Unhealthy Phenotype as Indicated by Salivary Biomarkers: Glucose, Insulin, VEGF-A, and IL-12p70 in Obese Kuwaiti Adolescents.
Here, we investigated the relationships between obesity and the salivary concentrations of insulin, glucose, and 20 metabolic biomarkers in Kuwaiti adolescents. Previously, we have shown that certain salivary metabolic markers can act as surrogates for blood concentrations. Salivary samples of whole saliva were collected from 8,317 adolescents. Salivary glucose concentration was measured by a high-sensitivity glucose oxidase method implemented on a robotic chemical analyzer. The concentration of salivary insulin and 20 other metabolic biomarkers was assayed in 744 randomly selected saliva samples by multiplexed bead-based immunoassay. Obesity was seen in 26.5% of the adolescents. Salivary insulin predicting hyperinsulinemia occurred in 4.3% of normal-weight adolescents, 8.3% of overweight adolescents, and 25.7% of obese adolescents (p < 0.0001). Salivary glucose predicting hyperglycemia was found in only 3% of obese children and was not predictive (p = 0.89). Elevated salivary glucose and insulin occurring together was associated with elevated vascular endothelial growth factor and reduced salivary interleukin-12. Considering the surrogate nature of salivary insulin and glucose, this study suggests that elevated insulin may be a dominant sign of metabolic disease in adolescent populations. It also appears that a proangiogenic environment may accompany elevated glucose in obese adolescents.


Expression optimization and synthetic gene networks in cell-free systems.
Synthetic biology offers great promise to a variety of applications through the forward engineering of biological function. Most efforts in this field have focused on employing living cells, yet cell-free approaches offer simpler and more flexible contexts. Here, we evaluate cell-free regulatory systems based on T7 promoter-driven expression by characterizing variants of TetR and LacI repressible T7 promoters in a cell-free context and examining sequence elements that determine expression efficiency. Using the resulting constructs, we then explore different approaches for composing regulatory systems, leading to the implementation of inducible negative feedback in Escherichia coli extracts and in the minimal PURE system, which consists of purified proteins necessary for transcription and translation. Despite the fact that negative feedback motifs are common and essential to many natural and engineered systems, this simple building block has not previously been implemented in a cell-free context. As a final step, we then demonstrate that the feedback systems developed using our cell-free approach can be implemented in live E. coli as well, illustrating the potential for using cell-free expression to fast track the development of live cell systems in synthetic biology. Our quantitative cell-free component characterizations and demonstration of negative feedback embody important steps on the path to harnessing biological function in a bottom-up fashion.


[Transient monocular vision loss].
Transient monocular vision loss (TMVL) caused by temporary disturbance of blood flow to the retina is a harbinger of future vascular complications. The diagnosis may be difficult, not only because it is solely dependent on history taking, but also because the range of monocular visual symptoms a patient may experience is wide. The classic pattern of a sudden black or grey visual field, or a curtain that is drooping in front of one eye, easily fits in the diagnosis of TMVL; however, coloured vision or flashes should not always be considered as benign. The distinction between visual symptoms of one or both eyes should receive attention during history taking. It is the professional expertise of the neurologist and ophthalmologist which should make it possible to establish the correct diagnosis. A patient suspected of a retinal TIA should be evaluated and treated with the same urgency as someone with a cerebral TIA.


Structure-activity of sulfones and sulfonamides on dihydropteroate synthetase from Neisseria meingitidis.
The molecular interaction of various sulfones and sulfonamides with partially purified dihydropteroate synthetase from Neisseria meningitidis M-166 has been examined. The mode of action of the sulfones was similar to that of the sulfonamides. Both groups of drugs were competitive inhibitors of dihydropteroate synthetase with respect to p-aminobenzoate in a partially purified enzyme preparation. 4,4'-Diaminodiphenylsulfone was three times more effective than sulfadiazine and nine times more effective than sulfanilamide as a competitive inhibitor of dihydropteroate synthetase. The inhibitory activity of 4-amino-4'-acetamidodiphenylsulfone and 4-amino-4'-formamidodiphenylsulfone in this system eliminated their prior conversion to 4,4'-diaminodiphenylsulfone as a requirement for activity.


Snakebite in domestic animals: First global scoping review.
Snakebite is a Neglected Tropical Disease estimated to cause more than 100,000 human deaths and disable more than 400,000 victims each year. It primarily affects poor agricultural workers, farmers, and cattle herders living in rural areas of developing countries. It is thus an occupational disease. However, the impact of snakebite on these rural communities could be even higher if a One Health approach is taken to consider the direct impact on domestic animals and indirect impact on the livelihood of affected communities. To explore this hypothesis we developed the first scoping review to identify and characterize the global literature on snakebite in domestic animals. Three bibliographic databases (PubMed, Web of Science and Agricola) were searched using terms related to snake, snakebite and domestic animals for publications up to December 31st, 2016. Two independent reviewers screened publications applying inclusion/exclusion criteria to select relevant material. Relevant information was then extracted from the selected literature. The global literature on snakebite in domestic animals (n = 143 observational studies, reviews and letters) mainly represented North America, Europe and Australia (69%) with less information from Central and South America, Asia and Africa (31%). Observational studies (n = 119) mostly concerned pets (78%) and to a lesser extent livestock (22%). Thirty-four snake species were reported as responsible for bites in domestic animals. WHO's Medically Important Venomous Snakes were more frequently involved. The social-ecological determinants of snakebite were poorly documented but the reviewed literature suggested a strong seasonality and a diversity of habitat. Snakebite in animals caused neurotoxic, cytotoxic and hemotoxic envenomation syndromes similar to humans and death. Half of publications on envenomed livestock reported a fatality rate above 47%. There was no literature on the indirect impact of snakebite on livelihood caused by animal morbidity and mortality. The results of this scoping review suggest a high and under-reported burden in terms of mortality in animals and a potential economic impact of snakebite in terms of losses in livelihood of affected communities. However, major knowledge gaps with respect to impact of snakebite on livestock and livelihood were identified. Filling these gaps is necessary for a full understanding of the impact of snakebite and to raise scientific, political and public awareness on this neglected issue.


Motion induced phase shifts in MR: acceleration effects in quantitative flow measurements--a reconsideration.
Magnetic resonance phase difference techniques are commonly used to study flow velocities in the human body. Acceleration is often present, either in the form of pulsatile flow, or in the form of convective acceleration. Questions have arisen about the exact time point at which the velocity is encoded, and also about the sensitivity to (convective) acceleration and higher order motion derivatives. It has become common practice to interpret the net phase shifts measured with a phase difference velocity technique as being the velocity at a certain (Taylor) expansion time point, chosen somewhere between the RF excitation and the echo readout. However, phase shifts are developed over the duration of the encoding magnetic field gradient wave form, and should therefore be interpreted as a more or less time-averaged velocity. It will be shown that the phase shift as measured with a phase difference velocity technique represents the velocity at the "gravity" center of the encoding bipolar gradient (difference) function, without acceleration contribution. Any attempt to interpret the measured phase shift in terms of velocity on any other time point than the gradient gravity point will automatically introduce acceleration sensitivity.


Impact of Race and Socioeconomic Status on Psychologic Outcomes in Childhood Cancer Patients and Caregivers.
Complex relationships between race and socioeconomic status have a poorly understood influence on psychologic outcomes in pediatric oncology. The Family Symptom Inventory was used to assess symptoms of depression and anxiety in pediatric patients with cancer and their caregivers. Separate hierarchical linear regression models examined the relationship between demographic variables, cancer characteristics, socioeconomic status, and access to care and patient or caregiver depression/anxiety. Participants included 196 pediatric patients with cancer (mean age, 11.21 y; 49% African American) and their caregivers. On average, caregivers reported low levels of depression/anxiety. Symptoms of depression and anxiety in patients were correlated with poorer mental health in caregivers (r=0.62; P<0.01). Self-reported financial difficulty (β=0.49; P<0.001) and brain cancer diagnosis for their child (β=0.42; P=0.008) were significantly associated with depression and anxiety in caregivers. Analysis did not reveal significant associations between race, household income, or access to care and patient or caregiver depression/anxiety. Perception of financial hardship can adversely impact mental health in caregivers of children with cancer. Psychosocial assessment and interventions may be especially important for caregivers of patients with brain tumors and caregivers who report feeling financial difficulty.


Characterization of Neutral Radicals from a Dissociative Electron Attachment Process.
Despite decades of gas-phase studies on dissociative electron attachment (DEA) to various molecules, as yet there has been no direct detection and characterization of the neutral radical species produced by this process. In this study, we performed stepwise electron spectroscopy to directly measure and characterize the neutrals produced upon zero-electron-energy DEA to the model molecule, carbon tetrachloride (CCl_{4}). We observed the direct yield of the trichloromethyl radical (CCl_{3}^{·}) formed by DEA to CCl_{4} and measured the appearance energies of all the other neutral species. By combining these experimental findings with high-level quantum chemical calculations, we performed a complete analysis of both the DEA to CCl_{4} and the subsequent electron-impact ionization of CCl_{3}^{·}. This work paves the way toward a complete experimental characterization of DEA processes, which will lead to a better understanding of the low-energy electron-induced formation of radical species.


Impact of epidemic cholera in a previously uninfected island population: evaluation of a new seroepidemiologic method.
During an investigation of a 1982 cholera outbreak in Truk, an area without endemic cholera, 254 post-outbreak serum specimens were collected from ill and well inhabitants of a single island. These were compared with 57 specimens collected in Truk in 1964, when heat-labile toxin-producing enterotoxigenic Escherichia coli was presumably endemic but cholera did not exist. The serum was tested for vibriocidal antibody and antitoxic antibodies to cholera toxin and heat-labile toxin and the ratio of the anti-cholera antitoxin to the anti-heat-labile antitoxin was calculated. The prevalences of elevated anti-cholera antitoxin and anti-heat-labile antitoxin levels were similar in both years: an elevated anti-cholera antitoxin was found in 30% of the 1964 and 80% of the 1982 specimens, while an elevated anti-heat-labile antitoxin was found in 40% (1964) and 84% (1982). In contrast, vibriocidal antibody titers were elevated in none of the 1964 but in 64% of the 1982 specimens, and the anti-cholera/anti-heat-labile antitoxin ratio was elevated in 4% (1964) and 42% (1982). The anti-cholera/anti-heat-labile antitoxin ratio appears to differentiate the antitoxic responses to Vibrio cholerae O1 and heat-labile toxin-producing enterotoxigenic E. coli, even in areas where both are prevalent, and should serve as a useful seroepidemiologic tool.


