Consensus of Heterogeneous Linear Multiagent Systems With Communication Time-Delays.
This paper studies the consensus problem of heterogeneous linear multiagent systems with arbitrarily large constant, time-varying, or distributed communication delays. Novel distributed dynamic controllers are proposed for such multiagent systems with fixed and switching directed communication topologies, respectively. It is shown that the controlled heterogeneous linear multiagent system can reach consensus for arbitrarily large constant, time-varying, and distributed communication delays under some sufficient conditions. Simulation examples are provided to demonstrate the effectiveness of the proposed controllers.


Developing an aging prepared community: collaboration among counties, consumers, professionals and organizations.
This paper reports on a collaborative process to create an "aging prepared community" in a four county region. The process benefited from a generous grant from the John A. Hartford Foundation that supported an 18 month planning period which included input from service providers and a vast array of aging persons and their families, including particular efforts to reach underserved populations from multicultural, inner- city and rural communities. Under the umbrella of the Elder Network of the Capital Region, the process is now beginning its implementation period with foci on the following: linking health, social service and faith communities; developing accessible health education and wellness programs; creating and implementing a regional system of information and assistance; and mounting a media campaign.


Current Perspectives in Cardiac Laterality.
The heart is the first organ to break symmetry in the developing embryo and onset of dextral looping is the first indication of this event. Looping is a complex process that progresses concomitantly to cardiac chamber differentiation and ultimately leads to the alignment of the cardiac regions in their final topology. Generation of cardiac asymmetry is crucial to ensuring proper form and consequent functionality of the heart, and therefore it is a highly regulated process. It has long been known that molecular left/right signals originate far before morphological asymmetry and therefore can direct it. The use of several animal models has led to the characterization of a complex regulatory network, which invariably converges on the Tgf-β signaling molecule Nodal and its downstream target, the homeobox transcription factor Pitx2. Here, we review current data on the cellular and molecular bases of cardiac looping and laterality, and discuss the contribution of Nodal and Pitx2 to these processes. A special emphasis will be given to the morphogenetic role of Pitx2 and to its modulation of transcriptional and functional properties, which have also linked laterality to atrial fibrillation.


Integrin-targeted nano-sized polymeric systems for paclitaxel conjugation: a comparative study.
The generation of rationally designed polymer therapeutics via the conjugation of low molecular weight anti-cancer drugs to water-soluble polymeric nanocarriers aims to improve the therapeutic index. Here, we focus on applying polymer therapeutics to target two cell compartments simultaneously - tumour cells and angiogenic endothelial cells. Comparing different polymeric backbones carrying the same therapeutic agent and targeting moiety may shed light on any correlation between the choice of polymer and the anti-cancer activity of the conjugate. Here, we compared three paclitaxel (PTX)-bound conjugates with poly-l-glutamic acid (PGA, 4.9 mol%), 2-hydroxypropylmethacrylamide (HPMA, 1.2 mol%) copolymer, or polyethyleneglycol (PEG, 1:1 conjugate). PGA and HPMA copolymers are multivalent polymers that allow the conjugation of multiple compounds within the same polymer backbone, while PEG is a bivalent commercially available Food and Drug Administration (FDA)-approved polymer. We further conjugated PGA-PTX and PEG-PTX with the integrin αvβ3-targeting moiety RGD (5.5 mol% and 1:1 conjugate, respectively). We based our selection on the overexpression of integrin αvβ3 on angiogenic endothelial cells and several types of cancer cells. Our findings suggest that the polymer structure has major effect on the conjugate's activity on different tumour compartments. A multivalent PGA-PTX-E-[c(RGDfK)2] conjugate displayed a stronger inhibitory effect on the endothelial compartment, showing a 50% inhibition of the migration of human umbilical vein endothelial cell cells, while a PTX-PEG-E-[c(RGDfK)2] conjugate possessed enhanced anti-cancer activity on MDA-MB-231 tumour cells (IC50 = 20 nM versus IC50 300 nM for the PGA conjugate).


Methods of defining the non-inferiority margin in randomized, double-blind controlled trials: a systematic review.
There is no consensus on the preferred method for defining the non-inferiority margin in non-inferiority trials, and previous studies showed that the rationale for its choice is often not reported. This study investigated how the non-inferiority margin is defined in the published literature, and whether its reporting has changed over time. A systematic PubMed search was conducted for all published randomized, double-blind, non-inferiority trials from January 1, 1966, to February 6, 2015. The primary outcome was the number of margins that were defined by methods other than the historical evidence of the active comparator. This was evaluated for a time trend. We also assessed the under-reporting of the methods of defining the margin as a secondary outcome, and whether this changed over time. Both outcomes were analyzed using a Poisson log-linear model. Predictors for better reporting of the methods, and the use of the fixed-margin method (one of the historical evidence methods) were also analyzed using logistic regression. Two hundred seventy-three articles were included, which account for 273 non-inferiority margins. There was no statistically significant difference in the number of margins that were defined by other methods compared to those defined based on the historical evidence (ratio 2.17, 95% CI 0.86 to 5.82, p = 0.11), and this did not change over time. The number of margins for which methods were unreported was similar to those with reported methods (ratio 1.35, 95% CI 0.76 to 2.43, p = 0.31), with no change over time. The method of defining the margin was less often reported in journals with low-impact factors compared to journals with high-impact factors (OR 0.20; 95% CI 0.10 to 0.37, p < 0.0001). The publication of the FDA draft guidance in 2010 was associated with increased reporting of the fixed-margin method (after versus before 2010) (OR 3.54; 95% CI 1.12 to 13.35, p = 0.04). Non-inferiority margins are not commonly defined based on the historical evidence of the active comparator, and they are poorly reported. Authors, reviewers, and editors need to take notice of reporting this critical information to allow for better judgment of non-inferiority trials.


Are psychoactive-drug-induced changes in plasma lipid and lipoprotein levels of significance for clinical remission in psychiatric disorders?
In the present pilot study, our aim was to investigate whether associations could be demonstrated in psychiatric patients between the changes in plasma lipid and lipoprotein levels expected during treatment with psychoactive drugs and the changes in the patients' depressive and hostile behavior. One hundred and fourteen patients with various psychiatric disorders (depressive episode in bipolar affective disorder, depressive episode or recurrent depressive disorder, paranoid schizophrenia, and schizoaffective disorders) were included in the study. The following examinations were carried out in each patient on admission and at discharge: (1) the plasma lipid parameters total cholesterol (TC), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), high-density lipoprotein (HDL), and triglycerides (TRI) were determined, and (2) the psychopathological features were recorded employing the AMDP system and the AMDP Syndrome Scales. Within the context of a naturalistic clinical setting with a choice of psychoactive drugs available, patients were subdivided at the end of treatment into eight treatment groups, as follows: group 1, treatment with butyrophenones; group 2, treatment with tricyclics; group 3, treatment with butyrophenones and tricyclics; group 4, treatment with butyrophenones, tricyclics and selective serotonin reuptake inhibitors; group 5, treatment with butyrophenones and lithium; group 6, treatment with tricyclics and lithium; group 7, treatment with butyrophenones, tricyclics and lithium; and group 8, treatment with butyrophenones, tricyclics, selective serotonin reuptake inhibitors and lithium. To compare the changes in the eight treatment groups, mixed general linear models including diagnosis, gender, age, body mass index changes, and baseline values were applied using proc GLM of SAS. Butyrophenones induce an increase in TC, LDL, and TC/TRI ratio, whereas tricyclics lead to an increase in TC, LDL, VLDL, and TRI. In combined medication of butyrophenones and tricyclics the effects of tricyclics predominate. Comedication of lithium inhibits the increase in TC and LDL induced by butyrophenones and/or tricyclics. Treatment groups with lipid changes of the same type (decrease, no change, or increase) were combined in "lipid change groups". Analyses of variance or covariance (with psychopathological admission value as covariate where there were significant differences in psychopathological admission mean values between the groups) of these lipid change groups with regard to the changes in the Depressive Syndrome Scale and the Hostility Syndrome Scale gave results which are interpreted as follows: an increase in TC or LDL inhibits the remission of hostility, whereas an increase in TRI with concomitant decrease in TC, or else a relatively greater increase in TRI than in TC promotes the remission of hostility. A decrease in TRI or VLDL promotes the remission of depression. Our data and findings published in the literature may suggest that systemic changes in plasma lipid parameters, at the cellular level, induce changes in the fluidity of brain cell membranes. We hypothesize that an increase in plasma TC or LDL and/or a decrease in plasma TRI or VLDL may induce a relative decrease in brain cell membrane fluidity with decreased presynaptic serotonin reuptake and increased postsynaptic serotonin function. This proposed increase in brain serotonin function would finally result in an anti-depressive, aggression-promoting effect. Conversely, a decrease in plasma TC or LDL and/or an increase in plasma TRI or VLDL may induce a relative increase in brain cell membrane fluidity with increased presynaptic serotonin reuptake and decreased postsynaptic serotonin function. This proposed decrease in brain serotonin function would result in an anti-aggressive, depression-promoting effect.


Person Re-ID by Fusion of Video Silhouettes and Wearable Signals for Home Monitoring Applications.
The use of visual sensors for monitoring people in their living environments is critical in processing more accurate health measurements, but their use is undermined by the issue of privacy. Silhouettes, generated from RGB video, can help towards alleviating the issue of privacy to some considerable degree. However, the use of silhouettes would make it rather complex to discriminate between different subjects, preventing a subject-tailored analysis of the data within a free-living, multi-occupancy home. This limitation can be overcome with a strategic fusion of sensors that involves wearable accelerometer devices, which can be used in conjunction with the silhouette video data, to match video clips to a specific patient being monitored. The proposed method simultaneously solves the problem of Person ReID using silhouettes and enables home monitoring systems to employ sensor fusion techniques for data analysis. We develop a multimodal deep-learning detection framework that maps short video clips and accelerations into a latent space where the Euclidean distance can be measured to match video and acceleration streams. We train our method on the SPHERE Calorie Dataset, for which we show an average area under the ROC curve of 76.3% and an assignment accuracy of 77.4%. In addition, we propose a novel triplet loss for which we demonstrate improving performances and convergence speed.


