Follicle Stimulating Hormone Receptor (FSHR) Polymorphisms and Polycystic Ovary Syndrome (PCOS).
Polycystic ovary syndrome (PCOS) is the commonest endocrine abnormality in women of reproductive age typically presenting with chronic oligo- or anovulation, clinical, or biochemical hyperandrogenism and polycystic ovarian morphology (PCOM). Restoring mono-ovulation is the ultimate goal of ovulation induction and most women do respond to ovulation inducing agents causing their Follicle-stimulating hormone (FSH) levels to rise. Familial clustering and the results from twin studies strongly support an underlying genetic basis for PCOS. Recent Genome wide association studies (GWAS) have identified several genetic variants being genome wide significantly associated with PCOS. Amongst those are variants in or near the Luteinizing hormone (LH) and FSH receptor genes as well as a variant in the FSH-β gene. The aim of this review is to summarize the available evidence as to whether single nucleotide polymorphisms are able to modify the PCOS phenotype or whether they constitute a risk factor for the syndrome. Data on the role of FSHR polymorphisms in PCOS are conflicting. It seems that in large Chinese studies FSHR polymorphisms are not associated with either PCOS risk or with PCOS treatment outcome. However, in large scale studies in Caucasians these polymorphisms seem to influence the risk of having PCOS. Moreover, these studies also showed that some polymorphisms might affect some clinical features of PCOS as well as treatment outcome. Although most research has focussed on the role of FSHR polymorphisms there seems to be also some evidence showing that single nucleotide polymorphisms (SNPs) in the LHCG-Receptor as well as those in FSH-β gene might also alter the phenotype of PCOS. In conclusion most studies confirm that FSHR polymorphisms do alter the phenotype of PCOS in that they either alter the response to exogenous FSH or hat they increase the risk of having PCOS.


In vivo facial tissue depth measurements for children and adults.
This study reports results of a facial tissue depth measurements project conducted over a two-year period on a modern sample of children and adults of both sexes and varying ages and races. The purpose of this research was to increase available tissue depth data for children and update facial tissue depth measurements for American adults. Most volunteers for this project were patients or visitors to the pediatric clinic at the Louisiana State University Medical Center, School of Dentistry, in New Orleans. Using state of-the-art ultrasound technology, we scanned 551 children and 256 adults at 19 points across the face. Thirteen of the scanned points were traditional landmarks while six others were areas not measured by previous researchers or were points for which very little data exist for both children and adults. For this presentation, we analyzed data for 515 children and 197 adults. Results of Pearson's correlations, analysis of variance, and paired t-tests indicate that age, sex, and race are significant factors when considering tissue depth means for different measurement locations across the human face. These new standards are compared to the work of other researchers. Our results provide valuable assistance in both two-dimensional and three-dimensional facial reproductions and superimpositions.


Association between attributes of a cyclist and bicycle seat pressure.
Bicycle seat pressure is thought to be the principal risk factor for bicycle seat injuries such as erectile dysfunction; however there is a lack of understanding regarding the characteristics of a cyclist that predict bicycle seat pressure. The purpose of this study was to determine if select attributes of a cyclist are associated with seat pressure during stationary bicycling. A secondary purpose was to determine which of the associated attributes were the best predictors of seat pressure and if they were consistent between two different seats. There were two data collection phases to this correlational study in which 40 males between the ages 20 and 50 years volunteered. For the first phase, select attributes of the cyclist (age, weight, flexibility, experience level, and ischial tuberosity width) were measured. The second phase required participants to ride a stationary cycle ergometer while pelvic tilt angles and seat pressures were measured on two different traditional seats. The main outcome is the mean and peak bicycle seat interface pressure over the anterior and total seat. Body weight explained up to 50% of the variance in mean total seat pressure (P=0.001). Regarding peak total pressure, pelvic tilt angle and flexibility explained 43% and 17% of the variance, respectively, for the two seats tested (P=0.01). These results indicate that predictors of mean seat pressure are not the same for peak pressure. Body weight alone accounted for the most variance in mean pressure whereas pelvic tilt and flexibility accounted for the most variance in peak pressure. These variables related to seat pressure may give some guidance to cyclists and clinicians who intend to prevent or alleviate the symptoms associated with bicycle seat injuries that include erectile dysfunction.


Male spider mites use chemical cues, but not the female mating interval, to choose between mates.
The choice of the partner an individual will mate with is expected to strongly impact its fitness. Hence, natural selection has favoured the evolution of cues to distinguish among mates that will provide different fitness benefits to the individual that is choosing. In species with first-male sperm precedence, this is particularly important for males, as mating with mated females will result in no offspring. In the spider mite Tetranychus urticae only the first mating is effective, except if the interval between first and second copulations is shorter than 24 h. In line with this, males prefer to mate with virgin over mated females. They do not, however, choose between females that have mated at different time intervals. Here, we tested which type of cues males use to distinguish between females with different mating status (virgin versus mated). To do so, we firstly confirmed that males prefer virgins over mated females and that they do not select females on the basis of their age or mating interval. Next, we tested whether contact and volatile compounds or chemical trails affected male discrimination between mated and virgin females, by systematically varying the exposure of males to these cues. We found that volatile compounds and chemical trails were sufficient to induce discrimination between virgin and mated females in males. Direct contact with females, however, does not seem to play a role in this discrimination. The composition of such chemical cues (trails and volatiles) remains to be identified.


The long-term safety of D-allulose administration in healthy dogs.
The safety and biological effects of a long-term dose of D-allulose were evaluated in healthy dogs. For 12 weeks, the dogs were administered D-allulose (0.2 g/kg) or placebo daily. Plasma total cholesterol concentrations in the D-allulose group were significantly lower than those in the control group at and after week 2 (P<0.05). D-Allulose administration did not cause clinical signs or changes in hematological and biochemical levels, except for lipids. D-Allulose administration also did not influence body weight. Plasma glucose and insulin concentrations in the glucose tolerance test, performed one day after the termination of D-allulose administration, were not different between groups, suggesting no cumulative effects of D-allulose on glucose metabolism in healthy dogs. In conclusion, long-term administration of D-allulose caused no harmful effects in dogs.