Improved characterization of visual evoked potentials in multiple sclerosis by topographic analysis.
In multiple sclerosis (MS), the combination of visual, somatosensory and motor evoked potentials (EP) has been shown to be highly correlated with the Expanded Disability Severity Scale (EDSS) and to predict the disease course. In the present study, we explored whether the significance of the visual EP (VEP) can be improved with multichannel recordings (204 electrodes) and topographic analysis (tVEP). VEPs were analyzed in 83 MS patients (median EDSS 2.0; 52 % with history of optic neuritis; hON) and 47 healthy controls (HC). TVEP components were automatically defined on the basis of spatial similarity between the scalp potential fields (topographic maps) of single subjects' VEPs and reference maps generated from HC. Non-ambiguous measures of latency, amplitude and configuration were derived from the maps reflecting the P100 component. TVEP was compared to conventional analysis (cVEP) with respect to reliability in HC, validity using descriptors of logistic regression models, and sensitivity derived from receiver operating characteristics curves. In tVEP, reliability tended to be higher for measurement of amplitude (p = 0.06). Regression models on diagnosis (MS vs. HC) and hON were more favorable using tVEP- versus cVEP-predictors. Sensitivity was increased in tVEP versus cVEP: 72 % versus 60 % for diagnosis, and 88 % versus 77 % for hON. The advantage of tVEP was most pronounced in pathological VEPs, in which cVEPs were often ambiguous. TVEP is a reliable, valid, and sensitive method of objectively quantifying pathological VEP in particular. In combination with other EP modalities, tVEP may improve the monitoring of disease course in MS.


Perspective on Improving the Relevance, Rigor, and Reproducibility of Botanical Clinical Trials: Lessons Learned From Turmeric Trials.
Plant-derived compounds, without doubt, can have significant medicinal effects since many notable drugs in use today, such as morphine or taxol, were first isolated from botanical sources. When an isolated and purified phytochemical is developed as a pharmaceutical, the uniformity and appropriate use of the product are well defined. Less clear are the benefits and best use of plant-based dietary supplements or other formulations since these products, unlike traditional drugs, are chemically complex and variable in composition, even if derived from a single plant source. This perspective will summarize key points-including the premise of ethnobotanical and preclinical evidence, pharmacokinetics, metabolism, and safety-inherent and unique to the study of botanical dietary supplements to be considered when planning or evaluating botanical clinical trials. Market forces and regulatory frameworks also affect clinical trial design since in the United States, for example, botanical dietary supplements cannot be marketed for disease treatment and submission of information on safety or efficacy is not required. Specific challenges are thus readily apparent both for consumers comparing available products for purchase, as well as for commercially sponsored vs. independent researchers planning clinical trials to evaluate medicinal effects of botanicals. Turmeric dietary supplements, a top selling botanical in the United States and focus of over 400 clinical trials to date, will be used throughout to illustrate both the promise and pitfalls associated with the clinical evaluation of botanicals.


Automated Detection and Quantification of Circadian Eye Blinks Using a Contact Lens Sensor.
To detect and quantify eye blinks during 24-hour intraocular pressure (IOP) monitoring with a contact lens sensor (CLS). A total of 249 recordings of 24-hour IOP patterns from 202 participants using a CLS were included. Software was developed to automatically detect eye blinks, and wake and sleep periods. The blink detection method was based on detection of CLS signal peaks greater than a threshold proportional to the signal amplitude. Three methods for automated detection of the sleep and wake periods were evaluated. These relied on blink detection and subsequent comparison of the local signal amplitude with a threshold proportional to the mean signal amplitude. These methods were compared to manual sleep/wake verification. In a pilot, simultaneous video recording of 10 subjects was performed to compare the software to observer-measured blink rates. Mean (SD) age of participants was 57.4 ± 16.5 years (males, 49.5%). There was excellent agreement between software-detected number of blinks and visually measured blinks for both observers (intraclass correlation coefficient [ICC], 0.97 for observer 1; ICC, 0.98 for observer 2). The CLS measured a mean blink frequency of 29.8 ± 15.4 blinks/min, a blink duration of 0.26 ± 0.21 seconds and an interblink interval of 1.91 ± 2.03 seconds. The best method for identifying sleep periods had an accuracy of 95.2 ± 0.5%. Automated analysis of CLS 24-hour IOP recordings can accurately quantify eye blinks, and identify sleep and wake periods. This study sheds new light on the potential importance of eye blinks in glaucoma and may contribute to improved understanding of circadian IOP characteristics.


Long-term adjustment in burn victims: a matched-control study.
To date, there is little information about how severely burned patients compare to unburned healthy individuals in terms of psychological profile and quality of life. As part of a larger study on the sensory consequences of burns, we assessed psychological functioning and quality of life in burned patients and unburned healthy control subjects. We also examined whether burn patients experiencing pain and/or paresthetic sensations (i.e. symptomatic patients) present a profile that is different from those who are asymptomatic. Forty-nine burned patients (% total body surface area = 34 59 % +/- 13.40; 82% males/18% females) were evaluated 63 59 +/- 28.1 months post-burn. They were matched with 49 unburned healthy volunteers on age, sex, and education level. All subjects were administered the Symptom Checklist 90-Revised (SCL-90-R) to assess psychological functioning and the 36-item Short-Form Health Survey (SF-36) to assess quality of life. Approximately 25% of the burn patients presented clinically-significant psychological disturbances compared to 12% in the control group. Burn patients enjoyed a quality of life comparable to that of the control subjects, although they perceived some deterioration in their general health. More symptomatic than asymptomatic patients suffered from clinically-relevant somatization and obsessive-compulsive disturbances. Severely burned patients adjust relatively well, although some develop clinically-significant psychological disturbances such as somatization and phobic anxiety. Burn patients experiencing abnormal sensations in their healed wounds (i.e. symptomatic patients) do not suffer from maladjustment to a greater extent than their asymptomatic counterparts, although more symptomatic patients experience somatization and obsessive-compulsive behaviours.


Alterations of glucose transporter systems in insulin-resistant uremic rats.
To further define the cellular alteration(s) involved in the impaired glucose transport associated with chronic uremia, we examined the concentration and translocation of glucose transport systems in adipocytes isolated from partially nephrectomized uremic rats. Uremic animals, compared with matched controls, had increased blood urea nitrogen and serum insulin, whereas serum glucose was unchanged. In agreement with previous work, 125I-insulin binding to its receptor was unaltered and transport of 2-deoxy-D-glucose was decreased in both the absence (basal) and presence of a maximal (7 nM) insulin concentration by 44 and 35%, respectively. To assess the movement and concentration of glucose transport systems in various membrane fractions prepared from basal and insulin-treated (20 nM) uremic fat cells, the technique of D-glucose-inhibitable cytochalasin B binding was utilized. In plasma membranes isolated from these cells the concentration of glucose transporters was decreased by 16 (P less than 0.01) and 30% (P less than 0.005) in basal and insulin-treated cells, respectively. Concomitantly, microsomal membranes prepared from uremic cells treated in the absence and presence of insulin had a 28 (P less than 0.01) and 15% (P less than 0.05) decrease in concentration of glucose transport systems, respectively. Additionally, glucose transporter concentration was significantly decreased by 17% (P less than 0.025) in total membranes prepared from uremic cells. Thus, impairment of glucose transport in uremic fat cells can be attributed to a postbinding defect that, at least in part, results from a decrease in the total concentration of glucose transporters.(ABSTRACT TRUNCATED AT 250 WORDS)


Sustained Activity of Hippocampal Parvalbumin-Expressing Interneurons Supports Trace Eyeblink Conditioning in Mice.
Although recent studies have revealed an involvement of hippocampal interneurons in learning the association among time-separated events, its underlying cellular mechanisms remained not fully clarified. Here, we combined multichannel recording and optogenetics to elucidate how the hippocampal parvalbumin-expressing interneurons (PV-INs) support associative learning. To address this issue, we trained the mice (both sexes) to learn hippocampus-dependent trace eyeblink conditioning (tEBC) in which they associated a light flash conditioned stimulus (CS) with a corneal air puff unconditioned stimuli (US) separated by a 250 ms time interval. We found that the hippocampal PV-INs exhibited learning-associated sustained activity at the early stage of tEBC acquisition. Moreover, the PV-IN sustained activity was positively correlated with the occurrence of conditioned eyeblink responses at the early learning stage. Suppression of the PV-IN sustained activity impaired the acquisition of tEBC, whereas the PV-IN activity suppression had no effect on the acquisition of delay eyeblink conditioning, a hippocampus-independent learning task. Learning-associated augmentation in the excitatory pyramidal cell-to-PVIN drive may contribute to the formation of PV-IN sustained activity. Suppression of the PV-IN sustained activity disrupted hippocampal gamma but not theta band oscillation during the CS-US interval period. Gamma frequency (40 Hz) activation of the PV-INs during the CS-US interval period facilitated the acquisition of tEBC. Our current findings highlight the involvement of hippocampal PV-INs in tEBC acquisition and reveal insights into the PV-IN activity kinetics which are of key importance for the hippocampal involvement in associative learning.SIGNIFICANCE STATEMENT The cellular mechanisms underlying associative learning have not been fully clarified. Previous studies focused on the involvement of hippocampal pyramidal cells in associative learning, whereas the activity and function of hippocampal interneurons were largely neglected. We herein demonstrated the hippocampal PV-INs exhibited learning-associated sustained activity, which was required for the acquisition of tEBC. Furthermore, we showed evidence that the PV-IN sustained activity might have arisen from the learning-associated augmentation in excitatory pyramidal cell-to-PVIN drive and contributed to learning-associated augmentation in gamma band oscillation during tEBC acquisition. Our findings provide more mechanistic understanding of the cellular mechanisms underlying the hippocampal involvement in associative learning.


Salt fingers observed in the mediterranean outflow.
Salt fingers, convection cells which constitute a possible mixing mechanism of the ocean, have now been observed in the Mediterranean outflow. The fingers, 6 millimeters in diamneter and 24 centimeters long, were photographed below the salinity maximum of the outflow, in an interface 22 centimeters thick where temperature and salinity decreased O. 15 degrees C and 0.03 per mil, respectively.