Facile synthesis of pure monoclinic and tetragonal zirconia nanoparticles and their phase effects on the behavior of supported molybdena catalysts for methanol-selective oxidation.
Pure monoclinic (m) and tetragonal (t) zirconia nanoparticles were readily synthesized from the reaction of inorganic zirconium salts (e.g., hydrated zirconyl nitrate) and urea in water and methanol, respectively, via a facile solvothermal method. The role of the solvents was crucial in the formation of the pure ZrO(2) phases, whereas their purity was essentially insensitive to other variables, including reaction temperature, reactant concentration, pH, and zirconium salts. Water as the solvent led to the transformation of hydrous ZrO(2) precipitates initially formed with tetragonal structures to thermodynamically more stable m-ZrO(2) via the dissolution-precipitation process, whereas methanol favored the removal of water molecules from the precursors via their reaction with urea, consequently maintaining the tetragonal structures. The obtained tetragonal samples were found to possess superior hydrothermal stability compared to those reported previously, which provides the possibility for systematically studying the effects of ZrO(2) phases on many catalytic reactions involving water as a reactant or product. Using these pure m- and t-ZrO(2) phases as supports, dispersed MoO(x) catalysts were synthesized at MoO(x) surface densities of approximately 5.0 Mo/nm(2), which is close to one monolayer of coverage. Characterization by X-ray diffraction and Raman spectroscopy confirmed that the pure ZrO(2) phases remained unchanged in the presence of the MoO(x) domains and the MoO(x) domains existed preferentially as 2D polymolybdate structures. The catalysts were subsequently examined for selective methanol oxidation as a test reaction. m-ZrO(2) support led to 2-fold greater oxidation rates than for t-ZrO(2) support, reflecting the higher intrinsic reactivity of the MoO(x) domains on m-ZrO(2). This is consistent with their higher reducibility probed by temperature-programmed reduction with H(2) (H(2) TPR). These observed effects of the ZrO(2) phases provide the basis for designing catalysts with tunable redox properties and reactivity.


Magnetic Resonance-Guided High-Intensity-Focused Ultrasound for Palliation of Painful Skeletal Metastases: A Pilot Study.
Bone is one of the most common sites of metastases, with bone metastases-related pain representing a significant source of morbidity among patients with cancer. Magnetic resonance-guided focused ultrasound is a noninvasive, outpatient modality with the potential for treating painful bone metastases. The aim of this study is to report our initial experience with magnetic resonance-guided focused ultrasound in the treatment of bone metastases and our preliminary analysis of urinary cytokine levels after therapy. This was a single-center pilot study of 10 patients with metastatic cancer to investigate the feasibility of magnetic resonance-guided focused ultrasound for primary pain control in device-accessible skeletal metastases. Treatments were performed on a clinical magnetic resonance-guided focused ultrasound system using a volumetric ablation technique. Primary efficacy was assessed using Brief Pain Inventory scores and morphine equivalent daily dose intake at 3 time points: before, day 14, and day 30 after the magnetic resonance-guided focused ultrasound treatment. Urine cytokines were measured 3 days before treatment and 2 days after the treatment. Of the 10 patients, 8 were followed up 14 days and 6 were followed up 30 days after the treatment. At day 14, 3 patients (37.5%) exhibited partial pain response and 4 patients (50%) exhibited an indeterminate response, and at day 30 after the treatment, 5 patients (83%) exhibited partial pain response. No treatment-related adverse events were recorded. Of the urine cytokines measured, only Transforming growth factor alpha (TGFα) demonstrated an overall decrease, with a trend toward statistical significance ( P = .078). Our study corroborates magnetic resonance-guided focused ultrasound as a feasible and safe modality as a primary, palliative treatment for painful bone metastases and contributes to the limited body of literature using magnetic resonance-guided focused ultrasound for this clinical indication.


Paritaprevir and Ritonavir Liver Concentrations in Rats as Assessed by Different Liver Sampling Techniques.
The liver is crucial to pharmacology, yet substantial knowledge gaps exist in the understanding of its basic pharmacologic processes. An improved understanding for humans requires reliable and reproducible liver sampling methods. We compared liver concentrations of paritaprevir and ritonavir in rats by using samples collected by fine-needle aspiration (FNA), core needle biopsy (CNB), and surgical resection. Thirteen Sprague-Dawley rats were evaluated, nine of which received paritaprevir/ritonavir at 30/20 mg/kg of body weight by oral gavage daily for 4 or 5 days. Drug concentrations were measured using liquid chromatography-tandem mass spectrometry on samples collected via FNA (21G needle) with 1, 3, or 5 passes (FNA1, FNA3, and FNA5); via CNB (16G needle); and via surgical resection. Drug concentrations in plasma were also assessed. Analyses included noncompartmental pharmacokinetic analysis and use of Bland-Altman techniques. All liver tissue samples had higher paritaprevir and ritonavir concentrations than those in plasma. Resected samples, considered the benchmark measure, resulted in estimations of the highest values for the pharmacokinetic parameters of exposure (maximum concentration of drug in serum [Cmax] and area under the concentration-time curve from 0 to 24 h [AUC0-24]) for paritaprevir and ritonavir. Bland-Altman analyses showed that the best agreement occurred between tissue resection and CNB, with 15% bias, followed by FNA3 and FNA5, with 18% bias, and FNA1 and FNA3, with a 22% bias for paritaprevir. Paritaprevir and ritonavir are highly concentrated in rat liver. Further research is needed to validate FNA sampling for humans, with the possible derivation and application of correction factors for drug concentration measurements.


Gene Therapies for Neovascular Age-Related Macular Degeneration.
Pathological neovascularization is a key component of the neovascular form (also known as the wet form) of age-related macular degeneration (AMD) and proliferative diabetic retinopathy. Several preclinical studies have shown that antiangiogenesis strategies are effective for treating neovascular AMD in animal models. Vascular endothelial growth factor (VEGF) is one of the main inducers of ocular neovascularization, and several clinical trials have shown the benefits of neutralizing VEGF in patients with neovascular AMD or diabetic macular edema. In this review, we summarize several preclinical and early-stage clinical trials with intraocular gene therapies, which have the potential to reduce or eliminate the repeated intravitreal injections that are currently required for the treatment of neovascular AMD.


An association of Alternaria alternata and Scopulariopsis brevicaulis in cutaneous phaeohyphomycosis.
Rare molds are increasingly emerging as a cause of deep and invasive fungal infections. We report here a rare case of cutaneous phaeohyphomycosis of the lower limbs due to Alternaria alternata associated with extra-ungual localization of Scopulariopsis brevicaulis. Diagnosis was made based on repeated, direct, microscopic mycological and histological examinations. The study revealed hyphae and fungal cells in a granulomatous dermal infiltrate. Identification of the molds was based on macroscopic appearance on culture of samples from the lesions on Sabouraud's dextrose agar and microscopic appearance on Lactophenol cotton blue following slide culture.


Colorimetric sensors: temperature-activated reverse sensing behavior of pd nanowire hydrogen sensors (small 2/2013).
The image shows an artistic version of a Pd nanowire surrounded by hydrogen molecules. The nanowire is electrically connected to the Pt electrodes of a sensor device by L. F. Fonseca and co-workers to study the effects of reduced temperature on its electrical response during hydrogen gas exposure. The TEM image shows the ordered crystal structure of the material. As described on page 188, when temperature is reduced, a crossover from a bulk- to a percolationcontrolled response is observed. This effect was confirmed in nanowires arrays on interdigitated electrodes and single nanowires integrated to MEMS devices.


Effects of carbon dioxide inhalation on hematology, coagulation, and serum clinical chemistry values in rats.
Blood samples from adult male and female Charles River Crl:CD (SD) BR rats were collected at weekly intervals for 4 wk to evaluate the effects of inhalation of an anesthetic dose of carbon dioxide (CO2) or of a carbon dioxide-oxygen mixture (CO2/O2) on hematology, coagulation, and serum biochemistry values. During the first 3 wk of the study, rats were assigned to 1 of 3 groups and were bled from the orbital sinus once weekly. Prior to the blood collection, rats in group 1 were exposed to room air only, rats in group 2 received CO2/O2 (approximately 66%:34% CO2:O2) by inhalation, and rats in group 3 received 100% CO2 by inhalation. In the rats exposed to CO2/O2 or CO2, leukocyte counts, lymphocyte counts, and glucose values were higher, and aspartate aminotransferase, creatine kinase, and calcium values were lower compared with those of rats exposed to room air only. Rats exposed to 100% CO2 had slightly (but statistically significant) lower mean corpuscular hemoglobin concentration when compared with rats exposed only to room air. During week 4, all rats were reassigned to 1 of 2 groups and were bled terminally via closed cardiac puncture following exposure to either CO2/O2 or CO2. Increased lymphocyte counts (males only) and glucose and chloride concentrations were noted for rats exposed to CO2/O2 compared with those exposed to CO2. These alterations reiterate the importance of comparing clinical pathology values to those of concurrent control groups that have experienced blood collection under identical conditions in order to avoid potential errors in the interpretation of data.


Hymenobacter rubripertinctus sp. nov., isolated from Antarctic tundra soil.
A red-pigmented, Gram-reaction-negative, aerobic, non-motile and rod-shaped bacterium, designated NY03-3-30T, was isolated from a soil sample collected from Inexpressible Island, Northern Victoria Land of the Antarctic Ross Orogen, and subjected to a polyphasic taxonomic study. Growth occurred at 4-28 °C (optimum 20 °C) and at pH 6.0-9.0 (optimum pH 7.0). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain NY03-3-30T belonged to the genus Hymenobacter in the family Cytophagaceae. 16S rRNA gene sequence similarities between strain NY03-3-30T and the type strains of Hymenobacter species with validly published names ranged from 92.7 to 96.2 %. Strain NY03-3-30T contained summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c), iso-C15 : 0, C16 : 0, C16 : 1ω5c, anteiso-C15 : 0 and summed feature 4 (iso-C17 : 1-I and/or anteiso-C17 : 1-B) as major cellular fatty acids, MK-7 as the respiratory quinone and phosphatidylethanolamine as the main polar lipid. The DNA G+C content of strain NY03-3-30T was 59.4 mol%. On the basis of phylogenetic, physiological and chemotaxonomic data, strain NY03-3-30T is considered to represent a novel species of genus Hymenobacter, for which the name Hymenobacter rubripertinctus sp. nov. is proposed. The type strain is NY03-3-30T (=CCTCC AB 2017095T=KCTC 62163T).


