments will pave the way for the evolution of the next generation of vascular scaffolds that can effectively crosstalk with the scaffold microenvironment and result in improved clinical outcomes.
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Probing peroxisome dynamics and biogenesis by fluorescence imaging.
Curr Protoc Cell Biol
PUBLISHED: 03-11-2014
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Peroxisomes are the most recently discovered classical organelles, and only lately have their diverse functions been truly recognized. Peroxisomes are highly dynamic structures, changing both morphologically and in number in response to both extracellular and intracellular signals. This metabolic organelle came to prominence due to the many genetic disorders caused by defects in its biogenesis or enzymatic functions. There is now growing evidence that suggests peroxisomes are involved in lipid biosynthesis, innate immunity, redox homeostasis, and metabolite scavenging, among other functions. Therefore, it is important to have available suitable methods and techniques to visualize and quantify peroxisomes in response to various cellular signals. This unit includes a number of protocols that will enable researchers to image, qualify, and quantify peroxisome numbers and morphology-with both steady-state and time-lapse imaging using mammalian cells. The use of photoactivatable fluorescent proteins to detect and measure peroxisome biogenesis is also described. Altogether, the protocols described here will facilitate understanding of the dynamic changes that peroxisomes undergo in response to various cellular signals.
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Ratio of hepatic arterial flow to recipient body weight predicts biliary complications after deceased donor liver transplantation.
HPB (Oxford)
PUBLISHED: 03-05-2014
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Adequate hepatic arterial (HA) flow to the bile duct is essential in liver transplantation. This study was conducted to determine if the ratio of directly measured HA flow to weight is related to the occurrence of biliary complications after deceased donor liver transplantation.
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Grandmothering drives the evolution of longevity in a probabilistic model.
J. Theor. Biol.
PUBLISHED: 03-05-2014
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We present a mathematical model based on the Grandmother Hypothesis to simulate how human post-menopausal longevity could have evolved as ancestral grandmothers began to assist the reproductive success of younger females by provisioning grandchildren. Grandmothers? help would allow mothers to give birth to subsequent offspring sooner without risking the survival of existing offspring. Our model is an agent-based model (ABM), in which the population evolves according to probabilistic rules governing interactions among individuals. The model is formulated according to the Gillespie algorithm of determining the times to next events. Grandmother effects drive the population from an equilibrium representing a great-ape-like average adult lifespan in the lower twenties to a new equilibrium with a human-like average adult lifespan in the lower forties. The stochasticity of the ABM allows the possible coexistence of two locally-stable equilibria, corresponding to great-ape-like and human-like lifespans. Populations with grandmothering that escape the ancestral condition then shift to human-like lifespan, but the transition takes longer than previous models (Kim et al., 2012). Our simulations are consistent with the possibility that distinctive longevity is a feature of genus Homo that long antedated the appearance of our species.
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Pan-Bcl-2 inhibitor, GX15-070 (obatoclax), decreases human T regulatory lymphocytes while preserving effector T lymphocytes: a rationale for its use in combination immunotherapy.
J. Immunol.
PUBLISHED: 02-10-2014
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Bcl-2 inhibitors are currently being evaluated in clinical studies for treatment of patients with solid tumors and hematopoietic malignancies. In this study we explored the potential for combining the pan-Bcl-2 inhibitor GX15-070 (GX15; obatoclax) with immunotherapeutic modalities. We evaluated the in vitro effects of GX15 on human T cell subsets obtained from PBMCs in terms of activation, memory, and suppressive function. Our results indicated that in healthy-donor PBMCs, mature-activated T cells were more resistant to GX15 than early-activated T cells, and that GX15 preserved memory but not non-memory T cell populations. Furthermore, GX15 increased the apoptosis of regulatory T cells (Tregs), profoundly downregulated FOXP3 and CTLA-4 in a dose-dependent manner, and decreased their suppressive function. Treating PBMCs obtained from ovarian cancer patients with GX15 also resulted in increased CD8(+):Treg and CD4(+):Treg ratios. These results support preclinical studies in which mice vaccinated before treatment with GX15 showed the greatest reduction in metastatic lung tumors as a result of increased apoptotic resistance of mature CD8(+) T cells and decreased Treg function brought about by GX15. Taken together, these findings suggest that when a Bcl-2 inhibitor is combined with active immunotherapy in humans, such as the use of a vaccine or immune checkpoint inhibitor, immunotherapy should precede administration of the Bcl-2 inhibitor to allow T cells to become mature, and thus resistant to the cytotoxic effects of the Bcl-2 inhibitor.
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A prospective cohort study of stroke mortality and arsenic in drinking water in Bangladeshi adults.
BMC Public Health
PUBLISHED: 02-05-2014
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Arsenic in drinking water causes increased coronary artery disease (CAD) and death from CAD, but its association with stroke is not known.
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Primary and secondary photodynamics of the violet/orange dual-cysteine NpF2164g3 cyanobacteriochrome domain from Nostoc punctiforme.
Biochemistry
PUBLISHED: 02-03-2014
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Cyanobacteriochromes (CBCRs) are cyanobacterial photoreceptors distantly related to phytochromes. Like phytochromes, CBCRs photointerconvert between two photostates that accompany photoisomerization of their bilin chromophores. While phytochromes typically exhibit red/far-red photocycles, CBCR photocycles are much more diverse, spanning the near-ultraviolet and the entire visible region. All CBCRs described to date have a conserved Cys residue covalently attached to the linear tetrapyrrole (bilin) chromophore; two CBCR subfamilies also exploit a second thioether linkage to the chromophore for detection of near-ultraviolet to blue light. Here, we present the photodynamic analysis of the insert-Cys CBCR NpF2164g3, a representative of the second class of two-cysteine CBCRs. Using broadband transient absorption pump-probe spectroscopy, we characterize the primary (100 fs to 10 ns) and secondary (10 ns to 1 ms) photodynamics in both directions, examining photodynamics over nine decades of time. Primary isomerization dynamics occur on a ~10 ps time scale for both forward and reverse reactions. In contrast to previous studies on Tlr0924, a representative of the other class of two-cysteine CBCRs, formation and elimination of the second linkage are slower than the 1 ms experimental range probed here. These results extend our understanding of dual-cysteine CBCR photocycles in the phytochrome superfamily.