A Geometric Tension Dynamics Model of Epithelial Convergent Extension.
Epithelial tissue elongation by convergent extension is a key motif of animal morphogenesis. On a coarse scale, cell motion resembles laminar fluid flow; yet in contrast to a fluid, epithelial cells adhere to each other and maintain the tissue layer under actively generated internal tension. To resolve this apparent paradox, we formulate a model in which tissue flow occurs through adiabatic remodelling of the cellular force balance causing local cell rearrangement. We propose that the gradual shifting of the force balance is caused by positive feedback on myosin-generated cytoskeletal tension. Shifting force balance within a tension network causes active T1s oriented by the global anisotropy of tension. Rigidity of cells against shape changes converts the oriented internal rearrangements into net tissue deformation. Strikingly, we find that the total amount of tissue extension depends on the initial magnitude of anisotropy and on cellular packing order. T1s degrade this order so that tissue flow is self-limiting. We explain these findings by showing that coordination of T1s depends on coherence in local tension configurations, quantified by a certain order parameter in tension space. Our model reproduces the salient tissue- and cell-scale features of germ band elongation during Drosophila gastrulation, in particular the slowdown of tissue flow after approximately twofold extension concomitant with a loss of order in tension configurations. This suggests local cell geometry contains morphogenetic information and yields predictions testable in future experiments. Furthermore, our focus on defining biologically controlled active tension dynamics on the manifold of force-balanced states may provide a general approach to the description of morphogenetic flow.


Synthesis, Characterization and Biological Properties of Type I Collagen-Chitosan Mixed Hydrogels: A Review.
Type I collagen and chitosan are two of the main biological macromolecules used to design scaffolds for tissue engineering. The former has the benefits of being biocompatible and provides biochemical cues for cell adhesion, proliferation and differentiation. However, collagen hydrogels usually exhibit poor mechanical properties and are difficult to functionalize. Chitosan is also often biocompatible, but is much more versatile in terms of structure and chemistry. Although it does have important biological properties, it is not a good substrate for mammalian cells. Combining of these two biomacromolecules is therefore a strategy of choice for the preparation of interesting biomaterials. The aim of this review is to describe the different protocols available to prepare Type I collagen-chitosan hydrogels for the purpose of presenting their physical and chemical properties and highlighting the benefits of mixed hydrogels over single-macromolecule ones. A critical discussion of the literature is provided to point out the poor understanding of chitosan-type I collagen interactions, in particular due to the lack of systematic studies addressing the effect of chitosan characteristics.


Characterization of an AA9 LPMO from Thielavia australiensis, TausLPMO9B, under industrially relevant lignocellulose saccharification conditions.
The discovery of lytic polysaccharide monooxygenases (LPMO) has changed our perspective on enzymatic degradation of plant biomass. Through an oxidative mechanism, these enzymes are able to cleave and depolymerize various polysaccharides, acting not only on crystalline substrates such as chitin and cellulose, but also on other polysaccharides, such as xyloglucan, glucomannan and starch. Despite their widespread use, uncertainties related to substrate specificity and stereospecificity, the nature of the co-substrate, in-process stability, and the nature of the optimal reductant challenge their exploitation in biomass processing applications. In this work, we studied the properties of a novel fungal LPMO from the thermophilic fungus Thielavia australiensis, TausLPMO9B. Heterologous expression of TausLPMO9B in Aspergillus niger yielded a glycosylated protein with a methylated N-terminal histidine showing LPMO activity. High sequence identity of the AA9 domain to that of MtLPMO9B (MYCTH_80312) from Myceliophthora thermophila (84%) indicated strictly C1-oxidizing activity on cellulose, which was confirmed experimentally by the analysis of products released from cellulose using HPAEC. The enzyme was stable and active at a pH ranging from 4 to 6, thus matching the conditions commonly used in industrial biomass processing, where a low pH (between 4 and 5) is used due to the pH-optima of commercial cellulases and a desire to limit microbial contamination. While the oxidative cleavage of phosphoric acid swollen cellulose (PASC) by TausLPMO9B was boosted by the addition of H2O2 as a co-substrate, this effect was not observed during the saccharification of acid pretreated corn stover. This illustrates key differences between the lab-scale tests with artificial, lignin-free substrates and industrial settings with lignocellulosic biomass as substrate.


Finite element analysis of hard and soft tissue contributions to thoracic response: sensitivity analysis of fluctuations in boundary conditions.
Thoracic trauma is the principle causative factor in 30% of road traffic deaths. Researchers have developed force-deflection corridors of the thorax for various loading conditions in order to elucidate injury mechanisms and to validate the mechanical response of ATDs and numerical human models. A corridor, rather than a single response characteristic, results from the variability inherent in biological experimentation. This response variability is caused by both intrinsic and extrinsic factors. The intrinsic factors are associated with individual differences among human subjects, e.g. the differences in material properties and in body geometry. The extrinsic sources of variability include fluctuations in the loading and supporting conditions in experimental tests. Recent studies have considered the intrinsic factors, especially the material-level response of the rib, which can be modified over a limited range within, e.g. a finite element (FE) model in order to fit a gross overall thoracic response corridor. Studies typically do not, however, consider uncertainty due to extrinsic factors. The purpose of this work was to estimate the contribution of selected extrinsic factors to the uncertainty in a response corridor by using a thorax FE model. The sensitivity of twelve response corridors to the relative positioning of the thorax, the loader and the test fixture was analyzed. Reasonable ranges of experimental uncertainty were established for loader angle, loader location, and thorax orientation, and response variability was analyzed for three tissue states (intact, denuded, and eviscerated) with four different loaders (hub, distributed belt, single diagonal belt, and double diagonal belts). Of the variables considered here, the thorax orientation has the largest effect on the force-deflection response, which increases and decreases the effective stiffness up to 20%. The simulation work isolated the extrinsic contribution from the corridor and indicated model deficiencies and refinements, which have the potential to improve model accuracy, particularly modeling the soft tissues and the costal cartilage.


Isolation of synthetic lethal mutants of ras1 in Schizosaccharomyces pombe.
Ras proteins are membrane-associated guanine nucleotide-binding proteins that serve as molecular switches for signal transduction pathways in a diverse array of organisms. Various cellular factors are known to interact with Ras proteins. In order to find the novel cellular factors that are associated with Ras function, we have constructed synthetic lethal mutants of the ras1+ gene in Schizosaccharomyces pombe and used them to identify the genes that are functionally dependent on the Ras1. We first constructed S. pombe strains in which chromosomal ras1+ gene is placed under the nmt1 promoter that is regulated by thiamine. This strain shows ras1+ phenotype in the absence of thiamine, whereas it shows ras1- phenotype in the presence of thiamine. Second, we mutated the constructed strains with ultraviolet light (UV) and selected two synthetic lethal mutants that could not grow when Ras1 function was repressed (ras1-). One of the mutants, KSC3, showed a swollen cell shape, aberrant deposition of septum materials, and aberrant nuclei. The other mutant, KSC4, showed sensitivity to hyper-osmolarity when Ras1 function is absent. These mutants, however, grow normally when Ras1 is expressed (ras1+). These two novel synthetic lethal mutants of ras1 provide the means to isolate the corresponding genes that function in association with Ras1 in S. pombe. Screening of a genomic library of S. pombe complementing the mutant phenotype allowed us to identify several novel genes associated with Ras1 of S. pombe.


Activate to eradicate: inhibition of Clostridium difficile spore outgrowth by the synergistic effects of osmotic activation and nisin.
Germination is the irreversible loss of spore-specific properties prior to outgrowth. Because germinating spores become more susceptible to killing by stressors, induction of germination has been proposed as a spore control strategy. However, this strategy is limited by superdormant spores that remain unaffected by germinants. Harsh chemicals and heat activation are effective for stimulating germination of superdormant spores but are impractical for use in a hospital setting, where Clostridium difficile spores present a challenge. Here, we tested whether osmotic activation solutes will provide a mild alternative for stimulation of superdormant C. difficile spores in the presence of germinants as previously demonstrated in several species of Bacillus. In addition, we tested the hypothesis that the limitations of superdormancy can be circumvented with a combined approach using nisin, a FDA-approved safe bacteriocin, to inhibit outgrowth of germinated spores and osmotic activation solutes to enhance outgrowth inhibition by stimulating superdormant spores. Exposure to germination solution triggered ~1 log(10) colony forming units (CFU) of spores to germinate, and heat activation increased the spores that germinated to >2.5 log(10)CFU. Germinating spores, in contrast to dormant spores, became susceptible to inhibition by nisin. The presence of osmotic activation solutes did not stimulate germination of superdormant C. difficile spores exposed to germination solution. But, in the absence of germination solution, osmotic activation solutes enhanced nisin inhibition of superdormant spores to >3.5 log(10)CFU. The synergistic effects of osmotic activation solutes and nisin were associated with loss of membrane integrity. These findings suggest that the synergistic effects of osmotic activation and nisin bypass the limitations of germination as a spore control strategy, and might be a novel method to safely and effectively reduce the burden of C.difficile spores on skin and environmental surfaces.


Healing rate calculation in the diabetic foot ulcer: comparing different methods.
The determination of healing rate in the diabetic foot wound is an important assessment parameter that is part of the overall clinical decision-making process in wound treatment. A number of methods that have been used to calculate healing, ranging from length and width measurement, surface area measure changes expressed as a function of time and linear advancement of the wound edge. The objective of this study was to compare surface area measures to linear advancement of the wound edge in 228 diabetic foot ulcers. Each wound was measured using the two methods and analyzed using linear regression to determine the best modeling of the healing process in these wounds. Results indicated that the total surface area change per day was superior to the linear advancement parameter in this group of wounds and that the area measurement was significantly more likely to predict the healing trajectory in the subgroup of wounds that took more than 28 days to heal. Contrary to expectations, the linear advancement method was correlated to initial wound size in the longer duration wounds suggesting that in these chronic wounds, differing healing phases render the surface area calculation method superior to the linear advancement parameter.