[Disseminated intravascular coagulation. II. Therapeutic problems].
The treatment of DIC often presents problems that are not easily solved given the difficulty of interpreting symptoms and haematological findings, the seriousness of the clinical situation and the rapid development of disease phenomena. Diagnostic questions must be answered before physiopathologically rational therapy can be applied. The identification and cure of the condition which triggers coagulation are also of primary importance in selecting a therapeutic response. Apart from specific treatment of the causal disease, the treatment of DIC is based on the one hand on the use of anticoagulants (heparin) to halt intravascular coagulation and transfusional integration with haemoderivatives and platelet concentrates to correct the haemostasis deficiency secondary to such massive consumption. On the other, direct methods are needed to control the state of shock, cardiorespiratory compromise and acute renal insufficiency which often complicate the course of the defibrination syndrome. Therapeutic success depends on timely intervention allied to the employment of adequate measures for each individual case.


Principle of structural equation modeling for exploring functional interactivity within a putative network of interconnected brain areas.
Functional neuroimaging first allowed researchers to describe the functional segregation of regionally activated areas during a variety of experimental tasks. More recently, functional integration studies have described how these functionally specialized areas, interact within a highly distributed neural network. When applied to the field of neurosciences, structural equation modeling (SEM) uses theoretical and/or empirical hypotheses to estimate the effects of an experimental task within a putative network. SEM represents a linear technique for multivariate analysis of neuroimaging data and has been developed to simultaneously examine ratios of multiple causality in an experimental design; the method attempts to explain a covariance structure within an anatomical constrained model. This method, when combined with the concept of effective connectivity, can provide information on the strength and direction of the functional interactions that take place between identified brain regions of a putative network.


Photoelectrochemical water splitting using dense and aligned TiO2 nanorod arrays.
Dense and aligned TiO2 nanorod arrays are fabricated using oblique-angle deposition on indium tin oxide (ITO) conducting substrates. The TiO2 nanorods are measured to be 800-1100 nm in length and 45-400 nm in width with an anatase crystal phase. Coverage of the ITO is extremely high with 25 x 10(6) mm(-2) of the TiO2 nanorods. The first use of these dense TiO2 nanorod arrays as working electrodes in photoelectrochemical (PEC) cells used for the generation of hydrogen by water splitting is demonstrated. A number of experimental techniques including UV/Vis absorption spectroscopy, X-ray diffraction, high-resolution scanning electron microscopy, energy-dispersive X-ray spectroscopy, and photoelectrochemistry are used to characterize their structural, optical, and electronic properties. Both UV/Vis and incident-photon-to-current-efficiency measurements show their photoresponse in the visible is limited but with a marked increase around approximately 400 nm. Mott-Schottky measurements give a flat-band potential (V(FB)) of +0.20 V, a carrier density of 4.5 x 10(17) cm(-3), and a space-charge layer of 99 nm. Overall water splitting is observed with an applied overpotential at 1.0 V (versus Ag/AgCl) with a photo-to-hydrogen efficiency of 0.1%. The results suggest that these dense and aligned one-dimensional TiO2 nanostructures are promising for hydrogen generation from water splitting based on PEC cells.


A 3D Lithiophilic Host for Dendrite-Free Lithium Metal Anode via One-Step Carbonization of an Energetic Metal-Organic Framework.
Low Coulombic efficiency (CE) and safety issues are huge problems that hinder the practical application of Li metal anodes. Constructing Li host structures decorated with functional species can restrain the growth of Li dendrites and alleviate the great volume change. Here, a 3D porous carbonaceous skeleton modified with rich lithiophilic groups (Zn, ZnO, and Zn(CN)2 ) is synthesized as a Li host via one-step carbonization of a triazole-containing metal-organic framework. The nano lithiophilic groups serve as preferred sites for Li nucleation and growth, regulating a uniform Li+ flux and uniform current density distribution. In addition, the 3D porous network functions as a Li reservoir that provides rich internal space to store Li, thus alleviating the volumetric expansion during Li plating/stripping process. Thanks to these component and structural merits, an ultra-low overpotential for Li deposition is achieved, together with high CE of over 99.5% for more than 500 cycles at 1 mA cm-2 and 1 mAh cm-2 in half cells. The symmetric cells exhibit a prolonged cycling of 900 h at 1 mA cm-2 . The full cells by coupling Zn/ZnO/Zn(CN)2 @C-Li anode with LiFePO4 cathode deliver a high capacity retention of 94.3% after 200 cycles at 1 C.


Sengers Syndrome-Associated Mitochondrial Acylglycerol Kinase Is a Subunit of the Human TIM22 Protein Import Complex.
Acylglycerol kinase (AGK) is a mitochondrial lipid kinase that catalyzes the phosphorylation of monoacylglycerol and diacylglycerol to lysophosphatidic acid and phosphatidic acid, respectively. Mutations in AGK cause Sengers syndrome, which is characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Here we identified AGK as a subunit of the mitochondrial TIM22 protein import complex. We show that AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins. Mitochondria isolated from Sengers syndrome patient cells and tissues show a destabilized TIM22 complex and defects in the biogenesis of carrier substrates. Consistent with this phenotype, we observe perturbations in the tricarboxylic acid (TCA) cycle in cells lacking AGK. Our identification of AGK as a bona fide subunit of TIM22 provides an exciting and unexpected link between mitochondrial protein import and Sengers syndrome.


Cost-effectiveness analysis of endoscopic eradication therapy for treatment of high-grade dysplasia in Barrett's esophagus.
The aim was to evaluate the cost-effectiveness of endoscopic eradication therapy (EET) with combined endoscopic mucosal resection and radiofrequency ablation for the treatment of high-grade dysplasia (HGD) arising in patients with Barrett's esophagus compared with endoscopic surveillance alone in the UK. The cost-effectiveness model consisted of a decision tree and modified Markov model. A lifetime time horizon was adopted with the perspective of the UK healthcare system. The base case analysis estimates that EET for the treatment of HGD is cost-effective at a GB£20,000 cost-effectiveness threshold compared with providing surveillance alone for HGD patients (incremental cost-effectiveness ratio: GB£1272). EET is likely to be a cost-effective treatment strategy compared with surveillance alone in patients with HGD arising in Barrett's esophagus in the UK.


Comparison of two different fixed doses of follitropin-beta in controlled ovarian hyperstimulation: A prospective randomized, double blind clinical trial.
A prospective randomized, double blind, single centre study was conducted to compare the efficacy, efficiency and clinical side effects of daily fixed dose regimen of either 100 IU or 200 IU of recombinant follicle stimulating hormone(rFSH) Follitropin beta in down-regulated women undergoing controlled ovarian hyperstimulation(COH) for either conventional in vitro fertilization(IVF) or intracytoplasmic sperm injection(ICSI). A total of sixty women were randomly allocated according to the criteria for the treatment by either 100 IU(n = 30) or 200 IU (n = 30) of FSH. Although more cycle cancellations due to low response were observed in the 100 IU group (n = 9 vs n = 2), two cases of mild and moderate ovarian hyperstimulation syndrome were noted in the higher dose group. Subjects in the group treated with 200 IU appeared to yield more follicles > 17 mm (4.4 vs 3.3, p = 0.05) and more oocytes compared to the group treated with 100 IU (9.2 versus 6.0 oocytes, NS). The total dosage required to develop at least three follicles according to the protocol was significantly lower in the group treated with 100 IU (1203.33 versus 2106. 67, P < 0.0001). In conclusion, a fixed daily dose of 200 IU of rFSH Follitropin beta compared to a fixed daily dose of 100 IU is more effective in terms of follicles > 17 mm development and the number of oocytes retrieved along with a lower cancellation rate, but less efficient as indicated by a higher total rFSH dose needed


Microbial Metabolic Potential of Phenol Degradation in Wastewater Treatment Plant of Crude Oil Refinery: Analysis of Metagenomes and Characterization of Isolates.
The drilling, processing and transportation of oil are the main sources of pollution in water and soil. The current work analyzes the microbial diversity and aromatic compounds degradation potential in the metagenomes of communities in the wastewater treatment plant (WWTP) of a crude oil refinery. By focusing on the degradation of phenol, we observed the involvement of diverse indigenous microbial communities at different steps of the WWTP. The anaerobic bacterial and archaeal genera were replaced by aerobic and facultative anaerobic bacteria through the biological treatment processes. The phyla Proteobacteria, Bacteroidetes and Planctomycetes were dominating at different stages of the treatment. Most of the established protein sequences of the phenol degradation key enzymes belonged to bacteria from the class Alphaproteobacteria. From 35 isolated strains, 14 were able to grow on aromatic compounds, whereas several phenolic compound-degrading strains also degraded aliphatic hydrocarbons. Two strains, Acinetobacter venetianus ICP1 and Pseudomonas oleovorans ICTN13, were able to degrade various aromatic and aliphatic pollutants and were further characterized by whole genome sequencing and cultivation experiments in the presence of phenol to ascertain their metabolic capacity in phenol degradation. When grown alone, the intermediates of catechol degradation, the meta or ortho pathways, accumulated into the growth environment of these strains. In the mixed cultures of the strains ICP1 and ICTN13, phenol was degraded via cooperation, in which the strain ICP1 was responsible for the adherence of cells and ICTN13 diminished the accumulation of toxic intermediates.


Complete Genome Sequences of Three Xanthomonas citri Strains from Texas.
The complete genome sequences of three Xanthomonas citri strains isolated from lime trees in Texas were found to belong to the Aw group. All carried nearly identical large plasmids with similarity to those of a citrus canker strain from India and to xanthomonads from Africa and Colombia. All three strains harbored unusual pthA homologs.


Plasmid incompatibility and control of replication: copy mutants of the R-factor R1 in Escherichia coli K-12.
Plasmid incompatibility was studied in Escherichia coli K-12. By double-antibiotic selection, clones were constructed that carried the two R-factors R1 and R100, both belonging to the compatibility group FII. After release of the selection pressure, each of the two plasmids was lost at the same rate (8% per generation). Mutants of R-factor R1 showing an increased number of copies per chromosome (copy mutants) were tested for their incompatibility towards R-factor R100. The results indicate that plasmid incompatibility is quantitative and not just a qualitative property. All copy mutants studied affected incompatibility, and there were two classes of mutants: one increasing and one decreasing the incompatiblity exerted towards the test plasmid R100. Evidence is presented that incompatibility is related to the mechanisms that control replication. The implications of such a relation on proposed models for control of replication are discussed. The data do not support the hypothesis that plasmid incompatibility is due to competition for a replicational or segregational site.