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A plastic surgery application in evolution: three-dimensional printing.
Plast. Reconstr. Surg.
PUBLISHED: 01-29-2014
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Three-dimensional printing represents an evolving technology still in its infancy. Currently, individuals and small business entities have the ability to manufacture physical objects from digital renderings, computer-aided design, and open source files. Design modifications and improvements in extrusion methods have made this technology much more affordable. This article explores the potential uses of three-dimensional printing in plastic surgery.
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Combined pancreaticoduodenectomy and colon resection for locally advanced peri-ampullary tumours: analysis of peri-operative morbidity and mortality.
HPB (Oxford)
PUBLISHED: 01-22-2014
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Combined pancreaticoduodenectomy (PD) and colonic resection may be necessary to achieve an R0 resection of peri-ampullary tumours. The aim of this study was to examine the morbidity and mortality associated with this procedure.
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Risk factors associated with complications in lower-extremity reconstruction with the distally based sural flap: a systematic review and pooled analysis.
J Plast Reconstr Aesthet Surg
PUBLISHED: 01-17-2014
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The distally based sural fasciocutaneous flap is one of the few options available for local flap reconstruction of soft-tissue defects in the lower one-third of the leg. Few studies have assessed risk factors associated with poor outcomes in this flap. A literature search was performed of MEDLINE, EMBASE, CINAHL and the Cochrane Library for articles evaluating the use of sural artery fasciocutaneous flaps for soft-tissue reconstruction of the leg. Data were pooled and a univariate analysis was performed to identify characteristics associated with increased morbidity. A logistic regression model was created, and odds ratios and p values associated with the development of complications were calculated. Sixty-one papers were identified which included data on 907 patients. The majority of sural flaps were used to cover defects of the heel (28.2%), foot (14.4%) or ankle (25.8%). Trauma was the most common indication, followed by ulcers and open fractures. Flap complications were recorded in 26.4% of cases with a flap loss rate of 3.2%. With multivariate analysis, venous insufficiency and increasing age were independent risk factors for complications. Patients with venous insufficiency had nine times the risk of developing a complication compared to patients without venous insufficiency.
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Equity in adherence to and effect of prenatal food and micronutrient supplementation on child mortality: results from the MINIMat randomized trial, Bangladesh.
BMC Public Health
PUBLISHED: 01-03-2014
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Evidence is often missing on social differentials in effects of nutrition interventions. We evaluated the adherence to and effect of prenatal food and micronutrient supplementations on mortality before the age of five years in different social groups as defined by maternal schooling.
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Radiographic scoring system to evaluate union of distal radius fractures.
J Hand Surg Am
PUBLISHED: 01-02-2014
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To evaluate the intra- and interobserver reliability of a scoring system for distal radius fracture union based on specific radiographic parameters obtainable from x-rays.
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High uptake of systematic HIV counseling and testing and TB symptom screening at a primary care clinic in South Africa.
PLoS ONE
PUBLISHED: 01-01-2014
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Timely diagnosis and treatment of tuberculosis (TB) and HIV is important to reduce morbidity and mortality, and break the cycle of ongoing transmission.
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Potential utility of the pan-Bcl-2 inhibitor GX15-070 (obatoclax) in cancer immunotherapy.
Oncoimmunology
PUBLISHED: 01-01-2014
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An exploration of the immunotherapeutic potential of the pan-Bcl-2 inhibitor GX15-070 (GX15) has revealed that early-activated T cells derived from human peripheral blood are more sensitive to GX15 than are prolonged-activated T cells. Furthermore, non-memory and regulatory T cells also exhibit higher sensitivity to GX15. The implication of these prior findings suggests that GX15 may enhance the efficacy of immunotherapies in clinical settings.
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Comparison of illumina and 454 deep sequencing in participants failing raltegravir-based antiretroviral therapy.
PLoS ONE
PUBLISHED: 01-01-2014
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The impact of raltegravir-resistant HIV-1 minority variants (MVs) on raltegravir treatment failure is unknown. Illumina sequencing offers greater throughput than 454, but sequence analysis tools for viral sequencing are needed. We evaluated Illumina and 454 for the detection of HIV-1 raltegravir-resistant MVs.
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Population-based incidence of severe acute respiratory virus infections among children aged <5 years in rural Bangladesh, June-October 2010.
PLoS ONE
PUBLISHED: 01-01-2014
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Better understanding the etiology-specific incidence of severe acute respiratory infections (SARIs) in resource-poor, rural settings will help further develop and prioritize prevention strategies. To address this gap in knowledge, we conducted a longitudinal study to estimate the incidence of SARIs among children in rural Bangladesh.
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PEX5 and ubiquitin dynamics on mammalian peroxisome membranes.
PLoS Comput. Biol.
PUBLISHED: 01-01-2014
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Peroxisomes are membrane-bound organelles within eukaryotic cells that post-translationally import folded proteins into their matrix. Matrix protein import requires a shuttle receptor protein, usually PEX5, that cycles through docking with the peroxisomal membrane, ubiquitination, and export back into the cytosol followed by deubiquitination. Matrix proteins associate with PEX5 in the cytosol and are translocated into the peroxisome lumen during the PEX5 cycle. This cargo translocation step is not well understood, and its energetics remain controversial. We use stochastic computational models to explore different ways the AAA ATPase driven removal of PEX5 may couple with cargo translocation in peroxisomal importers of mammalian cells. The first model considered is uncoupled, in which translocation is spontaneous, and does not immediately depend on PEX5 removal. The second is directly coupled, in which cargo translocation only occurs when its PEX5 is removed from the peroxisomal membrane. The third, novel, model is cooperatively coupled and requires two PEX5 on a given importomer for cargo translocation--one PEX5 with associated cargo and one with ubiquitin. We measure both the PEX5 and the ubiquitin levels on the peroxisomes as we vary the matrix protein cargo addition rate into the cytosol. We find that both uncoupled and directly coupled translocation behave identically with respect to PEX5 and ubiquitin, and the peroxisomal ubiquitin signal increases as the matrix protein traffic increases. In contrast, cooperatively coupled translocation behaves dramatically differently, with a ubiquitin signal that decreases with increasing matrix protein traffic. Recent work has shown that ubiquitin on mammalian peroxisome membranes can lead to selective degradation by autophagy, or 'pexophagy.' Therefore, the high ubiquitin level for low matrix cargo traffic with cooperatively coupled protein translocation could be used as a disuse signal to mediate pexophagy. This mechanism may be one way that cells could regulate peroxisome numbers.