Alpha-synuclein targets GluN2A NMDA receptor subunit causing striatal synaptic dysfunction and visuospatial memory alteration.
Parkinson's disease is a progressive neurodegenerative disorder characterized by altered striatal dopaminergic signalling that leads to motor and cognitive deficits. Parkinson's disease is also characterized by abnormal presence of soluble toxic forms of α-synuclein that, when clustered into Lewy bodies, represents one of the pathological hallmarks of the disease. However, α-synuclein oligomers might also directly affect synaptic transmission and plasticity in Parkinson's disease models. Accordingly, by combining electrophysiological, optogenetic, immunofluorescence, molecular and behavioural analyses, here we report that α-synuclein reduces N-methyl-d-aspartate (NMDA) receptor-mediated synaptic currents and impairs corticostriatal long-term potentiation of striatal spiny projection neurons, of both direct (D1-positive) and indirect (putative D2-positive) pathways. Intrastriatal injections of α-synuclein produce deficits in visuospatial learning associated with reduced function of GluN2A NMDA receptor subunit indicating that this protein selectively targets this subunit both in vitro and ex vivo. Interestingly, this effect is observed in spiny projection neurons activated by optical stimulation of either cortical or thalamic glutamatergic afferents. We also found that treatment of striatal slices with antibodies targeting α-synuclein prevents the α-synuclein-induced loss of long-term potentiation and the reduced synaptic localization of GluN2A NMDA receptor subunit suggesting that this strategy might counteract synaptic dysfunction occurring in Parkinson's disease.


Human lung cancer and hexavalent chromium exposure.
Workers chronically exposed to hexavalent chromium have higher incidence of lung cancer. Our study investigates incidence of lung cancer types, age at onset of the disease and survival time among chromium exposed workers (smelters, tapers, crane operators) in comparison to non-exposed persons. 64 chromium exposed workers and 104 male controls with diagnosed lung cancer were analysed. The average exposure time among workers was 16.71 +/- 10.02 (S.D.) years (range 1- 41 years). Chromium exposure significantly decreases the age at the onset of the disease by 3.51 years (62.20 +/- 9.08 years in exposed group and 65.71 +/- 10.50 years in control; P=0.018). Small cell lung carcinoma (SCLC) forms 25.0 % of all cases in chromium exposed workers and 16.34% in non exposed individuals. No correlation was found between the age at the diseases onset and time of exposure. The mean survival time in exposed group was 9.03 +/- 12.73 month, in control 12.14 +/- 21.94 month, but this difference was not significant (P=0.473). Occupational exposure to chromium was identified as an important risk factor of lung cancer, decreasing the age at the diseases onset. Higher percentage of SCLC was found in chromium exposed individuals.


Henoch-Schönlein purpura: a clinical case with dramatic presentation.
A case study involving a 55-year-old Caucasian male with end-stage glomerulosclerosis is presented here. Kidney biopsies showed no deposits on imunofluorescent microscopy. Relapsing massive haemoptysis and suspected bronchovascular malformation required lung lobectomy which revealed malformative and tortuous small blood vessels, with no vasculitis. Blood antinuclear antibodies, antineutrophil cytoplasmic antibodies and antiglomerular basement membrane antibodies were undetectable. Seric immunoglobulins and complement levels were normal. Three months later, arthralgia and joint oedema first appeared. Skin biopsy revealed vasculitis immune-reactive to immunoglobulin A. Systemic corticotherapy was then started. Two weeks later, the patient presented with abdominal pain melena and rectal bleeding (haematoquesia). Endoscopic study showed diffuse gastrointestinal haemorrhage. Angiographic study revealed diffuse lesions compatible with vasculitis and haemorrhage from multiple spots. Cyclophosphamide and then intravenous immunoglobulin were associated to treatment without response. Increasing blood loss occurred, with massive gastrointestinal haemorrhage and haemorrhagic ascitis. Death occurred due to uncontrolled diffuse bleeding. Necropsy findings showed generalised small vessels vasculitis compatible with Henoch-Schönlein purpura.


Hospital infection control: old problem - evolving challenges.
Hospital infection prevention and control (IPC) is often regarded by doctors as mundane and unnecessarily rigid, but the continued occurrence of preventable healthcare-associated infections, increasing antimicrobial resistance (to which hospitals are major contributors) and rare, but potentially devastating hospital outbreaks of emerging infectious diseases, suggest that IPC must be taken seriously. Healthcare professionals often fail to comply with effective, evidence-based IPC practices and there is ample evidence that doctors, generally, do so less consistently than nurses. However, doctors' practices are highly variable, apparently because of a perceived entitlement to clinical autonomy. In practice, most doctors observe safe IPC practices, most of the time. However, some are ignorant or dismissive of IPC policies and some respond angrily, when reminded. Among a small proportion of senior consultants, negative attitudes to IPC are perceived by their peers to correlate with a more general failure to meet their public hospital commitments, apparently because of conflicting demands, including private practice. The fact that breaches of IPC practice have significant, although often hidden, consequences indicates a need for continued improvement based on new strategies that might include: better surveillance, to identify and inform doctors of the true burdens of healthcare-associated infections; professional self-reflection on falsely dichotomous claims of medical professionalism namely: clinical autonomy versus regard for patient welfare by complying with 'rules' designed to protect them; and review of the consequences of recent changes in healthcare delivery, including proliferation of multiple, part-time consultant contracts at the expense of public hospital culture and status.