Synthesis, characterization, and debromination reactivity of cellulose-stabilized Pd/Fe nanoparticles for 2,2',4,4'-tretrabromodiphenyl ether.
In this study, two kinds of cellulose derivatives (polyanionic cellulose (PAC) and hydroxypropylmethyl cellulose (HPMC)) were selected as stabilizers of Pd/Fe nanoparticles (NPs) to investigate their influences on the debromination performances of 2,2',4,4'-tretrabromodiphenyl ether (BDE47). Field emission scanning electron microscope (FE-SEM) images revealed that the cellulose-stabilized Pd/Fe NPs were smaller and more uniform than the bare-Pd/Fe NPs. X-ray diffractometer (XRD) and X-ray photoelectron spectroscopy (XPS) results suggested that cellulose coatings found on Pd/Fe NPs surfaces featured some antioxidation abilities, which followed the order of HPMC < PAC. Sedimentation tests demonstrated that the stabilizing power of PAC for Pd/Fe NPs was higher than that of HPMC. Fourier transfer infrared spectrometer (FTIR) results indicated that PAC molecules were bound to the Pd/Fe NPs surfaces by polar covalent bonds and hydrogen bonds, while HPMC molecules interacted with the nanoparticles by hydrogen bonds. Batch debromination test for BDE47 demonstrated that the catalytic debromination rate with cellulose-stabilized Pd/Fe NPs was higher than that with bare-Pd/Fe NPs during reaction period of 15 min. Overall, this study indicated that both celluloses are beneficial to forming smaller, more regular, stable and antioxidative Pd/Fe NPs, leading to higher debromination reactivity for BDE47 compared with the bare-Pd/Fe NPs. Therefore Pd/Fe NPs can be utilized as a promising remediation technology for the contaminated groundwater and soils.


[Trace elements and sperm quality: An update].
With changes in the modes of life and work, infertility is becoming a serious international problem. The incidence of infertility is 10-15% of the couples of childbearing age in China and is increasing year by year, and 30-50% of the cases are related to male factors. Trace elements refer to the chemical elements that account for less than 1/10,000 of the total weight of the human body, of which less than 100 mg is required per person per day. They are important biochemical components in the semen. Trace elements are essential for normal spermatogenesis, sperm maturation and capacitation, and maintenance of normal sperm function, though sperm quality can be affected by genetic, epigenetic, environmental and lifestyle-related factors. This focuses on the latest progress in the studies of the effects of trace elements on sperm quality.


Comparison of Essential Oils Obtained from Different Extraction Techniques as an Aid in Identifying Aroma Significant Compounds of Nutmeg (Myristica fragrans).
Distribution of volatile constituents in the essential oil of nutmeg obtained by simultaneous distillation extraction (SDE), high vacuum distillation (HVD) and super critical fluid extraction (SFE) was compared with reduced pressure distillation (RPD) and head space (HS) analysis. HS and RPD volatiles were characterized by a high content of sabinene, followed by α-pinene and β-pinene. Interestingly, unlike the SDE, HVD and SFE oils, distillates from HS and RPD were marked by the absence of phenolic ethers namely myristicin, elemicin and safrole. The HS and RPD volatiles possessed a pleasant nutmeg aroma indicating a significant role of terpenic constituents in contributing to the top aroma note. GC-olfactometry (GC-O) of the oils aided in establishing the role of sabinene, α-pinene and β-pinene in contributing to the distinctive note of the spice. A high odor activity value (OAV) of sabinene and α-pinene established the role of these two constituents in imparting the characteristic nutmeg odor.


Extrinsic and intrinsic sources of calcitonin gene-related peptide immunoreactivity in the lamb ileum: a morphometric and neurochemical investigation.
To investigate extrinsic origins of calcitonin gene-related peptide immunoreactive (CGRP-IR) nerve fibres in the sheep ileum, the retrograde fluorescent tracer Fast Blue (FB) was injected into the ileum wall. Sections of thoraco-lumbar dorsal root ganglia (DRG) and distal (nodose) vagal ganglia showing FB-labelled neurons were processed for CGRP immunohistochemistry. The distribution of CGRP-IR in fibres and nerve cell bodies in the ileum was also studied. CGRP-IR enteric neurons were morphometrically analysed in myenteric (MP) and submucosal plexuses (SMP) of lambs (2-4 months). Sensory neurons retrogradely labelled with FB were scattered in T5-L4 DRG but most were located at the upper lumbar levels (L1-L3); only a minor component of the extrinsic afferent innervation of the ileum was derived from nodose ganglia. In the DRG, 57% of retrogradely labelled neurons were also CGRP-IR. In cryostat sections, a dense network of CGRP-IR fibres was observed in the lamina propria beneath the epithelium, around the lacteals and lymphatic follicles (Peyer's platches), and along and around enteric blood vessels. Rare CGRP-IR fibres were also present in both muscle layers. Dense pericellular baskets of CGRP-IR fibres were observed around CGRP-negative somata. The only CGRP-IR nerve cells were well-defined Dogiel type II neurons localised in the MP and in the external and internal components of the SMP. CGRP-IR neurons in the myenteric ganglia were significantly larger than those in the submucosal ganglia (mean profile areas: about 1,400 mum(2) for myenteric neurons, 750 mum(2) for submucosal neurons). About 6% of myenteric neurons and 25% of submucosal neurons were CGRP-IR Dogiel type II neurons. The percentages of CGRP-IR neurons that were also tachykinin-IR were about 9% (MP) and 42% (SMP), whereas no CGRP-IR neurons exhibited immunoreactivity for vasoactive intestinal peptide, nitric oxide synthase or tyrosine hydroxylase in either plexus. Thus, CGRP immunoreactivity occurs in the enteric nervous system of the sheep ileum (as in human small intestine and MP of pig ileum) in only one morphologically defined type of neuron, Dogiel type II cells. These are probably intrinsic primary afferent neurons.


Real-World Data of Anticoagulant Treatment in Non-valvular Atrial Fibrillation.
To assess the impact of anticoagulant treatment on risk for stroke and all-cause mortality of patients with atrial fibrillation using real-world data (RWD). Patients with prevalent or incident atrial fibrillation were selected throughout a study period of 5 years. Stroke, transitory ischemic attack, hemorrhagic stroke, and all-cause mortality were identified in the claims of the electronic health records (EHRs). Subjects were classified according to the anticoagulant treatment in four groups: untreated, vitamin K antagonists (VKAs), New Oral Anticoagulants (NOACs), and antiplatelet (AP). Risk of events and protection with anticoagulant therapy were calculated by Cox proportional hazard models adjusted by potential confounders. From a total population of 3,799,884 patients older than 18,123,227 patients with incident or prevalent atrial fibrillation (AF) were identified (mean age 75.2 ± 11.5 years old; 51.9% women). In a follow-up average of 3.2 years, 17,113 patients suffered from an ischemic stroke and transitory ischemic attack (TIA), 780 hemorrhagic stroke, and 42,558 all-cause death (incidence of 46, 8, 2, and 120 per 1,000 patients/year, respectively). Among CHA2DS2, VASc Score equal or >2, 11.7% of patients did not receive any anticoagulant therapy, and a large proportion of patients, 47%, shifted from one treatment to another. Although all kinds of anticoagulant treatments were significantly protective against the events and mortality, NOAC treatment offered significantly better protection compared to the other groups. In the real world, the use of anticoagulant treatments is far from guidelines recommendations and is characterized by variability in their use. NOACs offered better protection compared with VKAs.


The impact of sitagliptin in palmitic acid-induced insulin resistance in human HepG2 cells through the suppressor of cytokine signaling 3/phosphoinositide 3-kinase/protein kinase B pathway.
Patients with type 2 diabetes respond differently to sitagliptin, an oral anti-hyperglycemic medication. Patients whose blood sugar levels were effectively managed while using sitagliptin had significantly lower levels of a protein called suppressor of cytokine signaling 3 (SOCS3), according to our earlier research. In this study, we established an in vitro insulin resistance cell model for human HepG2 cells to investigate the possible mechanism of the effect of sitagliptin on glucose metabolism via the SOCS3/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. Since insulin resistance first develops in the liver, palmitic acid was used to generate an insulin resistance cell model in human HepG2 cells, after which small interfering ribonucleic acid (siRNA)-SOCS3 and sitagliptin were used to intervene. We then examined the changes in cell viability and biochemical indices in the insulin resistance cell model. SOCS3, Akt, and glycogen synthase kinase 3beta (GSK-3β) gene expression levels were quantified using reverse transcription-polymerase chain reaction, and the protein expression levels of SOCS3, Akt, phosphorylated Akt (p-Akt), GSK-3β, and phosphorylated GSK-3β (p-GSK-3β) were quantified using Western blot. In results: the expression of the SOCS3 gene was considerably raised in both the insulin resistance model group and the insulin resistance model + siRNA-negative control group, but decreased following treatment with sitagliptin. After sitagliptin intervention, the protein expression of Akt, p-Akt, and p-GSK-3β were dramatically decreased in the model group, while SOCS3 was significantly decreased. We conclude that sitagliptin can reduce insulin resistance by downregulating SOCS3 and regulating glucose metabolism in a hypoglycemic manner.


Semisynthesis of peptoid-protein hybrids by chemical ligation at serine.
Chemical ligation protocols were explored for generating semisynthetic peptoid-protein hybrid architectures containing a native serine residue at the ligation site. Peptoid oligomers bearing C-terminal salicylaldehyde esters were synthesized and ligated to the N-terminus of the RNase S protein or the therapeutic hormone PTH(1-34) polypeptide. This technique will expand the repertoire of strategies to enable design of hybrid macromolecules with novel structures and functions not accessible to fully biosynthesized proteins.


Collective resilience in times of crisis: Lessons from the literature for socially effective responses to the pandemic.
Most countries worldwide have taken restrictive measures and called on their population to adopt social distancing behaviours to contain the spread of the COVID-19 pandemic. At a time when several European countries are releasing their lockdown measures, new uncertainties arise regarding the further evolution of a crisis becoming multifaceted, as well as the durability of public determination to face and contain it. In this context, the sustained social efficacy of public health measures will depend more than ever on the level of acceptance across populations called on to temporarily sacrifice daily freedoms, while economic insecurity grows and social inequalities become more blatant. We seek to develop a framework for analysing how the requirements of 'social distancing' can be reconciled with the conditions that allow for the maintaining, or even strengthening, of social cohesion, mutual solidarity, and a sense of collective efficacy, throughout the crisis. To reach this goal, we propose a summary of relevant findings and pragmatic policy principles derived from them.