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An age-structured approach to modelling behavioural variation maintained by life-history trade-offs.
PLoS ONE
PUBLISHED: 01-01-2014
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There have been numerous empirical studies on the fitness consequences of behavioural syndromes in various animal taxa; however, the ecological and evolutionary implications on a population level are still poorly understood. To better understand these implications, we develop a non-linear age-structured mathematical model to qualitatively examine the evolutionary consequences of a heritable boldness personality trait within an animal population. We assume that this heritable boldness trait is positively correlated with boldness towards predators and intraspecific aggressiveness. This assumption leads to a growth/reproductive success versus mortality trade-off, which is thoroughly investigated and documented in the literature. Another life-history trade-off we include in the model is future versus current reproduction, which was shown by Wolf et al. to be a possible mechanism for the evolution of behavioural syndromes within an animal population. The stability of the system is analysed, whereby the characteristic equation is in the form of a homogeneous Fredholm equation of the second kind which depends on both the perturbation and equilibrium solution. The system is found to be stable due to the competition between individuals of similar boldness acting as a negative feedback mechanism. Using numerical simulations we examine the qualitative features of the solution to the system. In particular, we investigate the interplay between the mutation and competition strength between two individuals with different boldness, whereby we find that an increasing competition range acts to push individuals to both extremes of the shy-bold axis, while an increasing mutation range counteracts this effect. This qualitative trait of aggregation of individuals around the shy and bold extremes is also found when examining different birth, mortality and competition functions.
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Primary photodynamics of the green/red-absorbing photoswitching regulator of the chromatic adaptation E domain from Fremyella diplosiphon.
Biochemistry
PUBLISHED: 11-07-2013
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Phytochromes are red/far-red photosensory proteins that utilize the photoisomerization of a linear tetrapyrrole (bilin) chromophore to detect the red to far-red light ratio. Cyanobacteriochromes (CBCRs) are distantly related cyanobacterial photosensors with homologous bilin-binding GAF domains, but they exhibit greater spectral diversity. Different CBCR subfamilies have been described, with spectral sensitivity varying across the near-ultraviolet and throughout the visible spectrum, but all known CBCRs utilize photoisomerization of the bilin 15,16-double bond as the primary photochemical event. The first CBCR discovered was RcaE, responsible for tuning light harvesting to the incident color environment (complementary chromatic adaptation) in Fremyella diplosiphon. The green/red RcaE photocycle has recently been described in detail. We now extend this analysis by examining femtosecond photodynamics using ultrafast transient absorption techniques with broadband detection and multicomponent global analysis. Excited-state dynamics in both directions are significantly slower than those recently published for the red/green CBCR NpR6012g4. In the forward reaction, the primary Lumi-G photoproduct arises from the longer-lived excited-state populations, leading to a low photoproduct quantum yield. Using dual-excitation wavelength interleaved pump-probe spectroscopy, we observe multiphasic excited-state dynamics in the forward reaction ((15Z)Pg ? (15E)Pr), which we interpret as arising from ground-state inhomogeneity with different tautomers of the PCB chromophore. The reverse reaction ((15E)Pr ? (15Z)Pg) is characterized via pump-probe spectroscopy and also exhibits slow excited-state decay dynamics and a low photoproduct yield. These results provide the first description of excited-state dynamics for a green/red CBCR.
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The Boston marathon bombings: the early plastic surgery experience of one Boston hospital.
Plast. Reconstr. Surg.
PUBLISHED: 10-30-2013
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On April 15, 2013, at approximately 2:49 p.m. EDT, two improvised explosive devices detonated near the finish line of the 117th Boston Marathon. Patients were transported from the scene to several trauma centers, including the authors institution.
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Superior versus inferior conjunctival autografts combined with fibrin glue in the management of primary pterygia.
Cornea
PUBLISHED: 10-23-2013
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To compare the outcomes of superior versus inferior conjunctival autograft (CAU) in the prevention of recurrence after performing a pterygium surgery in patients with primary pterygia.
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Unraveling the Primary Isomerization Dynamics in Cyanobacterial Phytochrome Cph1 with Multi-pulse Manipulations.
J Phys Chem Lett
PUBLISHED: 10-22-2013
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The ultrafast mechanisms underlying the initial photoisomerization (Pr ? Lumi-R) in the forward reaction of the cyanobacterial photoreceptor Cph1 were explored with multipulse pump-dump-probe transient spectroscopy. A recently postulated multi-population model was used to fit the transient pump-dump-probe and dump-induced depletion signals. We observed dump-induced depletion of the Lumi-R photoproduct, demonstrating that photoisomerization occurs via evolution on both the excited- and ground-state electronic surfaces. Excited-state equilibrium was not observed, as shown via the absence of a dump-induced excited-state "Le Châtelier redistribution" of excited-state populations. The importance of incorporating the inhomogeneous dynamics of Cph1 in interpreting measured transient data is discussed.
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Effect of mature blood-stage Plasmodium parasite sequestration on pathogen biomass in mathematical and in vivo models of malaria.
Infect. Immun.
PUBLISHED: 10-21-2013
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Parasite biomass and microvasculature obstruction are strongly associated with disease severity and death in Plasmodium falciparum-infected humans. This is related to sequestration of mature, blood-stage parasites (schizonts) in peripheral tissue. The prevailing view is that schizont sequestration leads to an increase in pathogen biomass, yet direct experimental data to support this are lacking. Here, we first studied parasite population dynamics in inbred wild-type (WT) mice infected with the rodent species of malaria, Plasmodium berghei ANKA. As is commonly reported, these mice became moribund due to large numbers of parasites in multiple tissues. We then studied infection dynamics in a genetically targeted line of mice, which displayed minimal tissue accumulation of parasites. We constructed a mathematical model of parasite biomass dynamics, incorporating schizont-specific host clearance, both with and without schizont sequestration. Combined use of mathematical and in vivo modeling indicated, first, that the slowing of parasite growth in the genetically targeted mice can be attributed to specific clearance of schizonts from the circulation and, second, that persistent parasite growth in WT mice can be explained solely as a result of schizont sequestration. Our work provides evidence that schizont sequestration could be a major biological process driving rapid, early increases in parasite biomass during blood-stage Plasmodium infection.