Palmitic Acid-Enriched Diet Increases α-Synuclein and Tyrosine Hydroxylase Expression Levels in the Mouse Brain.
Background: Accumulation of the α-synuclein (α-syn) protein and depletion of dopaminergic neurons in the substantia nigra are hallmarks of Parkinson's disease (PD). Currently, α-syn is under scrutiny as a potential pathogenic factor that may contribute to dopaminergic neuronal death in PD. However, there is a significant gap in our knowledge on what causes α-syn to accumulate and dopaminergic neurons to die. It is now strongly suggested that the nature of our dietary intake influences both epigenetic changes and disease-related genes and may thus potentially increase or reduce our risk of developing PD. Objective: In this study, we determined the extent to which a 3 month diet enriched in the saturated free fatty acid palmitate (PA) influences levels of α-syn and tyrosine hydroxylase, the rate limiting enzyme in dopamine synthesis in mice brains. Methods: We fed the m-Thy1-αSyn (m-Thy1) mouse model for PD and its matched control, the B6D2F1/J (B6D2) mouse a PA-enriched diet or a normal diet for 3 months. Levels of α-syn, tyrosine hydroxylase, and the biogenic amines dopamine and dopamine metabolites, serotonin and noradrenaline were determined. Results: We found that the PA-enriched diet induces an increase in α-syn and TH protein and mRNA expression levels in m-Thy1 transgenic mice. We also show that, while it didn't affect levels of biogenic amine content in the B6D2 mice, the PA-enriched diet significantly reduces dopamine metabolites and increases the level of serotonin in m-Thy1 mice. Conclusion: Altogether, our results demonstrate that a diet rich in the saturated fatty acid palmitate can modulate levels of α-syn, TH, dopamine, and serotonin which all are proteins and neurochemicals that play key roles in increasing or reducing the risk for many neurodegenerative diseases including PD.


Tuning Gaps and Schottky Contacts of Graphene/Phosphorene Heterostructures by Vertical Electric Field and Strain.
We present a comprehensive study of the structural and electronic properties of a graphene/phosphorene (G/P) heterostructure in the framework of density functional theory, including van der Waals interaction in the exchange-correlation functional. While the G(4 × 1)/P(3 × 1) superlattice usually used in the literature is subject to a strain as high as about 7%, the in-plane strain could be drastically reduced to under 1% in the G(4 × 13)/P(3 × 12) heterostructure investigated here. Adapting the lattice constants of the rectangular lattices, the equilibrium configuration in the xy plane of phosphorene relative to the graphene layer is optimized. This results in an equilibrium interlayer distance of 3.5 Å and a binding energy per carbon atom of 37 meV, confirming the presence of weak van der Waals interaction between the graphene and the phosphorene layers. The electronic properties of the heterostructure are evaluated under different values of interlayer distance, strain and applied vertical electric field. We demonstrate that G/P heterostructures form an n-type Schottky contact, which can be transformed into p-type under external perturbations. These findings, together with the possibility to control the gaps and barrier heights, suggest that G/P heterostructures are promising for novel applications in electronics and may open a new avenue for the realization of innovative optoelectronic devices.


Pilot study of diet and microbiota: interactive associations of fibers and polyphenols with human intestinal bacteria.
Several studies have addressed the use of dietary fibers in the modulation of intestinal microbiota; however, information about other highly correlated components in foods, such as polyphenols, is scarce. The aim of this work was to explore the association between the intake of fibers and polyphenols from a regular diet and fecal microbiota composition in 38 healthy adults. Food intake was recorded using an annual food frequency questionnaire (FFQ). Quantification of microbial populations in feces was performed by quantitative PCR. A negative association was found between the intake of pectins and flavanones from oranges and the levels of Blautia coccoides and Clostridium leptum. By contrast, white bread, providing hemicellulose and resistant starch, was directly associated with Lactobacillus. Because some effects on intestinal microbiota attributed to isolated fibers or polyphenols might be modified by other components present in the same food, future research should be focused on diet rather than individual compounds.


Xylem development and cell wall changes of soybean seedlings grown in space.
Plants growing in altered gravity conditions encounter changes in vascular development and cell wall deposition. The aim of this study was to investigate xylem anatomy and arrangement of cellulose microfibrils in vessel walls of different organs of soybean seedlings grown in Space. Seeds germinated and seedlings grew for 5 d in Space during the Foton-M2 mission. The environmental conditions, other than gravity, of the ground control repeated those experienced in orbit. The seedlings developed in space were compared with those of the control test on the basis of numerous anatomical and ultrastructural parameters such as number of veins, size and shape of vessel lumens, thickness of cell walls and deposition of cellulose microfibrils. Observations made with light, fluorescence and transmission electron microscopy, together with the quantification of the structural features through digital image analysis, showed that the alterations due to microgravity do not occur at the same level in the various organs of soybean seedlings. The modifications induced by microgravity or by the indirect effect of space-flight conditions, became conspicuous only in developing vessels at the ultrastructural level. The results suggested that the orientation of microfibrils and their assembly in developing vessels are perturbed by microgravity at the beginning of wall deposition, while they are still able to orient and arrange in thicker and ordered structures at later stages of secondary wall deposition. The process of proper cell-wall building, although not prevented, is perturbed in Space at the early stage of development. This would explain the almost unaltered anatomy of mature structures, accompanied by a slower growth observed in seedlings grown in Space than on Earth.


Actions of TNF and IFN-gamma on angiogenesis in vitro.
We have developed a model system for studying angiogenesis in which microvascular fragments and myofibroblasts (Mf) isolated from lipid tissues are grown in co-culture. We have found that Mf induce capillary formation by producing an endothelial cell growth factor and by secreting an extracellular matrix that causes endothelial cells to form a cordlike structure. This system appeared to be well suited for examining the effects of vasoactive substances such as the TNF and INF-gamma on capillary growth. TNF-alpha,beta, and IFN-gamma not only significantly inhibited capillary growth induced by Mf, but also blocked capillary development induced by fibroblast growth factors (FGF), well-known potent angiogenic factors. Recently, we have found that platelet-derived growth factor (PDGF) enhances in vitro capillary formation, probably at least in part by acting on Mf. Just as with FGF, capillary growth in the presence of PDGF was almost completely blocked by IFN-gamma. We examined the mode by which IFN-gamma inhibits angiogenesis and found that IFN-gamma inhibits both the proliferation of endothelial cells and collagen(s) synthesis by Mf. These actions of TNF or IFN-gamma could limit vascular formation in solid tumors.


[Effects of centella asiatica granule on the expression of TGF-β1 and related down-stream signals in rats with early diabetic nephropathy].
To investigate the effects of centella asiatica (CA) granule on the expression of transform growth factor-β1(TGF-β1) and related down-stream signals in rats with early diabetic nephropathy(DN) and to clarify the molecular mechanisms of CA molecular mechanism of on preventing and curing early diabetic kidney disease DN by studying the effects of centella asiatica on TGF-β1 expression and related down-stream signals. Sixty male SD rats were divided into control group(n=10) and DN model group(n=50). The model rats were made a right nephrectomy. One week later, diabetic nephropathy was induced by intraperitoneal injection of streptocozin(30 mg/kg) for three consecutive days. High blood glucose level of Tail vein (fasting glucose ≥ 16.7 mmol/L) and high urinary protein level(total protein level in DN group was more than twice higher than the control group) were measured to confirm early DN in rats. In the sham operation group, the right renal capsule was damaged and the corresponding amount of saline was injected. The model rats were administrated by the means of intragastric administration. The DN model group were divided into DN group, DN+fosinopril group(1.6 mg/kg·d), DN+high CA group(16.8 mg/kg·d), DN+medium CA group(11.2 mg/kg·d) and DN+low CA group(5.6 mg/kg·d), and each group was intragastric administration one time every morning last for 16 weeks. The expressions of mRNA and protein of TGF-β1, TβR1, TβR2, Smad2/3, Smad7 and the level of Smad2/3 phosphorylation were detected by using real time quantitative polymerase chain reaction and Western blot. The expressions of mRNA and protein of TGF-β1, TβR1, TβR2, Smad2/3 and the level of Smad2/3 phosphorylation were significantly increased, the expressions of mRNA and protein of Smad7 were dramatically decreased. The fosinopril and high dosage CA could reverse the effects of DN. CA plays an important role in preventing and curing DN through regulating the TGF-β1/Smad signaling pathways.


Novel Conjugated Quinazolinone-Based Hydroxamic Acids: Design, Synthesis and Biological Evaluation.
The target-based approach to drug discovery currently attracts a great deal of interest from medicinal chemists in anticancer drug discovery and development. Histone deacetylase (HDAC) inhibitors represent an extensive class of targeted anti-cancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as vorinostat and belinostat. This study aims at developing novel HDAC inhibitors bearing conjugated quinazolinone scaffolds with potential cytotoxicity against different cancer cell lines. A series of novel N-hydroxyheptanamides incorporating conjugated 6-hydroxy-2 methylquinazolin- 4(3H)-ones (15a-l) was designed, synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines, including HepG-2, MCF-7 and SKLu-1. Molecular simulations were finally performed to gain more insight into the structureactivity relationships. It was found that among novel conjugated quinazolinone-based hydroxamic acids synthesized, compounds 15a, 15c and 15f were the most potent, both in terms of HDAC inhibition and cytotoxicity. Especially, compound 15f displayed up to nearly 4-fold more potent than SAHA (vorinostat) in terms of cytotoxicity against MCF-7 cell line with IC50 value of 1.86 μM, and HDAC inhibition with IC50 value of 6.36 μM. Docking experiments on HDAC2 isozyme showed that these compounds bound to HDAC2 with binding affinities ranging from -10.08 to -14.93 kcal/mol compared to SAHA (-15.84 kcal/mol). It was also found in this research that most of the target compounds seemed to be more cytotoxic toward SKLu-1than MCF-7 and HepG-2. The resesrch results suggest that some hydroxamic acids could emerge for further evaluation and the results are well served as basics for further design of more potent HDAC inhibitors and antitumor agents.