Going Granular: Equity of Health Financing at the District and Facility Level in India.
Health financing equity analysis rarely goes below the state level in India. This paper assesses the equity and effectiveness of public spending on health in the state of Odisha. Using district-level public spending data for the first time, it sheds light on the incidence of public spending by geography and by type of services. There are three key findings. First, it identifies the weak link between district spending and district need, proxied by poverty rates or lagging sectoral outcomes, highlighting the potential for a more needs-based approach to public resource allocation. Second, the results indicate that at the household level health spending by the state is not pro-poor, especially in public hospitals, underscoring the need to improve access to care for the bottom 40% at these facilities. Third, an exhaustive analysis of micro-level treasury data brings into focus the importance of reforming public finance data systems to support evidence-based policy at the sub-state level. Significant district-wise variation in key health financing and equity indicators, combined with growing policy interest in the district level, underscore the utility of further empirical work in this area.


Reduction of response time by data placement reflecting co-occurrence structures in structured overlay networks.
We propose a method to accelerate a response of structured overlay networks by reducing the number of hops required to answer multi-queries. In the proposed method, by copying data items to the redundant storage spaces in other storages, a good data placement reflecting co-occurrence structures in the structured overlay network is achieved. We formulate the optimization problem of the data placement in the limited redundant space of the storages as an integer programming. A greedy approach to solve the optimization problem is also proposed. Through several simulations, it is confirmed that the proposed method can reduce the average number of hops required to answer multi-queries by about 30% at the maximum in our simulation settings. The reduction rate of the average number of hops depends on the level of co-occurrence. Further, the reduction of the computation time to solve the optimization problem with the greedy approach is evaluated. We also confirm that the proposed method does not affect load balancing of structured overlay networks.


Decreased blood product usage during extracorporeal life support with reduced circuit volumes.
Activation and consumption of platelets (PLT) and clotting factors along with hemolysis occurs when blood contacts the extracorporeal life support (ECLS) circuit and its components. The objective was to examine the effects of reducing ECLS circuit volume by decreasing tubing length and changing components on blood product usage in neonatal and pediatric patients. Blood product administration was analyzed in 40 consecutive patients who required ECLS for respiratory or cardiac failure before (PRE) and after (POST) changes in circuit design and components. The total circuit volume was reduced from 500 mL (PRE) to 275 mL (POST). In the POST group, total blood product volume usage was 58% lower compared to the PRE group (81 mL/kg/day vs. 191 mL/kg/day, p = 0.003), 65% lower for fresh-frozen plasma (FFP; 15 mL/kg/day vs. 43 mL/kg/day, p = 0.001), and PLT volumes trended lower. In the subgroup of infants with respiratory or cardiac failure, there was a 55% reduction of a total blood product replacement (61 mL/kg/day vs. 136 mL/kg/day, p = 0.008), red blood cell (RBC) use was 61% lower (28 mL/kg/day vs. 71 mL/kg/day, p < 0.049), and there was a 73% reduction in FFP use (11 mL/kg/day vs. 41 mL/kg/day, p < 0.001). In the subgroup of postoperative infants, there was a 25% decrease in RBC use (86 mL/kg/day vs. 115 mL/kg/day, p = 0.03). Decreasing the ECLS circuit volume by reducing the tubing length and changing the components was associated with a significant reduction in blood product usage.


Intraplatelet serotonin and plasma 5-hydroxyindoles in health and disease.
Using a fluorometric test sensitive to serotonin (5-HT) and to other 5-hydroxyindoles (5-HIs) it was shown that platelets take up 5-HT and that the added 5-HT and the inherent test-positive material in platelet lysate can be directly measured. However, platelets do not take up 5-hydroxyindole acetic acid or the 5-HIs from the plasma. Thus, 5-HT and the other 5-HIs can be distinguished. Various methods of liberating intraplatelets 5-HT were investigated. Several anticoagulants, temperatures, and speeds of centrifugation were employed, with no effect on the results. It was found that in healthy donors, with increasing age, there was a decrease in intraplatelet 5-HT and an increase in plasma 5-HIs. The quantities of these substances were inversely related. In acute myocardial infarction, the 5-HT was normal taking age into account, but the plasma 5-HIs were increased. In postoperative patients, the platelet 5-HT was low and the plasma 5-HIs were normal. In patients with chest pain but no myocardial infarction, both platelet 5-HT and plasma 5-HIs were normal. The relevance of these findings to 5-HT metabolism and the evidence for in vivo activation of platelets is discussed.


Metastatic spinal cord compression as an oncology emergency: getting our act together.
Metastatic spinal cord compression is a dreaded complication of cancer affecting 5-10% of patients requiring urgent treatment. A clinical practice improvement project was carried out to review and fine tune the clinical pathway for the acute management of patients with metastatic spinal cord compression. To improve the quality of care for metastatic spinal cord compression over 6 months by ensuring that >90% of patients receive definitive treatment within 24 h of radiological diagnosis. Using clinical practice improvement project methodology, the clinical pathway of 17 patients treated with radiotherapy for metastatic spinal cord compression within the last 6 months were reviewed to identify gaps and delays in the system. Interventions to form a multidisciplinary acute spinal cord crisis team, fine tune clinical referral processes and formulate a standardized treatment protocol were then implemented. Post-intervention of 22 subsequent patients were monitored for time to start steroids and radiation therapy, length of stay and hospitalization bill. With the interventions implemented, the mean response time to start steroidal therapy was reduced from 8.4 to 2.6 days and radiotherapy from 9.9 to 3.9 days. These translated into shorter mean length of stay from 23.8 to 14.7 days and smaller hospitalization bill size from 13,723 to 8,808 Singapore dollars. A clinical practice improvement project, to improve the quality of care for patients with metastatic spinal cord compression, can shorten response time to start steroidal therapy and definitive radiotherapy resulting in shorter length of stay and smaller hospitalization bill.


Mitral paravalvular leak: caution in percutaneous occluder device deployment.
A frail 70-year-old woman presented with symptomatic mitral paravalvular leak 2 months after undergoing a double valve replacement for mixed mitral and aortic valve disease. There was no evidence of prosthetic valve endocarditis. Percutaneous closure of the paravalvular leak was attempted as an alternative to a high-risk surgical procedure. This therapy was successful in reducing the regurgitation but resulted in severe intravascular hemolysis and acute renal failure requiring hemodialysis.The development of new hemolysis and acute renal failure directed our attention to the Amplatzer device as a possible etiology for these complications. The assumption that her kidney injury was recent and likely reversible compelled us to think of the surgical method as a definitive option. A re-operative surgery was performed, which included retrieval of the occluder devices, pericardial patch repair, and re-replacement using a new biological prosthesis. The patient's urine output gradually improved, and the patient was dismissed with normal renal function.We present this case as an unusual complication of percutaneous device closure. It also highlights the reversible nature of acute renal failure due to intravascular hemolysis and demonstrates the importance of early surgical intervention for this condition.


Mediator influences Schizosaccharomyces pombe RNA polymerase II-dependent transcription in vitro.
The fission yeast Schizosaccharomyces pombe has proved an important model system for cross-species comparative studies of many fundamental processes in the eukaryotic cell, such as cell cycle control and DNA replication. The RNA polymerase II transcription machinery is, however, still relatively poorly understood in S. pombe, partially due to the absence of a reconstituted in vitro transcription system. We have now purified S. pombe RNA polymerase II and its general initiation factors TFIIB, TFIIF, TFIIE, and TFIIH to near homogeneity. These factors enable RNA polymerase II to initiate transcription from the S. pombe alcohol dehydrogenase promoter (adh1p) when combined with Saccharomyces cerevisiae TATA-binding protein. We use our reconstituted system to examine effects of Mediator on basal transcription in vitro. S. pombe Mediator exists in two distinct forms, a free form, which contains the spSrb8, spTrap240, spSrb10, and spSrb11 subunits, and a smaller form, which lacks these four subunits and associates with RNA polymerase II to form a holoenzyme. We find that spSrb8/spTrap240/spSrb10/spSrb11 containing Mediator repress basal transcription, whereas Mediator lacking these subunits has a stimulatory effect on transcription. Our findings thus demonstrate that the spSrb8/spTrap240/spSrb10/spSrb11 subcomplex governs the ability of Mediator to stimulate or repress basal transcription in vitro.


Do we know the diagnostic properties of the tests used in COVID-19? A rapid review of recently published literature.
COVID-19 has brought death and disease to large parts of the world. Governments must deploy strategies to screen the population and subsequently isolate the suspect cases. Diagnostic testing is critical for epidemiological surveillance, but the accuracy (sensitivity and specificity) and clinical utility (impact on health outcomes) of the current diagnostic methods used for SARS-CoV-2 detection are not known. I ran a quick search in PubMed/MEDLINE to find studies on laboratory diagnostic tests and rapid viral diagnosis. After running the search strategies, I found 47 eligible articles that I discuss in this review, commenting on test characteristics and limitations. I did not find any papers that report on the clinical utility of the tests currently used for COVID-19 detection, meaning that we are fighting a battle without proper knowledge of the proportion of false negatives that current testing is resulting in. This shortcoming should not be overlooked as it might hamper national efforts to contain the pandemic through testing community-based suspect cases.


First Report of Aedes aegypti Transmission of Chikungunya Virus in the Americas.
During a chikungunya fever outbreak in late 2014 in Chiapas, Mexico, entomovirological surveillance was performed to incriminate the vector(s). In neighborhoods, 75 households with suspected cases were sampled for mosquitoes, of which 80% (60) harbored Aedes aegypti and 2.7% (2) Aedes albopictus. A total of 1,170 Ae. aegypti and three Ae. albopictus was collected and 81 pools were generated. Although none of the Ae. albopictus pools were chikungunya virus (CHIKV)-positive, 18 Ae. aegypti pools (22.8%) contained CHIKV, yielding an infection rate of 32.3/1,000 mosquitoes. A lack of herd immunity in conjunction with high mosquito populations, poor vector control services in this region, and targeted collections in locations of human cases may explain the high infection rate in this vector. Consistent with predictions from experimental studies, Ae. aegypti appears to be the principal vector of CHIKV in southern Mexico, while the role of Ae. albopictus remains unknown.


Why 1-NH and 3-NH protons of D-biotin exhibit different activities in aqueous solution.
Quantum chemical calculations, combined with the molecular dynamics results, have been employed to explain why the 1- and 3-NH protons of biotin exhibit different activities in aqueous solution. They suggested that the relative proportion of the three different conformations of biotin in the solution was responsible for different activities of the two amide protons of biotin. The relative activity of the two amide protons calculated by theoretical work here is 6, which is in good agreement with the experimental data, which is 5, reinforcing the viewpoint that biotin jumps between the three conformations in aqueous solution and the relative proportion of extended, semifolded, and folded biotin in water is 24:3.6:1. The method for computing the relative activity of the two amide protons of biotin in water here may be used to predict the relative activity in other solutions. The behavior of biotin in aqueous solution may be helpful for better understanding the unusual strong biotin-(strept)avidin binding.