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Intracorneal ring segment explantation after intracorneal ring segment implantation combined with same-day corneal collagen crosslinking in keratoconus.
Cornea
PUBLISHED: 09-28-2013
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To report the outcome and the reversibility of refractive outcomes after intrastromal corneal ring segment (ICRS) explantation in patients with keratoconus treated with ICRS implantation and same-day collagen crosslinking (CXL).
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DO SELF-REPORTED HEALTH INDICATORS PREDICT MORTALITY? EVIDENCE FROM MATLAB, BANGLADESH.
J Biosoc Sci
PUBLISHED: 08-12-2013
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Summary In order to understand current and changing patterns of population health, there is a clear need for high-quality health indicators. The World Health Organization Study on Global AGEing and Adult Health (SAGE) survey platform and the International Network for the Demographic Evaluation of Populations and Their Health in developing countries (INDEPTH) generated data for this study. A total of 4300 people aged 50 years or older were selected randomly from the Matlab Health and Demographic Surveillance System of the International Centre for Diarrhoeal Disease Research, Bangladesh. The health indicators derived from these survey data are self-rated general health, overall health state, quality of life and disability levels. The outcome of the study is mortality over a 2-year follow-up since the survey. Among the four health indicators, only self-rated health was significantly associated with subsequent mortality irrespective of sex: those who reported bad health had higher mortality than those who reported good health, even after controlling for socio-demographic factors. For all other three health indicators, such associations exist but are significant only for males, while for females it is significant only for quality of life.
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The Effects of Beta Alanine Supplementation on Performance: A Systematic Review of the Literature.
Int J Sport Nutr Exerc Metab
PUBLISHED: 08-05-2013
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Purpose: To critically review the methodological quality and synthesize information from systematic reviews and high quality studies on the effects of beta alanine (BA) on exercise and athletic performance. Methods: A search strategy was developed in accordance with the standards for the reporting of scientific literature via systematic reviews. Five databases were thoroughly searched from inception to November 2012. Inclusion criteria were English language, human studies, used BA to increase exercise or athletic performance, systematic reviews or randomized controlled trials and were published in a peer-reviewed journal. Included studies were systematically graded for their methodological quality by rotating pairs of reviewers and the results were qualitatively synthesized. Results: One systematic review and nineteen randomized trials were included in this review. There is one systematic review with several methodological weaknesses that limit the confidence in its results. There are moderate to high quality studies that appear to support that BA may increase power output and working capacity, decrease the feeling of fatigue and exhaustion, and have of positive effect on body composition and carnosine content. The reporting of side effects from BA supplementation in the athletic population was generally under-reported. Conclusions: There appears to be some evidence from this review that supplementation with BA may increase athletic performance. However, there is insufficient evidence examining the safety of BA supplementation and its side effects. It is therefore recommended to err on the side of caution in using BA as an ergogenic aid until there is sufficient evidence confirming its safety.
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Factors associated with condom use negotiation by female sex workers in Bangladesh.
Int J STD AIDS
PUBLISHED: 07-15-2013
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Negotiation for condom use by female sex workers with their male clients can enhance condom use. A cross-sectional study was conducted among 1395 female sex workers; 439 from two brothels, 442 from 30 hotels, and 514 from streets of two cities in Bangladesh to determine the predictors of condom use negotiation. Consistent condom use rates in the 7 days prior to interview were reported to be 16.2%, 21.7%, and 4.5% among the brothel, hotel, and street-based female sex workers, respectively. Overall, 28.1% of female sex workers negotiated for condom use with their clients. Participation in behaviour change communication (BCC) programmes (AOR, 1.5; 95% CI, 1.2-2.0) and self-perceived risk of human immunodeficiency virus infection (AOR, 1.8 95% CI, 1.6-2.1) were positive predictors for condom negotiation. Compared to the hotel-based female sex workers, street (AOR, 0.6; 95% CI, 0.4-0.9) and brothel-based female sex workers (AOR, 0.7; 95% CI, 0.5-0.9) were less likely to negotiate for condom use. Female sex workers in Bangladesh are at high risk for sexually transmitted infection / human immunodeficiency virus infection because of low overall negotiation for condom use. Participation in BCC programmes had positive effect on condom negotiation by female sex workers, and should be strengthened in commercial sex venues.
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Reactive ground-state pathways are not ubiquitous in red/green cyanobacteriochromes.
J Phys Chem B
PUBLISHED: 06-19-2013
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Recent characterization of the red/green cyanobacteriochrome (CBCR) NpR6012g4 revealed a high quantum yield for its forward photoreaction [J. Am. Chem. Soc. 2012, 134, 130-133] that was ascribed to the activity of hidden, productive ground-state intermediates. The dynamics of the pathways involving these ground-state intermediates was resolved with femtosecond dispersed pump-dump-probe spectroscopy, the first such study reported for any CBCR. To address the ubiquity of such second-chance initiation dynamics (SCID) in CBCRs, we examined the closely related red/green CBCR NpF2164g6 from Nostoc punctiforme. Both NpF2164g6 and NpR6012g4 use phycocyanobilin as the chromophore precursor and exhibit similar excited-state dynamics. However, NpF2164g6 exhibits a lower quantum yield of 32% for the generation of the isomerized Lumi-R primary photoproduct, compared to 40% for NpR6012g4. This difference arises from significantly different ground-state dynamics between the two proteins, with the SCID mechanism deactivated in NpF2164g6. We present an integrated inhomogeneous target model that self-consistently fits the pump-probe and pump-dump-probe signals for both forward and reverse photoreactions in both proteins. This work demonstrates that reactive ground-state intermediates are not ubiquitous phenomena in CBCRs.
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Common peroneal nerve palsy following total hip arthroplasty: prognostic factors for recovery.