Neurocognition: clinical and functional outcomes in schizophrenia.
Schizophrenia is characterized by significant heterogeneity in outcome. The last decades have witnessed a significant interest in identifying factors that can moderate or influence clinical and functional outcomes in people with schizophrenia. One factor of particular interest is neurocognition, as performance on various measures of cognitive abilities, such as memory, attention, and executive functions, have been consistently related to functional outcome and, to a lesser extent, clinical outcome. This review aims to provide an up-to-date description of recent studies examining the association between neurocognition and clinical and (or) functional outcomes. In the first section, studies examining neurocognitive performance in relation to clinical outcome are examined. When clinical outcome is defined dichotomously (for example, comparing remitted and nonremitted), verbal memory performance consistently exhibits a strong association with clinical status, with the poor outcome group showing the largest deficits. In the second section, studies exploring the relation between neurocognition and various dimensions of functional outcome are reviewed. These dimensions include independent living, social functioning, and vocational functioning, among others. Again, a strong link between neurocognitive deficits and impairments in several aspects of functioning clearly emerges from this review. Finally, several measurement issues are discussed that pertain to the need to standardize definitions of clinical and (or) functional outcomes, the importance of defining cognitive domains consistently across studies, and distinguishing between one's competence to perform tasks and what one actually does in everyday life. Addressing these measurement issues will be key to studies examining the development of effective interventions targeting neurocognitive functions and their impact on clinical and functional outcomes.


Saikosaponin a increases interleukin-10 expression and inhibits scar formation after sciatic nerve injury.
Nerve scarring after peripheral nerve injury can severely hamper nerve regeneration and functional recovery. Further, the anti-inflammatory cytokine, interleukin-10, can inhibit nerve scar formation. Saikosaponin a (SSa) is a monomer molecule extracted from the Chinese medicine, Bupleurum. SSa can exert anti-inflammatory effects in spinal cord injury and traumatic brain injury. However, it has not been shown whether SSa can play a role in peripheral nerve injury. In this study, rats were randomly assigned to three groups. In the sham group, the left sciatic nerve was directly sutured after exposure. In the sciatic nerve injury (SNI) + SSa and SNI groups, the left sciatic nerve was sutured and continuously injected daily with SSa (10 mg/kg) or an equivalent volume of saline for 7 days. Enzyme linked immunosorbent assay results demonstrated that at 7 days after injury, interleukin-10 level was considerably higher in the SNI + SSa group than in the SNI group. Masson staining and western blot assay demonstrated that at 8 weeks after injury, type I and III collagen content was lower and nerve scar formation was visibly less in the SNI + SSa group compared with the SNI group. Simultaneously, sciatic functional index and nerve conduction velocity were improved in the SNI + SSa group compared with the SNI group. These results confirm that SSa can increase the expression of the anti-inflammatory factor, interleukin-10, and reduce nerve scar formation to promote functional recovery of injured sciatic nerve.


Spectrum effects of subglottal pressure variation in professional baritone singers.
The audio signal from five professional baritones was analyzed by means of spectrum analysis. Each subject sang syllables [pae] and [pa] from loudest to softest phonation at fundamental frequencies representing 25%, 50%, and 75% of his total range. Ten subglottal pressures, equidistantly spaced between highest and lowest, were selected for analysis along with the corresponding production of the vowels. The levels of the first formant and singer's formant were measured as a function of subglottal pressure. Averaged across subjects, vowels, and F0, a 10-dB increase at 600 Hz was accompanied by a 16-dB increase at 3 kHz.


(MgO)(-)(n) (n = 1-5) clusters: multipole-bound anions and photodetachment spectroscopy.
Photoelectron spectra of (MgO)(-)(n) (n = 1-5) reveal a surprising trend: The electron binding energy decreases from n = 1 to 4, and then increases from 4 to 5. Ab initio calculations suggest this pattern is related to the electrostatic interaction between the extra electron and the charge distribution of the neutral cluster. This interaction is significant in MgO (-) and (MgO)-5, for which the lowest nonvanishing multipole moment (LNM) is a dipole; it is smaller for (MgO)-2 and (MgO)-3, for which a quadrupole is the LNM; and it is the smallest for (MgO)-4, for which an octopole is the LNM. The cubic (MgO)-4 is the first octopole-bound anion yet observed experimentally and characterized theoretically.


Air pollution from wildfires and human health vulnerability in Alaskan communities under climate change.
Alaskan wildfires are becoming more frequent and severe, but very little is known regarding exposure to wildfire smoke, a risk factor for respiratory and cardiovascular illnesses. We estimated long-term, present-day and future exposure to wildfire-related fine particulate matter (PM2.5) across Alaska for the general population and subpopulations to assess vulnerability using observed data for the present day (1997-2010), modelled estimates for the present day (1997-2001), and modelled estimates for the future (2047-2051). First, we assessed wildfire-PM2.5 exposure by estimating monthly-average wildfire-specific PM2.5 levels across 1997-2010 for 158 Alaskan census tracts, using atmospheric transport modelling based on observed area-burned data. Second, we estimated changes in future (2047-2051) wildfire-PM2.5 exposure compared to the present-day (1997-2001) by estimating the monthly-average wildfire-specific PM2.5 levels for 29 boroughs/census areas (county-equivalent areas), under the Intergovernmental Panel on Climate Change (IPCC) A1B scenario from an ensemble of 13 climate models. Subpopulation risks for present and future exposure levels were estimated by summing area-weighted exposure levels utilizing the 2000 Census and State of Alaska's population projections. We assessed vulnerability by several subpopulation characteristics (e.g. race/ethnicity, urbanicity). Wildfire-PM2.5 exposure levels during 1997-2010 were highest in interior Alaska during July. Among subpopulations, average summer (June-August) exposure levels for urban dwellers and African-American/Blacks were highest at 9.1 μg m-3 and 10 μg m-3, respectively. Estimated wildfire-PM2.5 varied by Native American tribe, ranging from average summer levels of 2.4 μg m-3 to 13 μg m-3 for Tlingit-Haida and Alaskan Athabascan tribes, respectively. Estimates indicate that by the mid-21st century, under climate change, almost all of Alaska could be exposed to increases of 100% or more in levels of wildfire-specific PM2.5 levels. Exposure to wildfire-PM2.5 likely presents a substantial public health burden in the present day for Alaska communities, with different impacts by subpopulation. Under climate change, wildfire smoke could pose an even greater public health risks for most Alaskans.


Synthesis of a DOTA-C-glyco bifunctional chelating agent and preliminary in vitro and in vivo study of [68Ga]Ga-DOTA-C-glyco-RGD.
The design of bifunctional chelating agents (BFCA) allowing straightforward radiometal labelling of biomolecules is a current challenge. We report herein the development of a bifunctional chelating agent based on a DOTA chelator linked to a C-glycosyl compound, taking advantage of the robustness and hydrophilicity of this type of carbohydrate derivative. This new BFCA was coupled with success by CuAAC with c(RGDfK) for αvβ3 integrin targeting. As attested by in vitro evaluation, the conjugate DOTA-C-glyco-c(RGDfC) demonstrated high affinity for αvβ3 integrins (IC50 of 42 nM). [68Ga]Ga-DOTA-C-glyco-c(RGDfK) was radiosynthesized straightforwardly and showed high hydrophilic property (log D 7.4 = -3.71) and in vitro stability (>120 min). Preliminary in vivo PET study of U87MG engrafted mice gave evidence of an interesting tumor-to-non-target area ratio. All these data indicate that [68Ga]Ga-DOTA-C-glyco-c(RGDfK) allows monitoring of αvβ3 expression and could thus be used for cancer diagnosis. The DOTA-C-glycoside BFCA reported here could also be used with various ligands and chelating other (radio)metals opening a broad scope of applications in imaging modalities and therapy.


Effects of older age and multiple comorbidities on functional outcome after partial hip replacement surgery for hip fractures.
To assess clinical factors associated with partial hip replacement surgery failure and to develop a scoring system to predict it before treatment. This was a historical cohort study of hip fracture cases underwent partial hip replacement in Siaga Raya Hospital, Jakarta between January 1997 and December 2006. Patients' clinical assessment included sex, age at surgery, ambulatory state, the number of underlying disease or comorbidities, hemoglobin and serum albumin levels, type of fracture and elapsed time between the day of fracture and day of surgery. All patients underwent partial hip surgery. Functional outcome after surgery was assessed by Harris' Hip Score (HHS). A score below 80 points was considered poor. Kaplan-Meier curve with log-rank test was deployed and Cox proportional hazard model was performed to identify independent risk factors associated with poor HHS after surgery. Harris hip score could be obtained from 123 patients during the study period. The patients' mean age at surgery was 73+/-9.8 years old. Cox regression analysis showed several risk factors for poor HHS after partial hip replacement procedures, i.e. age at surgery 75 years or more, the presence of two or more comorbidities, anemia and Low albumin. In adjusted model, the number of comorbidities, anemia and Low albumin were confirmed to be independent risk factors for poor HHS after surgery. Our present study showed that several clinical factors could be used to predict poor Harris hip score after partial hip replacement surgery. Independent risk factors were the number of comorbidities, the presence of anemia and low albumin. Further studies are needed to confirm the prediction model in new, prospective cases.


Natural Killer Cell Reduction and Uteroplacental Vasculopathy.
Uterine natural killer cells are important for uteroplacental development and pregnancy maintenance. Their role in pregnancy disorders, such as preeclampsia, is unknown. We reduced the number of natural killer cells by administering rabbit anti-asialo GM1 antiserum in an established rat preeclamptic model (female human angiotensinogen×male human renin) and evaluated the effects at the end of pregnancy (day 21), compared with preeclamptic control rats receiving normal rabbit serum. In 100% of the antiserum-treated, preeclamptic rats (7/7), we observed highly degenerated vessel cross sections in the mesometrial triangle at the end of pregnancy. This maternal uterine vasculopathy was characterized by a total absence of nucleated/living cells in the vessel wall and perivascularly and prominent presence of fibrosis. Furthermore, there were no endovascular trophoblast cells within the vessel lumen. In the control, normal rabbit serum-treated, preeclamptic rats, only 20% (1/5) of the animals displayed such vasculopathy. We confirmed the results in healthy pregnant wild-type rats: after anti-asialo GM1 treatment, 67% of maternal rats displayed vasculopathy at the end of pregnancy compared with 0% in rabbit serum-treated control rats. This vasculopathy was associated with a significantly lower fetal weight in wild-type rats and deterioration of fetal brain/liver weight ratio in preeclamptic rats. Anti-asialo GM1 application had no influence on maternal hypertension and albuminuria during pregnancy. Our results show a new role of natural killer cells during hypertensive pregnancy in maintaining vascular integrity. In normotensive pregnancy, this integrity seems important for fetal growth.