Discrimination of modulation type (amplitude modulation or frequency modulation) with and without background noise.
These experiments compare the ability to detect amplitude modulation (AM) and frequency modulation (FM) with the ability to discriminate AM from FM, using 10-Hz sinusoidal modulation of a 1000-Hz carrier. Initially, psychometric functions were measured for the detection of AM and FM alone, using a two-alternative forced-choice (2AFC) task. In experiment 1, pairs of values of AM and FM were selected that would be equally detectable, and psychometric functions were measured for the discrimination of AM from FM, again in a 2AFC task. Values of d' for discriminating AM from FM were always lower than the values of d' for detection of the AM or FM. When the detectability of the AM and FM was low (d' = 0.66), two subjects were essentially unable to discriminate AM from FM. This was true both for stimuli presented in quiet and for stimuli presented with continuous noise chosen to mask either the lower or the upper side of the excitation pattern. In experiment 2, subjects were again required to discriminate AM from FM, but the AM depth was fixed within a block of trials, while the FM depth was varied across trials. The discriminability of AM from FM did not show distinct minima at specific FM depths. Again, this was true both for stimuli presented in quiet and for stimuli presented with continuous noise chosen to mask either the lower or the upper side of the excitation pattern. This result suggests that the discrimination of AM from FM was not based on monitoring just one side of the excitation pattern of the carrier.(ABSTRACT TRUNCATED AT 250 WORDS)


Patient-specific time to peak abdominal organ enhancement varies with time to peak aortic enhancement at MR imaging.
To retrospectively evaluate the relationship between the times to peak enhancement of the liver, pancreas, and jejunum with respect to the time to peak aortic enhancement at magnetic resonance (MR) imaging. The committee on human research approved this study and waived written informed consent. This study was HIPAA compliant. The study retrospectively identified 141 patients (63 men, 78 women; mean age, 57 years) who underwent abdominal MR imaging by using a test bolus that was monitored approximately every second for 2 minutes with a spoiled gradient-echo T1 transverse section through the upper abdomen. The times to peak enhancement of the aorta, liver, pancreas, and jejunum were recorded and correlated with the time to peak aortic enhancement, age, and sex by means of univariate and multivariate linear regression analyses. The mean time to peak aortic enhancement was 21.1 seconds (range, 8.7-41.8 seconds). The times to peak enhancement of the liver, pancreas, and jejunum were positively and linearly correlated with the time to peak aortic enhancement (r = 0.69, 0.86, and 0.80, respectively, all P < .001) and were 3.39, 1.64, and 2.04 times longer than the time to peak aortic enhancement, respectively. Age, sex, and history of heart disease did not give additional predictive information for determining the time to peak visceral enhancement. The times to peak enhancement of the liver, pancreas, and jejunum are linearly related to that of the aorta. These results could potentially allow tailored patient- and organ-specific scan delay optimization at contrast material-enhanced MR image evaluation.


The ability of new sugar-modified derivatives of antitumor anthracycline, daunorubicin, to stimulate NAD(P)H oxidation in different cellular oxidoreductase systems: NADH dehydrogenase, NADPH cytochrome P450 reductase, and xanthine oxidase.
Numerous data indicate that cellular oxidoreductases may be responsible for the cardiotoxic effects of antitumor anthracycline drugs as a consequence of the mediation by these agents of one-electron transfer from reduced nucleotides to atmospheric oxygen. This process is catalyzed primarily by NADH dehydrogenase, NADPH cytochrome P450 reductase, and xanthine oxidase and leads to the formation of reactive oxygen species (ROS). In this work the data on the ability of new amino sugar derivatives of daunorubicin to stimulate NAD(P)H oxidation in the above oxidoreductase systems are presented. They represent analogues of daunorubicin in which the amino sugar nitrogen is bounded to an unsubsituted, or amino- or nitro-substituted benzyl group. It was found that the ability of examined sugar-modified derivatives of daunorubicin to stimulate NAD(P)H oxidation differs considerably depending on the subsituent in the phenyl ring. It was also determined that this ability was not identical in the three enzymatic systems studied, showing that these derivatives have different affinities for the enzymes examined. More similarities were observed in their interaction with NADH dehydrogenase and NADPH cytochrome P450 reductase than with xanthine oxidase.


Promiscuous liberation of MHC-class I-binding peptides from the C termini of membrane and soluble proteins in the secretory pathway.
TAP can efficiently transport peptides up to twice as long as those bound to MHC class I molecules, suggesting a role for endoplasmic reticulum (ER) proteases in the trimming of TAP-transported peptides. To better define ER processing of antigenic peptides, we examined the capacity of TAP-deficient cells to present determinants derived from ER-targeted proteins encoded by recombinant vaccinia viruses. TAP-deficient cells failed to present antigenic peptides from internal locations in secreted proteins to MHC class I-restricted T lymphocytes. The same peptides were liberated from the C termini of a secreted protein and the lumenal domains of two membrane proteins delivered to the ER via different routes. These findings suggest that proteases in the secretory compartment can liberate C-terminal antigenic peptides from virtually any context. We propose that this activity often participates in the removal of N-terminal extensions from TAP-transported peptides, thereby creating optimally sized products for MHC class I binding. We further demonstrate that ER trimming of C termini can occur if we express an appropriate carboxypeptidase in the secretory pathway. The absence of such trimming under normal circumstances suggests that carboxypeptidase activity is generally deficient in the ER, consistent with the concordance between the specificity of TAP and MHC class I molecules for the same types of C-terminal residues.


Utilization of MHC class I transgenic mice for development of minigene DNA vaccines encoding multiple HLA-restricted CTL epitopes.
We engineered a multiepitope DNA minigene encoding nine dominant HLA-A2.1- and A11-restricted epitopes from the polymerase, envelope, and core proteins of hepatitis B virus and HIV, together with the PADRE (pan-DR epitope) universal Th cell epitope and an endoplasmic reticulum-translocating signal sequence. Immunization of HLA transgenic mice with this construct resulted in: 1) simultaneous CTL induction against all nine CTL epitopes despite their varying MHC binding affinities; 2) CTL responses that were equivalent in magnitude to those induced against a lipopeptide known be immunogenic in humans; 3) induction of memory CTLs up to 4 mo after a single DNA injection; 4) higher epitope-specific CTL responses than immunization with DNA encoding whole protein; and 5) a correlation between the immunogenicity of DNA-encoded epitopes in vivo and the in vitro responses of specific CTL lines against minigene DNA-transfected target cells. Examination of potential variables in minigene construct design revealed that removal of the PADRE Th cell epitope or the signal sequence, and changing the position of selected epitopes, affected the magnitude and frequency of CTL responses. Our results demonstrate the simultaneous induction of broad CTL responses in vivo against multiple dominant HLA-restricted epitopes using a minigene DNA vaccine and underline the utility of HLA transgenic mice in development and optimization of vaccine constructs for human use.


The effect of silicone gel bleed on capsular contracture: a generational study.
Capsular contracture has multiple causes, all of which lead to increased inflammation and scarring. There have been five generations of silicone breast implants; the most recent are filled with a highly cohesive gel thought to reduce capsular contracture. No independent data exist to support this claim. Eight Göttingen swine were each implanted with eight 50-cc custom gel implants. In phase 1 of the study, the implant shells were photochemically altered to produce a low-bleed shell or a high-bleed shell to simulate a second-generation implant. In phase 2, both the third/fourth generation and the newest, fifth generation (highly cohesive gel) devices were implanted. Half the implants were punctured with a 3-ml punch biopsy to simulate a ruptured implant. Capsule and implant specimens were harvested at 1 and 3 months and analyzed with a Bose strain gauge. Intracapsular fluid was tested for silicon levels with atomic emission spectrometry. Histologic analysis was prepared with hematoxylin and eosin, Masson trichrome, and α-smooth muscle actin immunohistochemistry stains. Gel bleed correlated with capsule stiffness in a dose-dependent manner (p < 0.05). High-bleed second-generation implants had the stiffest capsules, and nonruptured third- and fourth-generation implants had the softest. Histologic examination revealed an intermediate layer of spindle-like cells staining positive for α-smooth actin in the most contracted capsules. There is a dose-dependant relationship between silicone gel bleed and capsule compliance that is independent of the cohesivity of the silicone. Capsule thickness and a fibrotic, α-smooth muscle actin-positive layer are present within the most contracted capsules.


[Facial paralysis in chronic nonspecific inflammation of the parotid].
Benign diseases of the parotid gland only rarely cause facial nerve paralysis. A parotid gland tumour with peripheral facial nerve paralysis is generally accepted as being malignant, although this rule is not without exceptions. We report a case of chronic non-specific parotitis with an inflammatory pseudotumour causing a peripheral paralysis of the ipsilateral facial nerve. Antiinflammatory and antibiotic treatment caused the complete remission of the parotitis and facial nerve palsy within 6 weeks.


Cytolytic T-cell clones define HLA-A2-restricted human cutaneous melanoma peptide epitopes: correlation with T-cell receptor usage.
We studied the T-cell receptor alpha chain and beta chain variable region usage in HLA-A2-restricted and melanoma-specific T lymphocytes and correlated such T-cell receptor usage with HLA-A2-presented peptide-specific T-cell recognition. Tumor-infiltrating lymphocytes were isolated from a metastatic melanoma lesion and cloned by limiting dilution. Clonal and oligoclonal tumor-infiltrating lymphocytes were analyzed for major histocompatibility complex class I--presented melanoma peptide recognition by using acid-eluted and high-performance liquid chromatography--fractionated melanoma peptides presented by HLA-A2 as targets. The T-cell receptor variable regions of the alpha and beta chains of each individual T-cell clone or oligoclonal T-cell population were analyzed by mRNA extraction and reverse transcribed cDNA by polymerase chain reaction using a panel of T-cell receptor alpha and beta variable region specific primers. We demonstrated that individual T-cell clones are capable of recognizing peptides within multiple high-performance liquid chromatography fractions containing melanoma epitopes, and that individual high-performance liquid chromatography fractions containing melanoma epitopes can be recognized by T-cell clones exhibiting limited usage of the T-cell receptor alpha and beta variable region chains. These results confirm the heterogeneity of T-cell-defined melanoma antigens in a single individual and suggest the possibility of developing novel antimelanoma therapeutic reagents using either peptides (as immunogens) or the T-cell receptors themselves (as gene therapy when introduced into lymphoid effectors).