J Bone Joint Surg Am
PUBLISHED: 05-03-2013
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Common peroneal nerve palsy, although rare, is a serious complication of total hip arthroplasty. Although several publications have dealt with the risk factors for peroneal nerve palsy, there is little literature regarding the time it takes for the nerve to recover and the factors that influence its recovery. The purpose of this study was to elucidate the clinical course of this injury and identify prognostic factors for recovery.
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Associations of T cell activation and inflammatory biomarkers with virological response to darunavir/ritonavir plus raltegravir therapy.
J. Antimicrob. Chemother.
PUBLISHED: 04-18-2013
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One of the goals of antiretroviral therapy (ART) is to attenuate HIV-induced systemic immune activation and inflammation. We determined the dynamics of biomarkers of immune activation, microbial translocation and inflammation during initial ART with a nucleos(t)ide-sparing regimen of darunavir/ritonavir plus raltegravir. We also evaluated associations between these biomarkers and the virological response to the regimen.
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Dynamic rehabilitation of facial nerve injury: a review of the literature.
J Reconstr Microsurg
PUBLISHED: 04-05-2013
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Given the morbidity caused by facial nerve paralysis, there have been consistent approaches to treatment over the past 20 years in reanimation of the facial nerve. Treatment depends on accurate clinical examination, a good understanding of the anatomic course, and appropriate diagnostic tests. There are various options when it comes to dynamic facial nerve reanimation that range from nerve grafting, nerve anastomosis, crossover techniques and muscle transfer to microneurovascular muscle flaps, and-recently-potentially new concepts with microelectromechanical systems (MEMS) technology. The various dynamic facial nerve treatment modalities are discussed.
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Intracolonic Vancomycin for Severe Clostridium difficile Colitis.
Surg Infect (Larchmt)
PUBLISHED: 04-05-2013
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Abstract Background: Clostridium difficile colitis is associated with increased age, antibiotic usage, and hospitalization. Severe C. difficile colitis refractory to medical therapy may require surgical intervention including subtotal colectomy. We initiated an adjuvant intracolonic vancomycin (ICV) enema protocol for inpatients with severe C. difficile colitis and compared the response to this therapy in patients from the community and nursing homes. Methods: A single-hospital, retrospective chart review was done on 47 consecutive patients with C. difficile colitis treated with ICV (1?g/500?mL normal saline q6h) from January 2007 through October 2009. The proportions of patients with the outcomes of response to the ICV protocol, need for subtotal colectomy, and death were described. Associations of patient characteristics with these outcomes were examined with bivariate tests and multivariable logistic models with adjustment for age, hypoalbuminemia, acidosis, and nursing-home status. Results: Thirty-three of 47 patients (70%) with severe C. difficile colitis responded to adjunct ICV with complete resolution without surgery. Incomplete responders who had surgery were more likely to survive than those patients who did not undergo subtotal colectomy (p<0.01). Seven of nine patients who underwent surgery survived >90 d, and overall, 37 of 47 patients (79%) survived after ICV therapy. Nursing-home residence, acidosis, and hypoalbuminemia were significantly associated with the non-resolution of colitis in bivariate analyses (all p<0.01), whereas nursing-home residence and hypoalbuminemia showed non-significant trends toward association with death (p=0.07 and p=0.06, respectively). Multivariate logistic-regression models showed significant associations of acidosis with an incomplete response to ICV (p=0.02), of older age with death (p=0.04), and of hypoalbuminemia with both an incomplete response to ICV and death (both p=0.04). No complications were attributable to ICV. Conclusion: Complete resolution without surgery was achieved in 70% in this series of patients with severe C. difficile colitis who received adjunct ICV therapy. A clinical trial will be needed to determine whether ICV as compared with standard therapy alone can reduce the need for surgery with non-inferior or superior outcomes.
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Aberrant right hepatic artery in pancreaticoduodenectomy for adenocarcinoma: impact on resectability and postoperative outcomes.
HPB (Oxford)
PUBLISHED: 03-26-2013
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OBJECTIVES: An aberrant right hepatic artery (aRHA) may pose technical and oncologic challenges during pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PA) as a result of its proximity to the head of the pancreas. The aim of this study was to assess the impact of an aRHA on resectability, and perioperative and oncologic outcomes after PD for PA. METHODS: An 11-year retrospective cohort study was conducted. A total of 289 patients with PA scheduled for PD with intent for resection were included in the study. RESULTS: Of 289 patients, 249 underwent PD and 40 were found to have unresectable tumours. Incidences of aRHA in the resectable (14.9%) and unresectable (7.5%) groups were similar (P = 0.2); the main reasons for aborting PD were not directly related to the presence of an aRHA. In patients who underwent resection, complications occurred more frequently in the standard PD group (41.5% versus 24.3%; P = 0.04), but there was no difference in rates of positive margin (R1) resection (10.8% versus 16.0%; P = 0.4) or median overall survival (17 months versus 23 months; P = 0.1) between patients with and without an aRHA. CONCLUSIONS: The presence of an aRHA in patients with PA does not affect resectability. In patients with resectable tumours, the presence of an aRHA does not increase morbidity or R1 resection rates and does not impact on overall survival.
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Alignment of new tuberculosis drug regimens and drug susceptibility testing: a framework for action.
Lancet Infect Dis
PUBLISHED: 03-24-2013
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New tuberculosis drug regimens are creating new priorities for drug susceptibility testing (DST) and surveillance. To minimise turnaround time, rapid DST will need to be prioritised, but developers of these assays will need better data about the molecular mechanisms of resistance. Efforts are underway to link mutations with drug resistance and to develop strain collections to enable assessment of new diagnostic assays. In resource-limited settings, DST might not be appropriate for all patients with tuberculosis. Surveillance data and modelling will help country stakeholders to design appropriate DST algorithms and to decide whether to change drug regimens. Finally, development of practical DST assays is needed so that, in countries where surveillance and modelling show that DST is advisable, these assays can be used to guide clinical decisions for individual patients. If combined judiciously during both development and implementation, new tuberculosis regimens and new DST assays have enormous potential to improve patient outcomes and reduce the burden of disease.