[Coronary Computed Tomography Angiography in Patients with Stable Coronary Artery Disease].
The guidelines on the management of stable coronary artery disease (SCAD) recommend the use of coronary computed tomography angiography (CTA) in the process of diagnosing coronary artery disease in patients with low intermediate pre-test probability for SCAD. Particularly in cases where stress electrocardiogram or stress imaging provides unclear results, a computed tomographic examination can be considered as a reliable alternative to invasive coronary angiography. Due to its high negative predictive value, coronary CTA can provide accurate information on the presence of coronary artery stenosis and thus coronary artery disease can be reliably excluded without the risks associated with invasive procedures. Similarly, patients with unstable angina or chest pain without typical alterations in the electrocardiogram and without an elevation of troponin can also benefit from a non-invasive coronary CTA-based diagnostics as first approach as it allows ruling out the presence of disease or planning an intervention without the risks associated with a potentially inappropriate invasive approach.


[Surgical treatment of habitual dislocation of the shoulder].
In the article is presented the analysis of treatment of 32 patients with shoulder joint instability. There have been studied the outcomes of treatment after the arm "suspension" operations, interventions at the anterior region of an articulation, derotational osteotomies of an arm. There have been considered the problems of etiopathogenesis of shoulder joint instability. There have been analyzed the peculiarities of the tactical approach to the treatment of patients with shoulder joint instability. There is presented the principled position of the authors' approach to the selection of pathogenetically substantiated method of the habitual shoulder slip operative treatment.


Bacterial Retrons Enable Precise Gene Editing in Human Cells.
Retrons are bacterial genetic elements involved in anti-phage defense. They have the unique ability to reverse transcribe RNA into multicopy single-stranded DNA (msDNA) that remains covalently linked to their template RNA. Retrons coupled with CRISPR-Cas9 in yeast have been shown to improve the efficiency of precise genome editing via homology-directed repair (HDR). In human cells, HDR editing efficiency has been limited by challenges associated with delivering extracellular donor DNA encoding the desired mutation. In this study, we tested the ability of retrons to produce msDNA as donor DNA and facilitate HDR by tethering msDNA to guide RNA in HEK293T and K562 cells. Through heterologous reconstitution of retrons from multiple bacterial species with the CRISPR-Cas9 system, we demonstrated HDR rates of up to 11.4%. Overall, our findings represent the first step in extending retron-based precise gene editing to human cells.


[Integration of the Principles of Palliative Care In Intensive Care Medicine].
Recent scientific literature has shown a growing interest to integrate palliative medicine principles into the daily workflow in the intensive care unit (ICU). This article reviews this trend with the goal that its application might provide more understanding in the resolution of some current ethical issues. Patients with an advanced disease process and at the end of life who are admitted in the intensive care unit are in such a profound level of suffering and vulnerability that only an holistic and comprehensive approach can provide adequate relief to them. Nevertheless, the reality of the clinical care of these patients in the ICU is far beyond that ideal. Our primary end point is the improvement in the clinical care provided, especially when the patient is dying. It is indeed very complex to make progress in this field, but an effort has to be made. The project is to turn to palliative medicine as a role model for end of life care and as an holistic approach, and introduce palliative medicine principles in the ICU. The goal of this article is to reveal a practical approach to accomplish this, and make it functional in order to improve our patients' clinical and ethical care.


Superior vena caval syndrome in primary mediastinal germ cell tumors.
Upon examination, nine of 45 patients (20%) with primary mediastinal germ cell tumors were found to have superior vena caval syndrome. All patients were men (average age, 27). Superior vena caval syndrome was found with all mediastinal germ cell tumor cell types except mature teratoma. Primary mediastinal germ cell tumors should be strongly considered in the diagnosis of young men with a mediastinal mass and superior vena caval syndrome.


Vaccination and the theory of games.
Voluntary vaccination policies for childhood diseases present parents with a subtle challenge: if a sufficient proportion of the population is already immune, either naturally or by vaccination, then even the slightest risk associated with vaccination will outweigh the risk from infection. As a result, individual self-interest might preclude complete eradication of a vaccine-preventable disease. We show that a formal game theoretical analysis of this problem leads to new insights that help to explain human decision-making with respect to vaccination. Increases in perceived vaccine risk will tend to induce larger declines in vaccine uptake for pathogens that cause more secondary infections (such as measles and pertussis). After a vaccine scare, even if perceived vaccine risk is greatly reduced, it will be relatively difficult to restore prescare vaccine coverage levels.


The effect of municipal wastewater effluent on nitrogen levels in Onondaga Lake, a 36-year record.
This work presents a retrospective analysis of long-term trends in loading of forms of nitrogen (N) from the Metropolitan Syracuse Wastewater Treatment Plant (Metro), N concentrations in the receiving urban lake (Onondaga Lake, New York), and related water quality status for the period from 1972 to 2007. The history of the evolution of treatment and discharge at Metro, as it affected N loading, is reviewed and forms the basis for identification of five regimes during which unifying conditions of loading and in-lake conditions prevailed. Changes in industrial waste inputs have complicated the effects of upgrades in treatment at Metro from primary (until 1978) to advanced (starting in 2004). Current N loading from Metro is approximately 35% lower than the peak levels observed in the late 1980s to late 1990s, but the areal rate to the lake remains extremely high (approximately 97 g/m(2).y), representing approximately 75% of the overall N load. Implementation of year-round nitrification treatment has resulted in transformation of the composition of the N load from Metro from ammonia (T-NH3) to nitrate (NO3(-)) dominance. High N concentrations have prevailed in the upper waters of the lake throughout the study period with averages of total N ranging from 2.6 to 4.3 mg/L for the five regimes. Total N levels and partitioning among the forms in the lake generally have tracked Metro loading conditions for the five regimes. The effects of Metro loading on seasonal in-lake patterns are demonstrated to be modified by both hydrologic inputs from tributaries and in-lake operation of biochemical processes. Resolution of these effects is supported by application of both empirical and dynamic mass balance models. Water quality problems related to high concentrations of forms of N are documented, including (1) augmentation of dissolved oxygen depletion during fall mixing from in-lake nitrification events, enabled by high T-NH3 levels; (2) violations of ammonia toxicity limits; and (3) violations of nitrite toxicity standards. These problems were either greatly ameliorated or eliminated by Metro's most recent treatment upgrades. Prevailing conditions are considered in a management context, including (1) likelihood of exceedances of toxicity limits in the future and (2) potential role of elevated nitrate levels in preventing mobilization of methyl mercury from the lake's sediments.


The process of activated sludge ozonation: effect of ozone on cells, flocs, macromolecules and nutrient release.
The purpose of this research is to investigate the activated sludge ozonation process. Results revealed that bacteria destruction and cell solubilization were not obvious when ozone dose was lower than 11 mgO₃/gMLSS (MLSS: mixed liquor suspended solids), while pores appeared on the sludge and bacterial disappeared from floc surface. In the range of 11-90 mgO₃/gMLSS, ozone had significant effect on cell permeabilization and disruption. Meanwhile, a large quantity of macromolecules and nutrients were released from bacteria cells. Additionally, efficiency of ozone utilization was low but specific solubilization related to cell lysis was high at this level. Greater than 90 mgO₃/gMLSS, the number of live cells and dead cells were both stable, and the quantity of material in bulk liquid increased slowly. The specific solubilization ratio decreased while the efficiency of ozone utilization began to increase. This indicated that ozone oxidized the macromolecules in the bulk liquid instead of bacteria cells at high ozone dose.


Is the superiority of apoB over non-HDL-C as a marker of cardiovascular risk in the INTERHEART study due to confounding by related variables?
Patients with increased numbers of cholesterol-depleted apolipoprotein B (apoB) particles frequently have multiple other abnormalities, which might confound the comparison of apoB and non-high-density-lipoprotein-cholesterol (non-HDL-C) as markers of cardiovascular risk. We wanted to determine whether the superiority of apoB over non-HDL-C as a marker of cardiovascular risk in the INTERHEART study is due to such variables that act as confounders of the primary comparison. To test for confounding, cases and controls were first separated into 3 groups on the basis of the percentile levels within the study of non-HDL-C and apoB with discordance defined as a difference of 5 percentile points. Logistic regression was used to compute odds ratio of myocardial infarction (as an outcome) for different categories, assuming concordance as reference adjusted for other confounders. Plasma triglyceride and non-HDL-C levels were highest in the discordant group with lowest risk and lowest in the discordant group with highest risk, whereas apoB was highest in the discordant group with the highest risk and lowest in the discordant group with the lowest group. Moreover, no significant change was found in the odds ratio for either discordant group when adjusted for the effect of any of the variables examined, evidence that none confounded the primary comparison. Factors such as hypertriglyceridemia do not confound the comparison of apoB and non-HDL-C, further evidence that apoB is superior to non-HDL-C as a marker of the importance of the apoB atherogenic lipoproteins in cardiovascular risk.


Acute kidney injury: new concepts in definition, diagnosis, pathophysiology, and treatment.
Acute kidney injury (AKI) is increasingly recognized in all fields of medical practice. Unfortunately, this syndrome has been plagued by inconsistent definitions, simplistic pathophysiologic schemas, and insensitive diagnostic tools. Recent advances in defining AKI, understanding its pathophysiology, and improving the diagnostic accuracy of the testing tools available eventually will impact disease management and clinical outcomes. Prompt recognition and treatment of AKI remain the cornerstone of clinical management for this high-mortality, high-cost syndrome. The authors provide the most recent updates in the definition, diagnosis, pathophysiology, and treatment options for patients with AKI, providing a stepwise approach to clinical evaluation for use in all fields of medical practice.