Ultrasmall mode volumes in dielectric optical microcavities.
We theoretically demonstrate a mechanism for reduction of mode volume in high index contrast optical microcavities to below a cubic half wavelength. We show that by using dielectric discontinuities with subwavelength dimensions as a means of local field enhancement, the effective mode volume (V(eff)) becomes wavelength independent. Cavities with V(eff) on the order of 10(-2)(lambda/2n)(-3) can be achieved using such discontinuities, with a corresponding increase in the Purcell factor of nearly 2 orders of magnitude relative to previously demonstrated high index photonic crystal cavities.


Microbiota, metabolome, and immune alterations in obese mice fed a high-fat diet containing type 2 resistant starch.
We examined the intestinal and systemic responses to incorporating a type 2 resistant starch (RS) into a high fat diet fed to obese mice. Diet-induced obese, C57BL/6J male mice were fed an HF diet without or with 20% (by weight) high-amylose maize resistant starch (HF-RS) for 6 weeks. Serum adiponectin levels were higher with RS consumption, but there were no differences in weight gain and adiposity. With HF-RS, the expression levels of ileal TLR2 and Reg3g and cecal occludin, TLR2, TLR4, NOD1 and NOD2 were induced; whereas colonic concentrations of the inflammatory cytokine IL-17A declined. The intestinal, serum, liver, and urinary metabolomes were also altered. HF-RS resulted in lower amino acid concentrations, including lower serum branched chain amino acids, and increased quantities of urinary di/trimethylamine, 3-indoxylsulfate, and phenylacetylglycine. Corresponding to these changes were enrichments in Bacteroidetes (S24-7 family) and certain Firmicutes taxa (Lactobacillales and Erysipelotrichaceae) with the HF-RS diet. Parabacteroides and S24-7 positively associated with cecal maltose concentrations. These taxa and Erysipelotrichaceae, Allobaculum, and Bifidobacterium were directly correlated with uremic metabolites. Consumption of RS modified the intestinal microbiota, stimulated intestinal immunity and endocrine-responses, and modified systemic metabolomes in obese mice consuming an otherwise obesogenic diet.


Neoline from Aconitum flavum Hand.
The title compound, C(24)H(39)NO(6) [systematic name: (1α,6α,14α,16β)-N-ethyl-6,16-dimeth-oxy-4-meth-oxy-methylaconitane-1,8,14-triol], is a C(19)-diterpenoid alkaloid from the roots of Aconitum flavum Hand. The mol-ecule has an aconitane carbon skeleton with four six-membered rings and two five-membered rings. Both five-membered rings adopt envelope conformations. Two six-membered rings adopt chair conformations, whereas the other two adopt boat conformations. Intra-molecular O-H⋯O and O-H⋯N and inter-molecular O-H⋯O hydrogen bonds are present in the structure. In the crystal, one methyl group is disordered over two sites with an occupancy ratio of 0.70 (3):0.30 (3).


Enhancing nuclear emergency response through international cooperation.
Nuclear and radiological emergencies may easily become severe international emergencies requiring substantial resources in several or many states for an adequate response, which in some cases may require resources exceeding national capabilities. Through the development of a consistent, coherent and sustainable joint programme for improved and more efficient international responses to nuclear and radiological emergencies, it is believed that we could achieve a better and more cost-effective response capability for nuclear and radiological emergencies. This requires, however, that we be willing and able to establish mechanisms of assistance where information and resources are globally shared and that standardised/harmonised procedures be developed and implemented. If we are willing to make this investment, we believe that, in the long term, there will be a significant benefit for all of us.


Effect of nucleotide intake and nutritional recovery on insulin-like growth factor I and other hormonal biomarkers in severely malnourished children.
The objective of the present study is to demonstrate the effect of nucleotide intake and intensive nutritional support on the concentration of insulin-like growth factor I (IGF-I) and other hormonal biomarkers in severely malnourished children. Twenty-six severely malnourished children < 48 months of age received formula without lactose via enteral feeding for 2 weeks and ad libitum for an additional 2 weeks. Anthropometrical measurements were performed and serum concentrations of IGF-I, insulin-like growth factor binding protein-3 (IGFBP-3), leptin, soluble leptin receptor (sOB-R), as well as the estimated molar excess of sOB-R over leptin were obtained. Two groups were formed. One group received formula with nucleotides (NT+; n 13) and the other without nucleotides (NT-; n 13). A control group was included (n 13). Parametric and non-parametric tests as well as ANOVA models were used. Nutritional recovery, nucleotides intake, type of malnutrition, age and the interaction between gender and malnutrition influenced the concentration of IGF-I (P < 0.001). Nutritional recovery, nucleotides intake, gender and type of malnutrition had an effect on IGFBP-3 (P < 0.001). Nutritional recovery had a significant effect on serum leptin (P = 0.001). Age and nutritional recovery had an effect on sOB-R (P < 0.001); all variables included affected the molar excess of sOB-R over leptin (P < 0.001). In conclusion, nucleotide intake and nutritional recovery had a notable effect on IGF-I, IGFBP-3 and other hormonal biomarkers. This outcome could stimulate the catch-up growth of severely malnourished infants and toddlers during the nutritional recovery period.


Lipomatous pancreas facilitates late onset of renal cell carcinoma metastases.
Late metastasizing into pancreatic tissue is a special hallmark of renal cell carcinomas (RCC). A very low prevalence leads to scarce data about therapy, prognosis and spreading pathways. The aim of the study was to analyze whether a high fat content in the pancreas facilitates RCC metastases formation. A model for density measurement of pancreatic tissue has been developed and evaluated. Pancreatic fat content was measured comparing Hounsfield units (HU) of CT scans. In a consecutive single centre retrospective database of 3600 patients with pancreatic resections, only 12 patients (0.3%) cases of RCC metastases in the pancreas were found. HU were measured in 3 pancreatic regions: head, body and tail in patients' CT scans. HU values were compared to a control population and results aligned with recent literature. We revealed a prevalence of pancreatic metastases of RCC in 0.3% of cases. The formation of RCC in the pancreas occurred within 14 ± 5.6 years after initial diagnosis of RCC. 83.3% of the patients were alive after a follow-up period of up to 48 months. Clinical data analysis revealed an affinity for metastatic formation to lipomatous pancreas. This could be objectivized by HU analysis in CT scans. Pancreatic metastases occur late after the first diagnosis of renal carcinoma and show an affinity for lipomatous pancreatic tissues. Due to its rarity in occurrence, multicentric studies are highly recommended to further analyze this correlation between fatty pancreas and RCC.


Transcriptional synergy between Tat and PCAF is dependent on the binding of acetylated Tat to the PCAF bromodomain.
The human immunodeficiency virus (HIV) Tat protein plays an essential role in promoting efficient transcriptional elongation of viral transcripts. We report that the transcriptional co-activator PCAF and Tat interact and synergize to activate the HIV promoter. The binding of Tat and PCAF in vitro and in vivo is dependent on the acetylated state of Lys50 of Tat and on the PCAF bromodomain. Structural analysis of the acetylated Tat peptide bound to the PCAF bromodomain defined amino acids Y47 and R53 in Tat and V763, Y802, and Y809 in PCAF as critical interaction points between the two proteins. Mutation of each of these residues in either Tat or PCAF inhibited in a cumulative manner the Tat-PCAF interaction in vitro and in vivo, and abrogated the synergistic activation of the HIV promoter by both proteins. These observations demonstrate that acetylation of Tat establishes a novel protein-protein interaction domain at the surface of Tat that is necessary for the transcriptional activation of the HIV promoter.


[Sleep and brain function].
Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) catalyzes the isomerization of PGH2, a common precursor of various prostanoids, to produce PGD2, a potent endogenous somnogen. L-PGDS is localized in the leptomeninges, choroid plexus, and oligodendrocytes of the central nervous system. PGD2 is proposed to be a major humoral sleep-inducing factor accumulated in the brain during wakefulness. PGD2 stimulates DP, receptors localized in the basal forebrain and increases the local extracellular concentration of adenosine, which activates A2A receptor-possessing neurons in the basal forebrain and/or ventrolateral preoptic area (VLPO). The intracerebroventricular infusion of PGD2 or adenosine A2A receptor-agonists induces non-REM sleep and increases the expression of fos protein in VLPO. The activation of VLPO neurons is associated with decreased fos expression in the histaminergic tuberomammillary nucleus (TMN), one of the arousal centers. The GABAergic inhibition of TMN is involved in non-REM sleep induction by PGD2 or adenosine A2A receptor-agonists. The neural network between VLPO and TMN is considered to play a key role in the regulation of vigilance states.


A Caenorhabditis elegans nutrient response system partially dependent on nuclear receptor NHR-49.
Appropriate response to nutritional stress is critical for animal survival and metabolic health. To better understand regulatory networks that sense and respond to nutritional availability, we developed a quantitative RT-PCR strategy to monitor changes in metabolic gene expression resulting from short-term food deprivation (fasting) in Caenorhabditis elegans. Examining 97 fat and glucose metabolism genes in fed and fasted animals, we identified 18 genes significantly influenced by food withdrawal in all developmental stages. Fasting response genes fell into multiple kinetic classes, with some genes showing significant activation or repression just 1 h after food was removed. As expected, fasting stimulated the expression of genes involved in mobilizing fats for energy production, including mitochondrial beta-oxidation genes. Surprisingly, however, we found that other mitochondrial beta-oxidation genes were repressed by food deprivation. Fasting also affected genes involved in mono- and polyunsaturated fatty acid synthesis: four desaturases were induced, and one stearoyl-CoA desaturase (SCD) was strongly repressed. Accordingly, fasted animals displayed considerable changes in fatty acid composition. Finally, nuclear receptor nhr-49 played a key role in nutritional response, enabling induction of beta-oxidation genes upon food deprivation and facilitating activation of SCD in fed animals. Our characterization of a fasting response system and our finding that nhr-49 regulates a sector within this system provide insight into the mechanisms by which animals respond to nutritional signals.