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Tuberculosis comorbidity with communicable and non-communicable diseases: integrating health services and control efforts.
Lancet Infect Dis
PUBLISHED: 03-24-2013
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Recent data for the global burden of disease reflect major demographic and lifestyle changes, leading to a rise in non-communicable diseases. Most countries with high levels of tuberculosis face a large comorbidity burden from both non-communicable and communicable diseases. Traditional disease-specific approaches typically fail to recognise common features and potential synergies in integration of care, management, and control of non-communicable and communicable diseases. In resource-limited countries, the need to tackle a broader range of overlapping comorbid diseases is growing. Tuberculosis and HIV/AIDS persist as global emergencies. The lethal interaction between tuberculosis and HIV coinfection in adults, children, and pregnant women in sub-Saharan Africa exemplifies the need for well integrated approaches to disease management and control. Furthermore, links between diabetes mellitus, smoking, alcoholism, chronic lung diseases, cancer, immunosuppressive treatment, malnutrition, and tuberculosis are well recognised. Here, we focus on interactions, synergies, and challenges of integration of tuberculosis care with management strategies for non-communicable and communicable diseases without eroding the functionality of existing national programmes for tuberculosis. The need for sustained and increased funding for these initiatives is greater than ever and requires increased political and funder commitment.
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Drug-resistant tuberculosis: time for visionary political leadership.
Lancet Infect Dis
PUBLISHED: 03-24-2013
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Two decades ago, WHO declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. At that time, most strains of Mycobacterium tuberculosis were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. However, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (MDR) tuberculosis rising. WHO estimates roughly 630?000 cases of MDR tuberculosis worldwide, with great variation in the frequency of MDR tuberculosis between countries. In the past 8 years, extensively drug-resistant (XDR) tuberculosis has emerged, and has been reported in 84 countries, heralding the possibility of virtually untreatable tuberculosis. Increased population movement, the continuing HIV pandemic, and the rise in MDR tuberculosis pose formidable challenges to the global control of tuberculosis. We provide an overview of the global burden of drug-resistant disease; discuss the social, health service, management, and control issues that fuel and sustain the epidemic; and suggest specific recommendations for important next steps. Visionary political leadership is needed to curb the rise of MDR and XDR tuberculosis worldwide, through sustained funding and the implementation of global and regional action plans.
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Tuberculosis biomarkers discovery: developments, needs, and challenges.
Lancet Infect Dis
PUBLISHED: 03-24-2013
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Biomarkers are indispensable to the development of new tuberculosis therapeutics and vaccines. The most robust biomarkers measure factors that are essential to the underlying pathological process of the disease being treated, and thus can capture the full effects of many types of interventions on clinical outcomes in multiple prospective, randomised clinical trials. Many Mycobacterium tuberculosis and human biomarkers have been studied over the past decade. Present research focuses on three areas: biomarkers predicting treatment efficacy and cure of active tuberculosis, the reactivation of latent tuberculosis infection, and the induction of protective immune responses by vaccination. Many older, non-specific markers of inflammation, when considered in isolation, do not have sufficient predictive values for clinical use in tuberculosis. Although no new accurate, tuberculosis-specific biomarkers have yet been discovered, substantial progress has been made in some areas. However, the qualification of biomarkers as a surrogate for a clinical endpoint in tuberculosis is very challenging, and, for biomarkers that are non-culture-based, impossible to pursue without the availability of well characterised biobanks containing biospecimens from patients who have had adequate follow-up to establish long-term treatment outcome. We review progress in tuberculosis biomarker development and efforts being made to harness resources to meet future challenges.
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Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test.
Lancet Infect Dis
PUBLISHED: 03-24-2013
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Rapid progress has been made in the development of new diagnostic assays for tuberculosis in recent years. New technologies have been developed and assessed, and are now being implemented. The Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance, was endorsed by WHO in December, 2010. This assay was specifically recommended for use as the initial diagnostic test for suspected drug-resistant or HIV-associated pulmonary tuberculosis. By June, 2012, two-thirds of countries with a high tuberculosis burden and half of countries with a high multidrug-resistant tuberculosis burden had incorporated the assay into their national tuberculosis programme guidelines. Although the development of the Xpert MTB/RIF assay is undoubtedly a landmark event, clinical and programmatic effects and cost-effectiveness remain to be defined. We review the rapidly growing body of scientific literature and discuss the advantages and challenges of using the Xpert MTB/RIF assay in areas where tuberculosis is endemic. We also review other prospects within the developmental pipeline. A rapid, accurate point-of-care diagnostic test that is affordable and can be readily implemented is urgently needed. Investment in the tuberculosis diagnostics pipeline should remain a major priority for funders and researchers.
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Germline deletion of ?2 microglobulin or CD1d reduces anti-phospholipid antibody, but increases autoantibodies against non-phospholipid antigens in the NZB/W F1 model of lupus.
Arthritis Res. Ther.
PUBLISHED: 03-19-2013
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INTRODUCTION: ?2-microglobulin (?2m) is required for the surface expression of MHC class I and class I-like proteins such as CD1d, Qa1 and neonatal Fc receptor (FcRn), all of which may impact the development of autoimmunity. Since CD1d is known to bind and present phospholipid antigens to T cells, we asked if the deficiency of ?2m or CD1d will impact the development of anti-phospholipid antibodies as compared to other aspects of lupus autoimmunity. METHODS: We introgressed the ?2m-null genotype onto the NZB and NZW backgrounds for 12 to 14 generations to generate genetically lupus-susceptible (NZB/NZW)F1 (BWF1) mice that are ?2m-deficient (?2m°). Circulating immunoglobulins (Ig), rheumatoid factor (RF), anti-DNA and anti-cardiolipin (anti-CL) antibodies, and renal disease were analyzed in these and CD1d-deficient (CD1d°) BWF1 mice that we had previously generated. RESULTS: Whereas ?2m° BWF1 mice had reduced serum IgG, they had increased mortality, nephritis, serum IgG anti-DNA antibody and RF as compared to heterozygous and wild-type littermates. These effects were recapitulated in CD1d° BWF1 mice, except that they also had increased serum IgG as compared to control littermates. Intriguingly, both ?2m° and CD1d° mice had lower serum anti-CL antibody levels than in control littermates. Such CD1d dependence of anti-CL antibody production is not mediated by CD1d/glycolipid-reactive iNKT cells, as these cells reduced the production of RF and anti-DNA antibodies but had no effect on anti-CL antibodies. CONCLUSIONS: We report a novel dichotomous role of ?2m and CD1d, whereby these molecules differently regulate autoimmunity against phospholipid versus non-phospholipid autoantigens.