Ocular Manifestations in Hemodialysis Patients: Importance of Ophthalmic Examination in Prevention of Ocular Sequels.
Hemodialysis (HD)-associated ocular abnormalities are one of the causes of morbidity among people undergoing HD. This study evaluates the frequency of ocular abnormalities in end-stage renal disease (ESRD) patients undergoing HD and their potential link to HD and demographic parameters. This cross-sectional study examined 242 eyes of 121 patients with ESRD undergoing regular HD after excluding the ineligible subjects. The study was designed in two parts. Medical histories of each patient including age, gender, family history, medication history, past medical history, and duration of HD collected using a structured check list. All patients underwent complete ophthalmologic examination for evaluation of the best corrected visual acuity (BCVA), intraocular pressure (IOP), and anterior and posterior segments. In total, 121 patients, including 68 (56.2%) males and 53 (43.8%) females, were enrolled in the study. The mean ± SD age of the patients and their mean duration of dialysis were 51.59 ± 16.01 and 3.40 ± 2.75 years, respectively. The most prevalent etiology for HD was diabetes mellitus (39.67%), followed by hypertension (38.84%), and the most common ocular findings included cataract (142 eyes; 58.7%) and ectopic calcification of the conjunctiva and cornea (78 eyes; %32.2). There was at least one abnormal ocular finding in 89.3% of the cases. The BCVA was equal to or less than finger count in 70 eyes (28.92%). There was a significant relationship between conjunctival calcification and the duration of dialysis (P = 0.02). There was significant association between etiology of HD and conjunctival calcification (adjusted odds ratio, 2.44; 95% CI, 1.05-5.67; and P value, 0.03). Such significant associations were present for corneal calcification (P = 0.009), cataract (P = 0.02), and optic atrophy (P = 0.01). Regular ophthalmologic examinations are recommended due to the prevalence of clinical ocular abnormalities in HD patients.


Isolation of an autocrine growth factor from hepatoma HTC-SR cells.
A growth factor has been isolated from HTC-SR rat hepatoma tissue culture cells which specifically stimulates DNA synthesis and cell proliferation of the HTC cells that produce it. The factor can be isolated from HTC cell conditioned medium or from an HTC cell extract. This autocrine factor has been purified 640-fold from a postmicrosomal supernatant by successive steps, involving ethanol precipitation, heating at 80 degrees C for 10 min, chromatography on a DEAE Bio-Gel A column, and chromatography on a heparin-sepharose affinity column. The major peak of activity eluted from the heparin column migrates as a single band on SDS-PAGE with an apparent Mr of 60,000. The factor is resistant to acid, heat, and neuraminidase but sensitive to trypsin, papain, and protease. The autocrine nature of the factor is indicated by the finding that several other types of cells do not respond with increased DNA synthesis. Mouse L-cells, BHK cells, Novikoff hepatoma cells, hepatocytes in primary culture, and an epithelial-like rat liver-derived cell line (Clone 9) were tested, and none of the cells could be stimulated. Small amounts of the factor could be extracted from the Clone 9 cells, however. This material had the same physical and purification properties as the factor extracted from HTC cells, but it did not stimulate DNA synthesis in Clone 9 cells, only in HTC cells. Addition of the factor resulted in an almost immediate stimulation of DNA synthesis in a proliferating HTC cell population. When the factor was added together with [3H]thymidine for 2 h, a significant stimulation of DNA synthesis was observed, provided the addition was made between 18 and 48 h after the cells had been plated. Autoradiographic studies indicated that the factor both accelerates DNA synthesis in cells already making DNA and increases the number of cells entering the S period. The stimulation of DNA synthesis was completely inhibited by 10 mM hydroxyurea, whether the factor was present for 2, 24, or 48 h in the culture. A significant increase in cell number due to addition of the factor was also observed. This accelerated proliferation was detectable only after the cells had been in culture for at least 48 h with the factor present.


Comparison of Vaginal Hysterectomy Techniques and Interventions for Benign Indications: A Systematic Review.
To create evidence-based clinical practice guidelines based on a systematic review of published literature regarding the risks and benefits of available preoperative, intraoperative, and postoperative technical steps and interventions at the time of vaginal hysterectomy for benign indications. We systematically searched the literature to identify studies that compared technical steps or interventions during the preoperative, intraoperative, and postoperative periods surrounding vaginal hysterectomy. We searched MEDLINE, Cochrane Central Register of Controlled Trials, Health Technology Assessments, and ClinicalTrials.gov from their inception until April 10, 2016, using the MeSH term "Hysterectomy, Vaginal" and associated text words. We included comparative studies, single-group studies, and systematic reviews published in English. We double-screened 4,250 abstracts, identifying 60 eligible studies. Discrepancies were adjudicated by a third reviewer. We followed standard systematic review methodology and the Grades for Recommendation, Assessment, Development and Evaluation approach to evaluate the evidence and generate guideline recommendations. Because of limited literature, only 16 perioperative risks, technical steps, and interventions were identified: obesity, large uteri, prior surgery, gonadotropin-releasing hormone agonists, vaginal antisepsis, bilateral salpingo-oophorectomy, morcellation, apical closure, uterine sealers, hemostatic injectants, hot cone, retractor, cystoscopy, vaginal packing, bladder management, and accustimulation. We organized and reported these as four domains: patient selection, preoperative, intraoperative, and postoperative. We did not identify any patient characteristics precluding a vaginal approach; chlorhexidine or povidone is appropriate for vaginal antisepsis; vasopressin decreases blood loss by 130 cc; tissue-sealing devices decrease blood loss by 44 cc and operative time by 15 minutes with uncertain complication implications; vertical cuff closure results in 1-cm increased vaginal length; either peritoneum or epithelium can be used for colpotomy closure; and routine vaginal packing is not advised. Minimal data exist to guide surgeons with respect to planning and performing a vaginal hysterectomy. This study identifies available information and future areas for investigation.