CompaGB: An open framework for genome browsers comparison.
Tools to visualize and explore genomes hold a central place in genomics and the diversity of genome browsers has increased dramatically over the last few years. It often turns out to be a daunting task to compare and choose a well-adapted genome browser, as multidisciplinary knowledge is required to carry out this task and the number of tools, functionalities and features are overwhelming. To assist in this task, we propose a community-based framework based on two cornerstones: (i) the implementation of industry promoted software qualification method (QSOS) adapted for genome browser evaluations, and (ii) a web resource providing numerous facilities either for visualizing comparisons or performing new evaluations. We formulated 60 criteria specifically for genome browsers, and incorporated another 65 directly from QSOS's generic section. Those criteria aim to answer versatile needs, ranging from a biologist whose interest primarily lies into user-friendly and informative functionalities, a bioinformatician who wants to integrate the genome browser into a wider framework, or a computer scientist who might choose a software according to more technical features. We developed a dedicated web application to enrich the existing QSOS functionalities (weighting of criteria, user profile) with features of interest to a community-based framework: easy management of evolving data, user comments... The framework is available at http://genome.jouy.inra.fr/CompaGB. It is open to anyone who wishes to participate in the evaluations. It helps the scientific community to (1) choose a genome browser that would better fit their particular project, (2) visualize features comparatively with easily accessible formats, such as tables or radar plots and (3) perform their own evaluation against the defined criteria. To illustrate the CompaGB functionalities, we have evaluated seven genome browsers according to the implemented methodology. A summary of the features of the compared genome browsers is presented and discussed.


Metastability of Discrete-Symmetry Flocks.
We study the stability of the ordered phase of flocking models with a scalar order parameter. Using both the active Ising model and a hydrodynamic description, we show that droplets of particles moving in the direction opposite to that of the ordered phase nucleate and grow. We characterize analytically this self-similar growth and demonstrate that droplets spread ballistically in all directions. Our results imply that, in the thermodynamic limit, discrete-symmetry flocks-and, by extension, continuous-symmetry flocks with rotational anisotropy-are metastable in all dimensions.


miR-375 is activated by ASH1 and inhibits YAP1 in a lineage-dependent manner in lung cancer.
Lung cancers with neuroendocrine (NE) features are often very aggressive but the underlying molecular mechanisms remain elusive. The transcription factor ASH1/ASCL1 is a master regulator of pulmonary NE cell development that is involved in the pathogenesis of lung cancers with NE features (NE-lung cancers). Here we report the definition of the microRNA miR-375 as a key downstream effector of ASH1 function in NE-lung cancer cells. miR-375 was markedly induced by ASH1 in lung cancer cells where it was sufficient to induce NE differentiation. miR-375 upregulation was a prerequisite for ASH1-mediated induction of NE features. The transcriptional coactivator YAP1 was determined to be a direct target of miR-375. YAP1 showed a negative correlation with miR-375 in a panel of lung cancer cell lines and growth inhibitory activities in NE-lung cancer cells. Our results elucidate an ASH1 effector axis in NE-lung cancers that is functionally pivotal in controlling NE features and the alleviation from YAP1-mediated growth inhibition.


Time location sampling in men who have sex with men in the HIV context: the importance of taking into account sampling weights and frequency of venue attendance.
Sex between men is the most frequent mode of HIV transmission in industrialised countries. Monitoring risk behaviours among men who have sex with men (MSM) is crucial, especially to understand the drivers of the epidemic. A cross-sectional survey (PREVAGAY), based on time-location sampling, was conducted in 2015 among MSM attending gay venues in 5 metropolitan cities in France. We applied the generalised weight share method (GWSM) to estimate HIV seroprevalence for the first time in this population, taking into account the frequency of venue attendance (FVA). Our objectives were to describe the implementation of the sampling design and to demonstrate the importance of taking into account sampling weights, including FVA by comparing results obtained by GWSM and by other methods which use sample weights not including FVA or no weight. We found a global prevalence of 14.3% (95% CI (12.0-16.9)) using GWSM and an unweighted prevalence of 16.4% (95% CI (14.9-17.8)). Variance in HIV prevalence estimates in each city was lower when we did not take into account either the sampling weights or the FVA. We also highlighted an association of FVA and serological status in the most of investigated cities.


CRISPR/Cas9 Gene Editing of NtAITRs, a Family of Transcription Repressor Genes, Leads to Enhanced Drought Tolerance in Tobacco.
Tobacco is a cash crop throughout the world, and its growth and development are affected by abiotic stresses including drought stress; therefore, drought-tolerant breeding may help to improve tobacco yield and quality under drought stress conditions. Considering that the plant hormone ABA (abscisic acid) is able to regulate plant responses to abiotic stresses via activating ABA response genes, the characterization of ABA response genes may enable the identification of genes that can be used for molecular breeding to improve drought tolerance in tobacco. We report here the identification of NtAITRs (Nicotiana tabacum ABA-induced transcription repressors) as a family of novel regulators of drought tolerance in tobacco. Bioinformatics analysis shows that there are a total of eight NtAITR genes in tobacco, and all the NtAITRs have a partially conserved LxLxL motif at their C-terminus. RT-PCR results show that the expression levels of at least some NtAITRs were increased in response to ABA and drought treatments, and NtAITRs, when recruited to the Gal4 promoter via a fused GD (Gal4 DNA-binding domain), were able to repress transcription activator LD-VP activated expression of the LexA-Gal4-GUS reporter gene. Roles of NtAITRs in regulating drought tolerance in tobacco were analyzed by generating CRISPR/Cas9 gene-edited mutants. A total of three Cas9-free ntaitr12356 quintuple mutants were obtained, and drought treatment assays show that drought tolerance was increased in the ntaitr12356 quintuple mutants. On the other hand, results of seed germination and seedling greening assays show that ABA sensitivity was increased in the ntaitr12356 quintuple mutants, and the expression levels of some ABA signaling key regulator genes were altered in the ntaitr12356-c3 mutant. Taken together, our results suggest that NtAITRs are ABA-responsive genes, and that NtAITRs function as transcription repressors and negatively regulate drought tolerance in tobacco, possibly by affecting plant ABA response via affecting the expression of ABA signaling key regulator genes.


Maintenance of adequate hemodialysis access. Prevention of neointimal hyperplasia.
The maintenance of adequate hemodialysis vascular access is frequently complicated in the patient with polytetrafluoroethylene (PTFE) A-V hemodialysis grafts by venous anastomotic stenosis. This stenosis is caused by neointimal hyperplasia (NIH), a response to vascular injury. In this study, the authors prospectively analyzed the effect of a short-term regimen consisting of administration of two medications, heparin and low molecular weight dextran, on the development of NIH at the venous anastomosis in 79 patients with PTFE A-V hemodialysis grafts. In addition, they evaluated other parameters' effects on the development of NIH. In comparison with control subjects, heparin had some effect in minimizing the development of NIH in the PTFE grafts when evaluated radiologically at 3 months, although this effect was not statistically significant. Low molecular weight dextran, however, had no trend or statistically significant effect on this venous anastomotic narrowing. Interestingly, patient age, use of calcium channel blockers, and presence of diabetes mellitus (DM) all appeared to affect the development of NIH. Increasing age and use of calcium channel blockers was associated with decreased development of NIH; conversely, DM was associated with worsened NIH. In evaluation of access survival (time to first access failure), degree of venous anastomosis stenosis at 3 months was not predictive. Patient time on dialysis pre graft placement was the only measured parameter related to access failure. The method of dialysis pre graft placement (hemodialysis versus peritoneal dialysis) was not a significant factor in early access failure. Pharmacologic treatment of venous anastomotic narrowing in PTFE hemodialysis grafts due to NIH continues to be difficult. Short-term treatment with the tested medication failed to statistically affect NIH. Patient age, use of calcium channel blockers, and presence of DM were all factors in the development of NIH. Of measured parameters, time on dialysis pre graft placement was the only factor correlated with early access failure. In future treatment regimens, one should consider more prolonged treatment. In addition, noted risk factors should be considered when determining type of renal replacement therapy.


An assessment of staffing needs at a HIV clinic in a Western Kenya using the WHO workload indicators of staffing need WISN, 2011.
An optimal number of health workers, who are appropriately allocated across different occupations and geographical regions, are required to ensure population coverage of health interventions. Health worker shortages in HIV care provision are highest in areas that are worst hit by the HIV epidemic. Kenya is listed among countries that experience health worker shortages (<2.5 health workers per 1000 population) and have a high HIV burden (HIV prevalence 5.6 with 15.2% in Nyanza province). We set out to determine the optimum number of clinicians required to provide quality consultancy HIV care services at the Jaramogi Oginga Odinga Teaching and Referral Hospital, JOOTRH, HIV Clinic, the premier HIV clinic in Nyanza province with a cumulative client enrolment of PLHIV of over 20,000 persons. The World Health's Organization's Workload Indicators of Staffing Needs (WISN) was used to compute the staffing needs and sufficiency of staffing needs at the JOOTRH HIV clinic in Kisumu, Kenya, between January and December 2011. All people living with HIV (PLHIV) who received HIV care services at the HIV clinic at JOOTRH and all the clinicians attending to them were included in this analysis. The actual staffing was divided by the optimal staff requirement to give ratios of staffing excesses or shortages. A ratio of 1.0 indicated optimal staffing, less than 1.0 indicated suboptimal staffing, and more than 1 indicated supra optimal staffing. The HIV clinic is served by 56 staff of various cadres. Clinicians (doctors and clinical officers) comprise approximately one fifth of this population (n = 12). All clinicians (excluding the clinic manager, who is engaged in administrative duties and supervisory roles that consumes approximately one third of his time) provide full-time consultancy services. To operate at maximum efficiency, the clinic therefore requires 19 clinicians. The clinic therefore operates with only 60% of its staffing requirements. Our assessment revealed a severe shortage of clinicians providing consultation services at the HIV clinic. Human resources managers should oversee the rational planning, training, retention, and management of human resources for health using the WISN which is an objective and reliable means of estimating staffing needs.


Structural geology of the Earth's interior.
Seismology is providing a more sharply focused picture of the Earth's internal structure that should lead to improved models of mantle dynamics. Lateral variations in seismic wave speeds have been documented in all major layers of the Earth external to its core, with horizontal scale lengths ranging from 10 to 10(4) km. These variations can be described in terms of three types of heterogeneity: compositional, aeolotropic, and thermobaric. All three types are represented in the lithosphere, but the properties of the deeper inhomogeneities remain hypothetical. It is argued that sublithospheric continental root structures are likely to involve compositional as well as thermobaric heterogeneities. The high-velocity anomalies characteristic of subduction zones-seismic evidence for detached and sinking thermal boundary layers-in some areas appear to extend below the seismicity cutoff and into the lower mantle or mesosphere. Mass exchange between the upper and lower mantles is implied, but the magnitude of the flux relative to the total mass flux involved in plate circulations is as yet unknown. Other observations, such as the vertical travel time anomalies seen in the western Pacific, may yield additional constraints on the flow geometries, but further documentation is necessary. Thermobaric heterogeneities associated with a thermal boundary layer at the base of the mantle could provide the explanation for some of the observations of heterogeneities in the deep mantle. The evidence for very small scale inhomogeneities (<50 km) in region D'' and for topography on the core-mantle interface motivate the speculation that there is a chemical boundary layer at this interface, as well as a thermal one.