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Transepithelial phototherapeutic keratectomy combined with implantation of a single inferior intrastromal corneal ring segment and collagen crosslinking in keratoconus.
J Cataract Refract Surg
PUBLISHED: 03-11-2013
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To evaluate the efficacy of phototherapeutic keratectomy (PTK) combined with implantation of a single inferior intrastromal corneal ring segment (ICRS) and riboflavin with ultraviolet-A collagen crosslinking (CXL) performed sequentially on the same day in the management of keratoconus.
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Efficacy of single or paired intrastromal corneal ring segment implantation combined with collagen crosslinking in keratoconus.
J Cataract Refract Surg
PUBLISHED: 03-04-2013
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To evaluate the efficacy of single or paired intrastromal corneal ring segments (ICRS) combined with ultraviolet-A and riboflavin collagen crosslinking (CXL) in patients with keratoconus.
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Smoking-attributable mortality in Bangladesh: proportional mortality study.
Bull. World Health Organ.
PUBLISHED: 02-26-2013
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To directly estimate how much smoking contributes to cause-specific mortality in Bangladesh.
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Protective benefits of deep tube wells against childhood diarrhea in Matlab, Bangladesh.
Am J Public Health
PUBLISHED: 02-14-2013
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We investigated whether deep tube wells installed to provide arsenic-free groundwater in rural Bangladesh have the added benefit of reducing childhood diarrheal disease incidence.
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Minimally invasive resynchronization pacemaker: a pediatric animal model.
Ann. Thorac. Surg.
PUBLISHED: 02-13-2013
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We developed a minimally invasive epicardial pacemaker implantation method for infants and congenital heart disease patients for whom a transvenous approach is contraindicated. The piglet is an ideal model for technical development.
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Corneal endothelial safety following subconjunctival and intrastromal injection of bevacizumab for corneal neovascularization.
Int Ophthalmol
PUBLISHED: 02-12-2013
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The purpose of this study is to determine the effect on endothelial cell density and morphology of combined subconjunctival and intracorneal injection of bevacizumab for the treatment of corneal neovascularization (NV). The charts and specular microscopy images of ten consecutive patients with corneal NV, who received combined subconjunctival+intracorneal injections of bevacizumab were reviewed. Patients received three injections of bevacizumab 25 mg/mL (1.25 mg/0.05 mL subconjunctival and 1.25 mg/0.05 mL intrastromal) 4-6 weeks apart. Endothelial cell counts (ECCs) and morphological changes were assessed by non-contact specular microscopy performed at baseline, 1 month after each injection and at 3 and 6 months after the last injection. There were no significant changes in ECCs (p = 0.663), coefficient of variation (p = 0.076), percentage of hexagonal cells (p = 0.931) or mean corneal thickness (p = 0.462) from pre-injection values to the 6-month follow-up values. There were no intraoperative or postoperative complications. In our series, the use of combined subconjunctival and intracorneal bevacizumab did not cause any decrease in ECCs or morphological alterations up to 6 months after the last of three injections. Further studies are required to confirm long-term safety in a larger sample population with longer follow-up, as well as the ideal dose, route of administration and frequency of bevacizumab administration.
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Efficacy and safety of thoracoscopic thymectomy in the treatment of juvenile myasthenia gravis.
Pediatr. Surg. Int.
PUBLISHED: 02-05-2013
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Thymectomy is a well-established treatment for generalized myasthenia gravis in adults, but predictors of long-term efficacy and the optimum timing for intervention in juvenile myasthenia remain controversial.
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Increased childhood mortality and arsenic in drinking water in Matlab, Bangladesh: a population-based cohort study.
PLoS ONE
PUBLISHED: 01-28-2013
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Arsenic in drinking water was associated with increased risk of all-cause, cancer, and cardiovascular death in adults. However, the extent to which exposure is related to all-cause and deaths from cancer and cardiovascular condition in young age is unknown. Therefore, we prospectively assessed whether long-term and recent arsenic exposures are associated with all-cause and cancer and cardiovascular mortalities in Bangladeshi childhood population.
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Tumor biology and pre-transplant locoregional treatments determine outcomes in patients with T3 hepatocellular carcinoma undergoing liver transplantation.
Clin Transplant
PUBLISHED: 01-28-2013
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Liver transplantation is the optimal treatment for patients with hepatocellular carcinoma (HCC) and cirrhosis. This study was conducted to determine the impact of pre-transplant locoregional therapy (LRT) on HCC and our institutions experience with expansion to United Network of Organ Sharing Region 4 T3 (R4T3) criteria. Two hundred and twenty-five patients with HCC (176 meeting Milan and 49 meeting R4T3 criteria) underwent liver transplantation from 2002 to 2008. Compared with the Milan criteria, HCCs in R4T3 criteria displayed less favorable biological features such as higher median alpha-fetoprotein level (21.9 vs. 8.5 ng/mL, p = 0.01), larger tumor size, larger tumor number, and higher incidence of microvascular invasion (22% vs. 5%, p = 0.002). As a result, patients meeting Milan criteria had better five-yr survival (79% vs. 69%, p = 0.03) and a trend toward lower HCC recurrence rates (5% vs. 13%, p = 0.05). Pre-transplant LRT did not affect post-transplant outcomes in patients meeting Milan criteria but did result in lower three-yr HCC recurrence (7% vs. 75%, p < 0.001) and better three-yr survival (p = 0.02) in patients meeting R4T3 criteria. Tumor biology and pre-transplant LRT are important factors that determine the post-transplant outcomes in patients with HCC who meet R4T3 criteria.
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Models of contrasting strategies of rhinovirus immune manipulation.