Obesity, metabolic syndrome and risk of atrial fibrillation: a Swedish, prospective cohort study.
We aimed to investigate whether different measures of obesity could similarly predict atrial fibrillation, and whether the atrial fibrillation risk associated with obesity is dependent on presence of metabolic syndrome. We performed our study in a population-based longitudinal cardiovascular study, comprising 1 924 men and 2 097 women, aged 60 years, from Stockholm. Body mass index, waist circumference, sagittal abdominal diameter and components of metabolic syndrome (systolic- and diastolic blood pressure, fasting glucose, triglycerides, high-density lipoprotein-cholesterol) were recorded at baseline. Participants were classified by their body mass index (normal weight, overweight or obese), waist circumference (normal, semi-elevated or elevated), and according to presence of metabolic syndrome. Atrial fibrillation risk was estimated by Cox proportional hazards regression models, adjusted for common atrial fibrillation risk factors, expressed as HR and 95% CI. During a mean follow-up of 13.6 years, 285 incident atrial fibrillation cases were recorded. One standard deviation increment of each obesity measure was associated with increased atrial fibrillation risk as: body mass index 1.25 (1.12 - 1.40), waist circumference 1.35 (1.19 - 1.54) and sagittal abdominal diameter 1.28 (1.14 - 1.44). Compared to normal weight subjects without metabolic syndrome, increased atrial fibrillation risk was noted for overweight subjects with metabolic syndrome, 1.67 (1.16 - 2.41), obese subjects without metabolic syndrome, 1.75 (1.11 - 2.74) and obese subjects with metabolic syndrome, 1.92 (1.34 - 2.74). Compared to subjects with normal waist circumference without metabolic syndrome, subjects with elevated waist circumference and metabolic syndrome suffered increased atrial fibrillation risk, 2.03 (1.44 - 2.87). Body mass index, waist circumference and sagittal abdominal diameter could similarly predict atrial fibrillation. Obesity was associated with an increased atrial fibrillation risk regardless of metabolic syndrome, whereas overweight and elevated waist circumference was associated with increased atrial fibrillation risk only if metabolic syndrome was present.


Developing a social autopsy tool for dengue mortality: a pilot study.
Dengue fever is a public health problem in the tropical and sub-tropical world. Dengue cases have grown dramatically in recent years as well as dengue mortality. Colombia has experienced periodic dengue outbreaks with numerous dengue related-deaths, where the Santander department has been particularly affected. Although social determinants of health (SDH) shape health outcomes, including mortality, it is not yet understood how these affect dengue mortality. The aim of this pilot study was to develop and pre-test a social autopsy (SA) tool for dengue mortality. The tool was developed and pre-tested in three steps. First, dengue fatal cases and 'near misses' (those who recovered from dengue complications) definitions were elaborated. Second, a conceptual framework on determinants of dengue mortality was developed to guide the construction of the tool. Lastly, the tool was designed and pre-tested among three relatives of fatal cases and six near misses in 2013 in the metropolitan zone of Bucaramanga. The tool turned out to be practical in the context of dengue mortality in Colombia after some modifications. The tool aims to study the social, individual, and health systems determinants of dengue mortality. The tool is focused on studying the socioeconomic position and the intermediary SDH rather than the socioeconomic and political context. The SA tool is based on the scientific literature, a validated conceptual framework, researchers' and health professionals' expertise, and a pilot study. It is the first time that a SA tool has been created for the dengue mortality context. Our work furthers the study on SDH and how these are applied to neglected tropical diseases, like dengue. This tool could be integrated in surveillance systems to provide complementary information on the modifiable and avoidable death-related factors and therefore, be able to formulate interventions for dengue mortality reduction.


DNA sequence and shape are predictive for meiotic crossovers throughout the plant kingdom.
A better understanding of genomic features influencing the location of meiotic crossovers (COs) in plant species is both of fundamental importance and of practical relevance for plant breeding. Using CO positions with sufficiently high resolution from four plant species [Arabidopsis thaliana, Solanum lycopersicum (tomato), Zea mays (maize) and Oryza sativa (rice)] we have trained machine-learning models to predict the susceptibility to CO formation. Our results show that CO occurrence within various plant genomes can be predicted by DNA sequence and shape features. Several features related to genome content and to genomic accessibility were consistently either positively or negatively related to COs in all four species. Other features were found as predictive only in specific species. Gene annotation-related features were especially predictive for maize, whereas in tomato and Arabidopsis propeller twist and helical twist (DNA shape features) and AT/TA dinucleotides were found to be the most important. In rice, high roll (another DNA shape feature) and low CA dinucleotide frequency in particular were found to be associated with CO occurrence. The accuracy of our models was sufficient for Arabidopsis and rice (area under receiver operating characteristic curve, AUROC > 0.5), and was high for tomato and maize (AUROC ≫ 0.5), demonstrating that DNA sequence and shape are predictive for meiotic COs throughout the plant kingdom.


Short-Term Effects of Kefir-Fermented Milk Consumption on Bone Mineral Density and Bone Metabolism in a Randomized Clinical Trial of Osteoporotic Patients.
Milk products are good sources of calcium that may reduce bone resorption and help prevent bone loss as well as promote bone remodeling and increase bone formation. Kefir is a product made by kefir grains that degrade milk proteins into various peptides with health-promoting effects, including antithrombotic, antimicrobial and calcium-absorption enhancing bioactivities. In a controlled, parallel, double-blind intervention study over 6 months, we investigated the effects of kefir-fermented milk (1,600 mg) supplemented with calcium bicarbonate (CaCO3, 1,500 mg) and bone metabolism in 40 osteoporosis patients, and compared them with CaCO3 alone without kefir supplements. Bone turnover markers were measured in fasting blood samples collected before therapy and at 1, 3, and 6 months. Bone mineral density (BMD) values at the spine, total hip, and hip femoral neck were assessed by dual-energy x-ray absorptiometry (DXA) at baseline and at 6 months. Among patients treated with kefir-fermented milk, the relationships between baseline turnover and 6 months changes in DXA-determined BMD were significantly improved. The serum β C-terminal telopeptide of type I collagen (β-CTX) in those with T-scores > -1 patients significantly decreased after three months treatment. The formation marker serum osteocalcin (OC) turned from negative to positive after 6 months, representing the effect of kefir treatment. Serum parathyroid hormone (PTH) increased significantly after treatment with kefir, but decreased significantly in the control group. PTH may promote bone remodeling after treatment with kefir for 6 months. In this pilot study, we concluded that kefir-fermented milk therapy was associated with short-term changes in turnover and greater 6-month increases in hip BMD among osteoporotic patients. ClinicalTrials.gov NCT02361372.