PPE26 induces TLR2-dependent activation of macrophages and drives Th1-type T-cell immunity by triggering the cross-talk of multiple pathways involved in the host response.
The pathophysiological functions and the underlying molecular basis of PE /PPE proteins of M. tuberculosis remain largely unknown. In this study, we focused on the link between PPE26 and host response. We demonstrated that PPE26 can induce extensive inflammatory responses in macrophages through triggering the cross-talk of multiple pathways involved in the host response, as revealed by iTRAQ-based subcellular quantitative proteomics. We observed that PPE26 is able to specifically bind to TLR2 leading to the subsequent activation of MAPKs and NF-κB signaling. PPE26 functionally stimulates macrophage activation by augmenting pro-inflammatory cytokine production (TNF-α, IL-6 and IL-12 p40) and the expression of cell surface markers (CD80, CD86, MHC class I and II). We observed that PPE26-treated macrophages effectively polarizes naïve CD4(+) T cells to up-regulate CXCR3 expression, and to secrete IFN-γ and IL-2, indicating PPE26 contributes to the Th1 polarization during the immune response. Importantly, rBCG::PPE26 induces stronger antigen-specific TNF-α and IFN-γ activity, and higher levels of the Th1 cytokines TNF-α and IFN-γ comparable to BCG. Moreover, PPE26 effectively induces the reciprocal expansion of effector/memory CD4(+)/CD8(+) CD44(high)CD62L(low) T cells in the spleens of mice immunized with this strain. These results suggest that PPE26 may be a TLR2 agonist that stimulates innate immunity and adaptive immunity, indicating that PPE26 is a potential antigen for the rational design of an efficient vaccine against M. tuberculosis.


Decoupling Hydrogen and Oxygen Production in Acidic Water Electrolysis Using a Polytriphenylamine-Based Battery Electrode.
Hydrogen production through water splitting is considered a promising approach for solar energy harvesting. However, the variable and intermittent nature of solar energy and the co-production of H2 and O2 significantly reduce the flexibility of this approach, increasing the costs of its use in practical applications. Herein, using the reversible n-type doping/de-doping reaction of the solid-state polytriphenylamine-based battery electrode, we decouple the H2 and O2 production in acid water electrolysis. In this architecture, the H2 and O2 production occur at different times, which eliminates the issue of gas mixing and adapts to the variable and intermittent nature of solar energy, facilitating the conversion of solar energy to hydrogen (STH). Furthermore, for the first time, we demonstrate a membrane-free solar water splitting through commercial photovoltaics and the decoupled acid water electrolysis, which potentially paves the way for a new approach for solar water splitting.


Laboratory Diagnosis of Infections in Cancer Patients: Challenges and Opportunities.
Infections remain a significant cause of morbidity and mortality in cancer patients. The differential diagnosis for these patients is often wide, and the timely selection of the right clinical tests can have a significant impact on their survival. However, laboratory findings with current methodologies are often negative, challenging clinicians and laboratorians to continue the search for the responsible pathogen. Novel methodologies are providing increased sensitivity and rapid turnaround time to results but also challenging our interpretation of what is a clinically significant pathogen in cancer patients. This minireview provides an overview of the most common infections in cancer patients and discusses some of the challenges and opportunities for the clinical microbiologist supporting the care of cancer patients.


TNF-α blockade impairs in vitro tuberculous granuloma formation and down modulate Th1, Th17 and Treg cytokines.
Tuberculosis (TB) is a granulomatous disease that has affected humanity for thousands of years. The production of cytokines, such as IFN-γ and TNF-α, is fundamental in the formation and maintenance of granulomas and in the control of the disease. Recently, the introduction of TNF-α-blocking monoclonal antibodies, such as Infliximab, has brought improvements in the treatment of patients with chronic inflammatory diseases, but this treatment also increases the risk of reactivation of latent tuberculosis. Our objective was to analyze, in an in vitro model, the influence of Infliximab on the granulomatous reactions and on the production of antigen-specific cytokines (TNF-α, IFN-γ, IL-12p40, IL-10 and IL-17) from beads sensitized with soluble Bacillus Calmette-Guérin (BCG) antigens cultured in the presence of peripheral blood mononuclear cells (PBMC) from TB patients. We evaluated 76 individuals, with tuberculosis active, treated and subjects with positive PPD. Granuloma formation was induced in the presence or absence of Infliximab for up to 10 days. The use of Infliximab in cultures significantly blocked TNF-α production (p <0.05), and led to significant changes in granuloma structure, in vitro, only in the treated TB group. On the other hand, there was a significant reduction in the levels of IFN-γ, IL-12p40, IL-10 and IL-17 after TNF-α blockade in the three experimental groups (p <0.05). Taken together, our results demonstrate that TNF-α blockade by Infliximab directly influenced the structure of granuloma only in the treated TB group, but negatively modulated the production of Th1, Th17 and regulatory T cytokines in the three groups analyzed.


Comparative toxicity of two glyphosate-based formulations to Eisenia andrei under laboratory conditions.
Glyphosate-based products are the leading post-emergent agricultural herbicides in the world, particularly in association with glyphosate tolerant crops. However, studies on the effects of glyphosate-based formulations on terrestrial receptors are scarce. This study was conducted to evaluate the comparative toxicity of two glyphosate-based products: Roundup FG (monoammonium salt, 72% acid equivalent, glyphosate-A) and Mon 8750 (monoammonium salt, 85.4% acid equivalent, glyphosate-B), towards the earthworm Eisenia andrei. Median lethal concentration (LC50) showed that glyphosate-A was 4.5-fold more toxic than glyphosate-B. Sublethal concentrations caused a concentration-dependent weight loss, consistent with the reported effect of glyphosate as uncoupler of oxidative phosphorylation. Glyphosate-A showed deleterious effects on DNA and lysosomal damage at concentrations close to the applied environmental concentrations (14.4 μg ae cm(-2)). With glyphosate-B toxic effects were observed at higher doses, close to its LC50, suggesting that the higher toxicity of formulate A could be attributed to the effects of some of the so-called "inert ingredients", either due to a direct intrinsic toxicity, or to an enhancement in the bioavailability and/or bioaccumulation of the active ingredient. Our results highlight the importance of ecotoxicological assessment not only of the active ingredients, but also of the different formulations usually employed in agricultural practices.


Regenerative Peripheral Nerve Interface Surgery: Anatomic and Technical Guide.
Regenerative peripheral nerve interface (RPNI) surgery has been demonstrated to be an effective tool as an interface for neuroprosthetics. Additionally, it has been shown to be a reproducible and reliable strategy for the active treatment and for prevention of neuromas. The purpose of this article is to provide a comprehensive review of RPNI surgery to demonstrate its simplicity and empower reconstructive surgeons to add this to their armamentarium. This article discusses the basic science of neuroma formation and prevention, as well as the theory of RPNI. An anatomic review and discussion of surgical technique for each level of amputation and considerations for other etiologies of traumatic neuromas are included. Lastly, the authors discuss the future of RPNI surgery and compare this with other active techniques for the treatment of neuromas.


How do women who choose not to participate in population-based cervical cancer screening reason about their decision?
In Stockholm, Sweden, women are invited to a cost-free population-based cervical cancer screening programme (PCCSP) at regular intervals. Despite this, many women choose not to attend screening at all or to take opportunistic tests instead. This study explores how women who actively declined participation in the PCCSP reasoned about their choice. Qualitative telephone interviews and fax messages from women who actively declined participation in the PCCSP were analysed inductively. The manner in which women defined and conceptualized distinctions between, and the roles and responsibilities of, both private and public spheres were found to be central in explanations of decision making. Factors related to women's decisions not to participate in screening at all include a lack of confidence in the benefits of screening, previous negative health care and preventive experiences, a belief in one's own ability to discern health changes or a belief that one was not at risk for cervical cancer, as well as a number of unconventional standpoints on social and political issues. Women who chose not to participate in the organized PCCSP, but who did use private opportunistic screening, generally motivated this with direct or indirect criticism of the screening programme itself. Not only was the examination itself sensitive but also all facets of the PCCSP, from invitation letter on, were found to influence women's decisions. Using Jepson et al.'s ethical framework to peruse the evidence-base underlying women's 'informed decision-making' about CCS is suggested to be more constructive than discussing potential participants' knowledge versus lack of knowledge.


Blockage of bacterial FimH prevents mucosal inflammation associated with Crohn's disease.
An Escherichia coli (E. coli) pathotype with invasive properties, first reported by Darfeuille-Michaud and termed adherent-invasive E. coli (AIEC), was shown to be prevalent in up to half the individuals with Crohn's Disease (CD), suggesting that these bacteria could be involved in the pathophysiology of CD. Among the genes related to AIEC pathogenicity, fim has the potential to generate an inflammatory reaction from the intestinal epithelial cells and macrophages, as it interacts with TLR4, inducing the production of inflammatory cytokines independently of LPS. Therefore, targeting the bacterial adhesion of FimH-expressing bacteria seems a promising therapeutic approach, consisting of disarming bacteria without killing them, representing a selective strategy to suppress a potentially critical trigger of intestinal inflammation, without disturbing the intestinal microbiota. We analyzed the metagenomic composition of the gut microbiome of 358 patients with CD from two different cohorts and characterized the presence of FimH-expressing bacteria. To assess the pathogenic role of FimH, we used human intestinal explants and tested a specific FimH blocker to prevent bacterial adhesion and associated inflammation. We observed a significant and disease activity-dependent enrichment of Enterobacteriaceae in the gut microbiome of patients with CD. Bacterial FimH expression was functionally confirmed in ileal biopsies from 65% of the patients with CD. Using human intestinal explants, we further show that FimH is essential for adhesion and to trigger inflammation. Finally, a specific FimH-blocker, TAK-018, inhibits bacterial adhesion to the intestinal epithelium and prevents inflammation, thus preserving mucosal integrity. We propose that TAK-018, which is safe and well tolerated in humans, is a promising candidate for the treatment of CD and in particular in preventing its recurrence. Video abstract.


Flexible and directional fibre optic ultrasound transmitters using photostable dyes.
All-optical ultrasound transducers are well-suited for use in imaging during minimally invasive surgical procedures. This requires highly miniaturised and flexible devices. Here we present optical ultrasound transmitters for imaging applications based on modified optical fibre distal tips which allow for larger transmitter element sizes, whilst maintaining small diameter proximal optical fibre. Three optical ultrasound transmitter configurations were compared; a 400 µm core optical fibre, a 200 µm core optical fibre with a 400 µm core optical fibre distal tip, and a 200 µm core optical fibre with a 400 µm core capillary distal tip. All the transmitters used a polydimethylsiloxane-dye composite material for ultrasound generation. The material comprised a photostable infra-red absorbing dye to provide optical absorption for the ultrasound transduction. The generated ultrasound beam profile for the three transmitters was compared, demonstrating similar results, with lateral beam widths <1.7 mm at a depth of 10 mm. The composite material demonstrates a promising alternative to previously reported materials, generating ultrasound pressures exceeding 2 MPa, with corresponding bandwidths ca. 30 MHz. These highly flexible ultrasound transmitters can be readily incorporated into medical devices with small lateral dimensions.