J. Theor. Biol.
PUBLISHED: 01-22-2013
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Rhinoviruses, consisting of well over one hundred serotypes that cause a plurality of common colds, are completely cleared by the host immune system after causing minimal cell death, but often without inducing long-term immune memory. We develop mathematical models of two kinds of rhinoviruses, the major group and minor group, that use different receptors to enter target cells. Roughly the 90 serotypes in the major group bind to ICAM-1, a molecule that is upregulated on antigen-presenting cells, and alter the timing, location and type of the immune response. The 12 members of the minor group do not so modulate the response. Our model predicts similar virus dynamics for the major and minor groups but with quite different underlying mechanisms. Over a range of key parameters that quantify immune manipulation, disease outcomes lie within a triangle in the plane describing damage and memory, of which the major and minor group form two corners. This model of infection by a highly adapted and low virulence virus provides a starting point for understanding the development of asthma and other pathologies.
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Static treatment modalities in facial paralysis: a review.
J Reconstr Microsurg
PUBLISHED: 01-09-2013
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Facial nerve dysfunction can be attributed to several different causes. Several techniques have been developed to help treat the appearance and functional limitation of patients with sequelae of facial nerve dysfunction. There are options regarding static techniques of facial nerve injury treatment that range from facial musculature plication or shortening, fascial sling suspension via allograft or autograft, injectables and implants (ENDURAGen, AlloDerm, LifeCell, Bridgewater, New Jersey, USA) to techniques such as brow lift, open and endoscopic facelifts, and various eyelid surgeries with upper and lower lid procedures. In this review the various static facial nerve treatment modalities are discussed.
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Modelling a Wolbachia invasion using a slow-fast dispersal reaction-diffusion approach.
Bull. Math. Biol.
PUBLISHED: 01-08-2013
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This paper uses a reaction-diffusion approach to examine the dynamics in the spread of a Wolbachia infection within a population of mosquitoes in a homogeneous environment. The formulated model builds upon an earlier model by Skalski and Gilliam (Am. Nat. 161(3):441-458, 2003), which incorporates a slow and fast dispersal mode. This generates a faster wavespeed than previous reaction-diffusion approaches, which have been found to produce wavespeeds that are unrealistically slow when compared with direct observations. In addition, the model incorporates cytoplasmic incompatibility between male and female mosquitoes, which creates a strong Allee effect in the dynamics. In previous studies, linearised wavespeeds have been found to be inaccurate when a strong Allee effect is underpinning the dynamics. We provide a means to approximate the wavespeed generated by the model and show that it is in close agreement with numerical simulations. Wavespeeds are approximated for both Aedes aegypti and Drosophila simulans mosquitoes at different temperatures. These wavespeeds indicate that as the temperature decreases within the optimal temperature range for mosquito survival, the speed of a Wolbachia invasion increases for Aedes aegypti populations and decreases for Drosophila simulans populations.
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Elevated manganese concentrations in drinking water may be beneficial for fetal survival.
PLoS ONE
PUBLISHED: 01-01-2013
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Elevated exposure to the essential element manganese (Mn) can be toxic. Manganese concentrations in ground water vary considerably, and reported associations between Mn and early-life mortality and impaired development have raised concern. We assessed the effects of drinking water Mn exposure during pregnancy upon fetal and infant survival.
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PEX16: a multifaceted regulator of peroxisome biogenesis.
Front Physiol
PUBLISHED: 01-01-2013
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the growth and fission of mature peroxisomes and de novo synthesis at the endoplasmic reticulum (ER). While many of the molecular mechanisms underlying these two pathways remain to be elucidated, it is generally accepted that their relative contribution to peroxisome formation may vary depending on the species, cell type and/or physiological status of the organism. One pertinent example of the apparent differences in the regulation of peroxisome biogenesis among evolutionarily diverse species is the involvement of the peroxin PEX16. In Yarrowia lipolytica, for instance, PEX16 is an intraperoxisomal peripheral membrane protein that participates in peroxisomal fission. By contrast, Human PEX16 is an integral membrane protein that is thought to function at the ER during the early stages of de novo peroxisome formation and also recruits peroxisomal membrane proteins directly to mature peroxisomes. Similarly, PEX16 in the plant Arabidopsis thaliana is speculated to be a PMP receptor at the ER and peroxisomes, and is also required for the formation of other ER-derived organelles, such as oil and protein bodies. Here we briefly review the current knowledge of Y. lipolytica, human and A. thaliana PEX16 in the context of our overall understanding of peroxisome biogenesis and the role of the ER in this process in these three divergent species.
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Second-chance forward isomerization dynamics of the red/green cyanobacteriochrome NpR6012g4 from Nostoc punctiforme.
J. Am. Chem. Soc.
PUBLISHED: 12-15-2011
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The primary ultrafast Z-to-E isomerization photodynamics of the phytochrome-related cyanobacteriochrome NpR6012g4 from Nostoc punctiforme was studied by transient absorption pump-dump-probe spectroscopy. A 2 ps dump pulse resonant with the stimulated emission band depleted 21% of the excited-state population, while the initial photoproduct Lumi-R was depleted by only 11%. We observed a red-shifted ground-state intermediate (GSI) that we assign to a metastable state that failed to isomerize fully. Multicomponent global analysis implicates the generation of additional Lumi-R from the GSI via crossing over the ground-state thermal barrier for full isomerization, explaining the discrepancy between excited-state and Lumi-R depletion by the dump pulse. This second-chance ground-state dynamics provides a plausible explanation for the unusually high quantum yield of 40% for the primary isomerization step in the forward reaction of NpR6012g4.
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A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome: description of two unrelated cases from Brazil.
Arthritis Rheum.
PUBLISHED: 12-01-2011
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Monogenic autoinflammatory diseases are disorders of Mendelian inheritance that are characterized by mutations in genes that regulate innate immunity and whose typical features are systemic inflammation without high-titer autoantibodies or antigen-specific T cells. Skin and bone inflammation in the newborn period have been described in 3 of these autoinflammatory disorders: neonatal-onset multisystem inflammatory disease, Majeed syndrome, and deficiency of interleukin-1 (IL-1) receptor antagonist (DIRA) syndrome. This study was undertaken to present the characteristics of the DIRA syndrome in 2 cases from Brazil, and describe a novel mutation in IL1RN.
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