Integrity of mitochondria in a mammalian cell mutant defective in mitochondrial protein synthesis.
A defect in mitochondrial protein synthesis has previously been identified in the respiration-deficient Chinese hamster lung fibroblast mutant V79-G7. The present work extends the characterization of this mutant. A more sensitive analysis has shown that mutant mitochondria synthesize all mitochondrially encoded peptides, but in significantly reduced amounts. This difference is also seen when isolated mitochondria are tested for in vitro protein synthesis. To distinguish between a defect in the translational machinery and a defect in the transcription of mitochondrial DNA, we investigated the synthesis of the 16S and 12S mitochondrial rRNA species and found them to be made in normal amounts in G7 mitochondria. These rRNA species appear to be assembled into subunits whose sedimentation behavior is virtually indistinguishable from that of the wild-type subunits. We also examined the consequences of the defect in mitochondrial protein synthesis on mutant cells and their mitochondria-utilizing techniques of electron microscopy, two-dimensional gel electrophoresis and immunochemical analysis. G7 mitochondria have a characteristic ultrastructure distinguished by predominantly tubular cristae, but the overall biochemical composition of mitochondrial membrane and matrix fractions appears essentially unaltered except for the absence of a few characteristic peptides. Specifically, we identify the absence of two mitochondrially encoded subunits of cytochrome c oxidase on two-dimensional gels and demonstrate a drastic reduction of both cytoplasmically and mitochondrially synthesized subunits of enzyme in immunoprecipitates of G7 mitochondria.


Plant genotypic diversity interacts with predation risk to influence an insect herbivore across its ontogeny.
A growing number of studies have manipulated intraspecific plant diversity and found dramatic changes in the densities of associated insect herbivores and their predators. While these studies have been essential for quantifying the net ecological consequences of intraspecific plant diversity, they have been less effective at uncovering the ways in which plant diversity alters trophic interactions within arthropod communities. We manipulated intraspecific plant diversity and predation risk in the field in a factorial design to reveal how a mixture of plant genotypes changes the response of an herbivorous beetle (Leptinotarsa decemlineata) to a common stink bug predator (Podisus maculiventris). We repeated the manipulations twice across the ontogeny of the beetle to examine how the effects of diversity on the predator-prey interaction differ between larval and adult stages. We found that intraspecific plant diversity, mixtures of susceptible and resistant varieties of potato (Solanum tuberosum), reduced larval survival by 20% and adult oviposition by 34%, which surprisingly put survival and oviposition lower in the mixed-genotype plots than in the resistant monocultures. Moreover, we found that predation risk reduced larval survival 25% and 11% in resistant and susceptible monocultures, respectively, but had no effect in the mixture. This result indicated that our genotypic mixing treatment interacted nonadditively with predation risk such that plant diversity altered the predator-prey interaction by changing the responses of the beetles to their stink bug predators. In addition, even though predation risk reduced larval survival, it increased adult overwintering survival by 9%, independently of plant treatment, suggesting that these interactions change through ontogeny. A key implication of our study is that plant diversity influences arthropod communities not only by changing resource quality, as past studies have suggested, but also by changing interactions between species within the arthropod community.


Why is climate sensitivity so unpredictable?
Uncertainties in projections of future climate change have not lessened substantially in past decades. Both models and observations yield broad probability distributions for long-term increases in global mean temperature expected from the doubling of atmospheric carbon dioxide, with small but finite probabilities of very large increases. We show that the shape of these probability distributions is an inevitable and general consequence of the nature of the climate system, and we derive a simple analytic form for the shape that fits recent published distributions very well. We show that the breadth of the distribution and, in particular, the probability of large temperature increases are relatively insensitive to decreases in uncertainties associated with the underlying climate processes.


Evolution of the immune system influences speciation rates in teleost fishes.
Teleost fishes constitute the most species-rich vertebrate clade and exhibit extensive genetic and phenotypic variation, including diverse immune defense strategies. The genomic basis of a particularly aberrant strategy is exemplified by Atlantic cod, in which a loss of major histocompatibility complex (MHC) II functionality coincides with a marked expansion of MHC I genes. Through low-coverage genome sequencing (9-39×), assembly and comparative analyses for 66 teleost species, we show here that MHC II is missing in the entire Gadiformes lineage and thus was lost once in their common ancestor. In contrast, we find that MHC I gene expansions have occurred multiple times, both inside and outside this clade. Moreover, we identify an association between high MHC I copy number and elevated speciation rates using trait-dependent diversification models. Our results extend current understanding of the plasticity of the adaptive immune system and suggest an important role for immune-related genes in animal diversification.


Drug utilization pattern during pregnancy in North India.
Pregnancy is a special physiological condition, where drug treatment presents a special concern. To evaluate the drug utilization pattern during pregnancy and to evaluate the effect of the educational and economic status on it.. The retrospective cross-sectional study. The postgraduate Department of Pharmacology and Therapeutics of a medical college. and the antenatal clinic of the institution. Medical students filled 405 questionnaires after interviewing pregnant women (243 primigravida and 152 multigravida). All the collected questionnaires were analysed for various study parameters. Inter-group comparison was done using chi-square test. P value < 0.05 was considered statistically significant. A total of 700, 1086 and 686 drugs, with an average of 1.73, 2.89 and 2.49 drugs per pregnant women, were used during first, second and third trimester of pregnancy, respectively. A majority of the drugs used, were from category-A, followed by category-B and category-D. However, category C and X drugs constituted 2.90 (20) and 5.71% (40) of drugs used during the third trimester and first trimester, respectively. Herbal/homeopathic drugs constituted 6.42 (45), 3.68 (40) and 1.46% (10) of the drugs used in the first, second and third trimester of pregnancy, respectively (P=649). 33.33% (135) women believed that drug use during pregnancy is dangerous to both mother and child and 37.03% (150) believed that drugs are dangerous throughout pregnancy. 55.55% (225) females advocated the use of iron/folic acid during pregnancy. 24.69% (100) of women had knowledge about barrier contraceptives. Self-medication and homeopathic/ herbal drugs use was found more in graduates than in undergraduates; as well as, it was more in the higher socioeconomic group than the lower socioeconomic group. There is a need to educate and counsel women of child-bearing age, regarding the advantages and disadvantages of drug use during pregnancies, with special reference to alternative therapies and self-medication.