Two transfer RNA (1-methylguanine) methylases from yeast.
Two distinct tRNA (m-1G) methylases have been found in the yeast Saccharomyces cerevisiae. They differ in their chromatographic properties on hydroxyapatite, in their response to spermine, and in their site specificity. Only one of the methylases is active against normal tRNA from Escherichia coli.


Multiplex proteomics analysis of gender-associated proteins in Brugia malayi.
Gender-associated (GA) genes are important for the development and reproduction of filarial nematodes. Identification and characterization of GA genes may provide insight into major pathways and processes involved in development and reproduction. The recent completion of the Brugia malayi genome has provided a good foundation for proteomics studies. Multiplex protein labelling and two-dimensional difference in-gel electrophoresis (2D-DIGE) combined with MALDI-TOF/TOF tandem MS were used to identify GA proteins. Thirty male and 32 female associated proteins were identified in this study. Many of these GA genes have homologues in Caenorhabditis elegans (83% male and 69% female), and most of the homologues have severe RNA interference (RNAi) phenotypes (72% male and 55% female) in C. elegans. Functional analysis showed that the male-associated genes are enriched for energy production, metabolic processes and cytoskeleton, while the female-associated genes are enriched for RNA modification and transcription. GA genes encode many excreted/secreted proteins. In situ localization studies showed that GA genes are mainly expressed in reproductive organs, and this is further evidence for their involvement in reproduction. Improved understanding of the basic biology of filarial nematodes may lead to improved tools for prevention and treatment of filarial infections. This study combined proteomics, in situ hybridization (ISH) and bioinformatics in a systems biology approach to improve understanding of gender differences and key proteins involved in reproduction in filarial worms. Advanced proteomics methods and bioinformatics led to the identification of 62 GA proteins for B. malayi. ISH revealed that most of those GA genes are expressed during embryogenesis or spermatogenesis. ISH results were consistent with RNAi data for C. elegans that linked the homologues of the B. malayi proteins to gamete production and embryogenesis.


RB1 loss triggers dependence on ESRRG in retinoblastoma.
Retinoblastoma (Rb) is a deadly childhood eye cancer that is classically initiated by inactivation of the RB1 tumor suppressor. Clinical management continues to rely on nonspecific chemotherapeutic agents that are associated with treatment resistance and toxicity. Here, we analyzed 103 whole exomes, 20 whole transcriptomes, 5 single-cell transcriptomes, and 4 whole genomes from primary Rb tumors to identify previously unknown Rb dependencies. Several recurrent genomic aberrations implicate estrogen-related receptor gamma (ESRRG) in Rb pathogenesis. RB1 directly interacts with and inhibits ESRRG, and RB1 loss uncouples ESRRG from negative regulation. ESRRG regulates genes involved in retinogenesis and oxygen metabolism in Rb cells. ESRRG is preferentially expressed in hypoxic Rb cells in vivo. Depletion or inhibition of ESRRG causes marked Rb cell death, which is exacerbated in hypoxia. These findings reveal a previously unidentified dependency of Rb cells on ESRRG, and they implicate ESRRG as a potential therapeutic vulnerability in Rb.


Electromyographic activity of masticatory, neck and trunk muscles of subjects with different mandibular divergence. A cross-sectional evaluation.
To record and compare the surface electromyographic (sEMG) activity of masticatory, neck, and trunk muscles at different functional requirements of the stomatognathic system in an adult sample classified according to the mandibular divergence angle (SN-GoGn angle). 60 Caucasian adult subjects were classified on the basis of SN-GoGn angle: 20 subjects with normal mandibular divergence, 20 subjects with lower angles, and 20 subjects with higher angles. Their sEMG activity was recorded at mandibular rest position and during maximal voluntary clenching. sEMG activity of subjects with a lower angle was significantly higher than that of subjects in the other two groups at mandibular rest position for the masseter, the anterior temporal, the upper trapezius, and the posterior cervical muscles. During maximal voluntary clenching, no significant difference was observed in the sEMG activity of the masticatory muscles among the three groups. However, the sEMG activity of the posterior cervicals and that of the upper trapezius were significantly higher in subjects with a lower angle than in the other two groups. Skeletal class does seem to affect the sEMG pattern activity of the masticatory, neck, and trunk muscles.


Epigenetic alterations in liver of C57BL/6J mice after short-term inhalational exposure to 1,3-butadiene.
1,3-Butadiene (BD) is a high-volume industrial chemical and a known human carcinogen. The main mode of BD carcinogenicity is thought to involve formation of genotoxic epoxides. In this study we tested the hypothesis that BD may be epigenotoxic (i.e., cause changes in DNA and histone methylation) and explored the possible molecular mechanisms for the epigenetic changes. We administered BD (6.25 and 625 ppm) to C57BL/6J male mice by inhalation for 2 weeks (6 hr/day, 5 days a week) and then examined liver tissue from these mice for signs of toxicity using histopathology and gene expression analyses. We observed no changes in mice exposed to 6.25 ppm BD, but glycogen depletion and dysregulation of hepatotoxicity biomarker genes were observed in mice exposed to 625 ppm BD. We detected N-7-(2,3,4-trihydroxybut-1-yl)guanine (THB-Gua) adducts in liver DNA of exposed mice in a dose-responsive manner, and also observed extensive alterations in the cellular epigenome in the liver, including demethylation of global DNA and repetitive elements and a decrease in histone H3 and H4 lysine methylation. In addition, we observed down-regulation of DNA methyltransferase 1 (Dnmt1) and suppressor of variegation 3-9 homolog 1, a histone lysine methyltransferase (Suv39h1), and up-regulation of the histone demethylase Jumonji domain 2 (Jmjd2a), proteins responsible for the accurate maintenance of the epigenetic marks. Although the epigenetic effects were most pronounced in the 625-ppm exposure group, some effects were evident in mice exposed to 6.25 ppm BD. This study demonstrates that exposure to BD leads to epigenetic alterations in the liver, which may be important contributors to the mode of BD carcinogenicity.


Clinical course and predictors of total colectomy in ulcerative colitis; a referral center experience from Turkey.
We aimed to describe the clinical course of Ulcerative colitis (UC) and the factors that predict the need for total colectomy in Turkish patients with severe UC receiving regular follow up. We analyzed the demographic and clinical characteristics of 612 patients with UC receiving regular follow up between 1994 and 2010 in a tertiary referral center in Ankara. Men accounted for 58% of patients (M:F ratio, 1.4:1), and the mean age at diagnosis was 37.9 years. Of these, 32% had distal colitis and 8.8% had further extension, and 39 patients (6.4%) had chronic active disease. Steroid dependency and steroid resistance rates were 7.5% and 17.2%, respectively. In multivariate analysis, steroid dependency (p=0.04), steroid resistance (p=0.002), further extension (p<0.001), presence of extensive disease (p=0.006), and chronic active disease (p<0.001) were independent predictors of the need for total colectomy. Patients with chronic active disease had lower total colectomy free survival (p<0.001). The predictors of total colectomy were comparable with those previously reported in the literature. However, we identified further extension in disease localization to predict the need for total colectomy.


Anaesthetic Management of a Patient with Brugada Syndrome in Total Knee Arthroplasty.
We report the case of a 52-year-old female diagnosed with Brugada syndrome (BrS) scheduled to undergo right total knee arthroplasty. General anaesthesia was induced and maintained with thiopental intravenous sodium + remifentanil and sevoflurane + remifentanil infusion, respectively. Rocuronium bromide was used as the muscle relaxant. The defibrillator was ready for use with the electrodes on the patient. Sugammadex was used for muscle relaxant antagonization. Postoperative analgesia was provided by intermittent morphine HCL via an epidural catheter, intravenous patient-controlled analgesia (Meperidine), and intravenous tenoxicam. The patient was discharged on the 6th day without any problem. Anaesthetic management of patients with BrS is challenging for anaesthesiologists, because fatal cardiac arrhythmias can be triggered by many drugs commonly used in the perioperative period such as bupivacaine, lidocaine, neostigmine, propofol, succinylcholine, ketamine, and tramadol. In these cases, a detailed preoperative evaluation including family history, avoidance of drugs triggering arrhythmia, taking precautions against arrhythmia, and using the agents that are reported to be safe are essential for patient safety.


Feasibility of removing surface deposits on stone using biological and chemical remediation methods.
The study was conducted on alterations found on stone artwork and integrates microbial control and a biotechnological method for the removal of undesirable chemical substances. The Demetra and Cronos sculptures are two of 12 stone statues decorating the courtyard of the Buonconsiglio Castle in Trento (Italy). An initial inspection of the statues revealed putative black crusts and highlighted the microbial contamination causing discoloration. In 2006, the Cultural Heritage Superintendence of Trento commissioned us to study and remove these chemical and biological stains. Stereomicroscopy characterised the stone of the sculptures as oolitic limestone, and infrared analyses confirmed the presence of black crusts. To remove the black crusts, we applied a remediation treatment of sulphate-reducing bacteria, which removes the chemical alteration but preserves the original stone and the patina noble. Using traditional and biomolecular methods, we studied the putative microbial contamination and confirmed the presence of biodeteriogens and chose biocide Biotin N for the removal of the agents causing the discolouration. Denaturing gradient gel electrophoresis fluorescent in situ hybridisation established that Cyanobacteria and green algae genera were responsible for the green staining whereas the black microbial contamination was due to dematiaceous fungi. After the biocide Biotin N treatment, we applied molecular methods and demonstrated that the Cyanobacteria, and most of the green algae and dematiaceous fungi, had been efficiently removed. The reported case study reveals that conservators can benefit from an integrated biotechnological approach aimed at the biocleaning of chemical alterations and the abatement of biodeteriogens.