Studies on the mechanism of general anesthesia.
Inhaled anesthetics are a chemically diverse collection of hydrophobic molecules that robustly activate TWIK-related K+ channels (TREK-1) and reversibly induce loss of consciousness. For 100 y, anesthetics were speculated to target cellular membranes, yet no plausible mechanism emerged to explain a membrane effect on ion channels. Here we show that inhaled anesthetics (chloroform and isoflurane) activate TREK-1 through disruption of phospholipase D2 (PLD2) localization to lipid rafts and subsequent production of signaling lipid phosphatidic acid (PA). Catalytically dead PLD2 robustly blocks anesthetic TREK-1 currents in whole-cell patch-clamp recordings. Localization of PLD2 renders the TRAAK channel sensitive, a channel that is otherwise anesthetic insensitive. General anesthetics, such as chloroform, isoflurane, diethyl ether, xenon, and propofol, disrupt lipid rafts and activate PLD2. In the whole brain of flies, anesthesia disrupts rafts and PLDnull flies resist anesthesia. Our results establish a membrane-mediated target of inhaled anesthesia and suggest PA helps set thresholds of anesthetic sensitivity in vivo.


Adenophostin A and ribophostin, but not inositol 1,4,5-trisphosphate or manno-adenophostin, activate the Ca2+ release-activated Ca2+ current, I(CRAC), in weak intracellular Ca2+ buffer.
Under physiological conditions of weak intracellular Ca(2+) buffering (0.1 mM EGTA), the second messenger Ins(1,4,5)P(3) often fails to activate any detectable store-operated Ca(2+) current. However, it has been reported that the fungal metabolite adenophostin A [which has a severalfold higher affinity than Ins(1,4,5)P(3) for Ins(1,4,5)P(3) receptors] consistently activates the current under similar conditions. Here, whole-cell patch clamp experiments have been performed to examine how adenophostin A can activate the store-operated Ca(2+) current (I(CRAC)) in RBL-1 (rat basophilic leukaemia) cells. In a strong intracellular Ca(2+) buffer, saturating concentrations of adenophostin A activated I(CRAC) maximally and the current amplitude and kinetics were indistinguishable from those obtained with high concentrations of Ins(1,4,5)P(3). In a weak Ca(2+) buffer, adenophostin A consistently activated I(CRAC), but the current was submaximal. High concentrations of Ins(1,4,5)P(3) or the non-metabolizable analogue Ins(2,4,5)P(3) were largely ineffective under these conditions. The size of I(CRAC) to adenophostin A in weak Ca(2+) buffer could be significantly increased by either inhibiting sarcoplasmic/endoplasmic-reticulum Ca(2+)-ATPase ('SERCA') pumps with thapsi-gargin or enhancing mitochondrial Ca(2+) uptake, although blocking the mitochondrial Ca(2+) uniporter with Ruthenium Red did not suppress the activation of the current. Changing the levels of free ATP in the recording pipette did not enhance the size of I(CRAC) evoked by adenophostin A. We also examined two structurally distinct analogues of adenophostin A (manno-adenophostin and ribophostin), for which the affinities for the Ins(1,4,5)P(3) receptor are similar to that of Ins(1,4,5)P(3) in equilibrium binding experiments. Although these analogues were able to activate I(CRAC) to its maximal extent in strong buffer, ribophostin, but not manno-adenophostin, consistently activated the current in weak buffer. We conclude that adenophostin A and ribophostin are able to activate I(CRAC) in weak buffer through a mechanism that is quite distinct from that employed by Ins(1,4,5)P(3) and manno-adenophostin and is not related to equilibrium affinities.


Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.
Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.


Telepsychiatry integration of mental health services into rural primary care settings.
From a population health perspective, the mental health care system in the USA faces two fundamental challenges: (1) a lack of capacity and (2) an inequitable geographic distribution of services. Telepsychiatry can help address the equity problem, and if applied thoughtfully, can also help address the capacity problem. In this paper we describe how telepsychiatry can be used to address the capacity and equity challenges related to the delivery of mental health services in rural areas. Five models of telepsychiatry are described, including (1) the traditional telepsychiatry referral model, (2) The telepsychiatry collaborative care model, (3) the telepsychiatry behavioural health consultant model, (4) the telepsychiatry consultation-liaison model, and (5) the telepsychiatry curbside consultation model. The strong empirical evidence for the telepsychiatry collaborative care model is presented along with two case studies of telepsychiatry consultation in the context of the telepsychiatry collaborative care model. By placing telepsychiatrists and tele-therapists in consultation roles, telepsychiatry collaborative care has the potential to leverage scarce specialist mental health resources to reach more patients, thereby allowing these providers to have a greater population level impact compared to traditional referral models of care. Comparative effectiveness trials are needed to identify which models of telepsychiatry are the most appropriate for patients with complex psychiatric disorders.


Effectiveness of 2-year application of school-based chlorhexidine varnish, sodium fluoride gel, and dental health education programs in high-risk adolescents.
To compare the caries preventive effects of 2-year application of school-based chlorhexidine varnish, sodium fluoride gel, and dental health education programs among a high-risk group of 11- to 13-year-olds with low caries activity. A total of 149 subjects who had previous caries experience in the primary dentition and Streptococcus mutans levels higher than 10(5) at baseline with 0 DMFS index were selected for this randomized clinical trial. Subjects were allocated to one of 3 groups for treatment with chlorhexidine varnish (n = 50), sodium fluoride gel (n = 50), or a dental health education program (n = 49), which were repeated throughout the 2-year study. The outcomes examined at the end of the study were the caries increment (DMFS index), dental plaque scores, and salivary S mutans counts. The subjects in the education group showed a significant increase in the salivary levels of S mutans in comparison with the other groups (P = .004), but there was no significant difference among the groups in the caries increment after 2 years, with mean DMFS +/- SD as 0.95 +/- 1.33, 0.88 +/- 1.47, and 1.05 +/- 2.01 in the chlorhexidine varnish, sodium fluoride gel, and education groups, respectively. There were also no significant differences in the pre- and posttreatment plaque scores between the groups. Although all 3 preventive programs in this high-caries-risk group of children with low caries activity resulted in similar plaque and caries values after 2 years, longer follow-up studies are needed to clarify the effect of reduction in S mutans growth by chemotherapeutic agents in caries incidence.


Trend-Centric Motion Visualization: Designing and Applying a New Strategy for Analyzing Scientific Motion Collections.
In biomechanics studies, researchers collect, via experiments or simulations, datasets with hundreds or thousands of trials, each describing the same type of motion (e.g., a neck flexion-extension exercise) but under different conditions (e.g., different patients, different disease states, pre- and post-treatment). Analyzing similarities and differences across all of the trials in these collections is a major challenge. Visualizing a single trial at a time does not work, and the typical alternative of juxtaposing multiple trials in a single visual display leads to complex, difficult-to-interpret visualizations. We address this problem via a new strategy that organizes the analysis around motion trends rather than trials. This new strategy matches the cognitive approach that scientists would like to take when analyzing motion collections. We introduce several technical innovations making trend-centric motion visualization possible. First, an algorithm detects a motion collection's trends via time-dependent clustering. Second, a 2D graphical technique visualizes how trials leave and join trends. Third, a 3D graphical technique, using a median 3D motion plus a visual variance indicator, visualizes the biomechanics of the set of trials within each trend. These innovations are combined to create an interactive exploratory visualization tool, which we designed through an iterative process in collaboration with both domain scientists and a traditionally-trained graphic designer. We report on insights generated during this design process and demonstrate the tool's effectiveness via a validation study with synthetic data and feedback from expert musculoskeletal biomechanics researchers who used the tool to analyze the effects of disc degeneration on human spinal kinematics.


Safety and Efficacy of Medical Cannabis in Fibromyalgia.
Chronic pain may be treated by medical cannabis. Yet, there is scarce evidence to support the role of medical cannabis in the treatment of fibromyalgia. The aim of the study was to investigate the characteristics, safety, and effectiveness of medical cannabis therapy for fibromyalgia. A prospective observational study with six months follow-up period based on fibromyalgia patients who were willing to answer questionnaire in a specialized medical cannabis clinic between 2015 and 2017. Among the 367 fibromyalgia patients, the mean age was 52.9 ± 15.1, of whom 301 (82.0%) were women. Twenty eight patients (7.6%) stopped the treatment prior to the six months follow-up. The six months response rate was 70.8%. Pain intensity (scale 0-10) reduced from a median of 9.0 at baseline to 5.0 (p < 0.001), and 194 patients (81.1%) achieved treatment response. In a multivariate analysis, age above 60 years (odds ratio [OR] 0.34, 95% C.I 0.16-0.72), concerns about cannabis treatment (OR 0.36, 95% C.I 0.16-0.80), spasticity (OR 2.26, 95% C.I 1.08-4.72), and previous use of cannabis (OR 2.46 95% C.I 1.06-5.74) were associated with treatment outcome. The most common adverse effects were mild and included dizziness (7.9%), dry mouth (6.7%), and gastrointestinal symptoms (5.4%). Medical cannabis appears to be a safe and effective alternative for the treatment of fibromyalgia symptoms. Standardization of treatment compounds and regimens are required.


The Prevalence of Frailty and its Associated Factors in Japanese Hemodialysis Patients.
The population undergoing dialysis is aging worldwide, particularly in Japan. The clinical condition of frailty is the most problematic expression in the elderly population. Potential pathophysiological factors of frailty present in patients with CKD and are accentuated in patients with ESRD. The aim of this study was to identify the prevalence and predictors of frailty in Japanese HD patients. This study was a multicenter, cross-sectional and observational investigation conducted at 6 institutions. To evaluate frailty, the modified Fried's frailty phenotype adjusted for Japanese as the self-reported questionnaire was used. Of the 542 patients visiting each institution, 388 were enrolled in this study. In total, 26.0% of participants were categorized as not-frailty, 52.6% as pre-frailty and 21.4% as frailty. The prevalence of frailty increased steadily with age and was more prevalent in females than in males and the subjects with frailty received polypharmacy. A multivariate logistic regression analysis revealed that the factors independently associated with frailty were the following: female gender (odds ratio [OR] = 3.661, 95% confidence interval [CI] 1.398-9.588), age (OR = 1.065, 95% CI 1.014-1.119), age ≥ 75 years old (OR = 4.892, 95% CI 1.715-13.955), body mass index (BMI) < 18.5 (OR = 0.110, 95% CI 0.0293-0.416), number of medications being taken (OR = 1.351, 95% CI 1.163-1.570), diabetes mellitus (DM) (OR = 2.765, 95% CI 1.081-7.071) and MNA-SF ≤ 11 (OR = 7.405, 95% CI 2.732-20.072). Frailty was associated with the accumulation of risk factors. The prevalence of frailty in Japanese patients with HD was relatively lower than that previously reported in Western developed countries; however, it was extremely high compared to the general population regardless of age. Our findings suggest that frailty might be associated with an increase in the prevalence of adverse health outcomes in patients with HD.


Impact of fiber outer boundaries on leaky mode losses in leakage channel fibers.
In a leakage channel fiber, the desired fundamental mode (FM) has negligible waveguide loss. Higher-order modes (HOM) are designed to have much higher waveguide losses so that they are practically eliminated during propagation. Coherent reflection at the fiber outer boundary can lead to additional confinement especially for highly leaky HOM, leading to lower HOM losses than what are predicted by conventional FEM mode solver considering infinite cladding. In this work, we conducted, for the first time, careful measurements of HOM losses in two leakage channel fibers (LCF) with circular and rounded hexagonal boundary shapes respectively. Impact on HOM losses from coiling, fiber boundary shapes and coating indexes were studied in comparison to simulations. This work, for the first time, demonstrates the limit of the simulation method commonly used in the large-mode-area fiber designs and the need for an improved approach. More importantly, this work also demonstrates that a deviation from circular fiber outer shape may be an effective method to mitigate HOM loss reduction from coherent reflection from fiber outer boundary, even in double-clad fibers, with HOM losses in excess of 20 dB/m measured in the hexagonal LCF with ~50 µm core diameter while keeping FM loss negligible.


Important aspects of care and assistance for parents of children, 0-18 years of age, on or off treatment for cancer. Parent and nurse perceptions.
Important aspects of care and assistance for parents of children (0-18 years) diagnosed with cancer were investigated. Parents (N=114) and nurses (N=121) were asked the following questions: 'What caring aspects are important for you/the parent to feel cared for?' and 'What help, if any, do you/the parent need outside the hospital?' Nurses were asked to answer for a certain parent. Data were analyzed by content analysis. The following aspects of care were identified: accessible care, clinical competence, continuity, emotional support, information, participation in care, participation in decision making, physical ambience, shift in parenting roles, social competence, temporary assistance, own child is well cared for, and time. Most parents mentioned the importance of social competence and information, most nurses mentioned the importance of information and emotional support. The following aspects of assistance were identified: accessible care, emotional support, financial support, instrumental support, and support to live a normal family/social life. A third of the parents and a fourth of the nurses were of the opinion that the parent did not need any assistance. Most parents who mentioned a need of assistance mentioned a need for emotional and instrumental support. Most nurses mentioned a parental need for emotional support and accessible care.


DIFFERENTIAL FERRIOXAMINE TEST FOR MEASURING CHELATABLE BODY IRON.
The differential ferrioxamine test is a simple method for the measurement of chelation of body iron by desferrioxamine. A single six-hour specimen of urine is obtained after intravenous Desferal, accompanied by (59)Fe-ferrioxamine. Two values are measured: F(d), the excretion of ferrioxamine derived from body iron by chelation, and F(ex), the proportion of ferrioxamine excreted from a known intravenous dose. The data enables F(v), chelation of iron in vivo, to be calculated by simple proportion. Desferrioxamine chelation proceeds for about half an hour after injection. The results in normal subjects, in cases with known high iron stores, and in cases of iron-deficiency anaemia are described. High, normal, and low body iron states have been differentiated. F(v) values in the higher ranges obtained in iron-storage diseases and in haemolytic states are differentiated by the pattern of excretion, high F(d) values and low F(ex) values respectively. IT IS SUGGESTED THAT THERE ARE TWO MAIN SOURCES OF CHELATABLE BODY IRON: as ferritin-haemosiderin and as iron newly released from haem in a more readily chelatable form. The significance of variable chelation susceptibility in iron metabolism is briefly discussed. It is suggested that variable chelatability of different sources of body iron may explain the preferential utilization of iron released from red cells or absorbed from the intestine, rather than storage iron, in the biosynthesis of haem.


[Cortical spreading depression and molecular genetics in migraine].
Cortical spreading depression (CSD) is a slowly propagated wave of depolarization of neurons and glial cells, followed by a subsequent sustained suppression of spontaneous neuronal activity. Functional imaging studies of migraine patients have shown dramatic changes in blood flow and brain activity whose characteristics are similar to those of CSD, implicated in migraine visual aura. Although the trigeminal nerve innervates the meninges and participates in the genesis of migraine headaches, triggering mechanisms remain controversial and poorly understood. It is demonstrated by animal models that CSD activates trigeminovascular afferents and evokes a series of cortical meningeal and brainstem events consistent with the development of headache. Three familial hemiplegic migraine, a rare monogenic subtype of migraine with aura, genes have been identified, which all encode ion transporters, suggesting that disturbances in ion and neurotransmitter balances in the brain are responsible for this migraine type. Additional molecular insight into the pathophysiology of migraine may come from other monogenic syndromes such as CADASIL, RVCL. Several genetic associations with candidate migraine genes like ESR1, MTHFR, and INSR, have been convincingly replicated. The genome-wide association studies may be a successful strategy toward identification of migraine susceptibility genes.


Heme oxygenase-1 deficiency leads to disrupted response to acute stress in stem cells and progenitors.
An effective response to extreme hematopoietic stress requires an extreme elevation in hematopoiesis and preservation of hematopoietic stem cells (HSCs). These diametrically opposed processes are likely to be regulated by genes that mediate cellular adaptation to physiologic stress. Herein, we show that heme oxygenase-1 (HO-1), the inducible isozyme of heme degradation, is a key regulator of these processes. Mice lacking one allele of HO-1 (HO-1(+/-)) showed accelerated hematopoietic recovery from myelotoxic injury, and HO-1(+/-) HSCs repopulated lethally irradiated recipients with more rapid kinetics. However, HO-1(+/-) HSCs were ineffective in radioprotection and serial repopulation of myeloablated recipients. Perturbations in key stem cell regulators were observed in HO-1(+/-) HSCs and hematopoietic progenitors (HPCs), which may explain the disrupted response of HO-1(+/-) HPCs and HPCs to acute stress. Control of stem cell stress response by HO-1 presents opportunities for metabolic manipulation of stem cell-based therapies.


Soy protein, phytate, and iron absorption in humans.
The effect of reducing the phytate in soy-protein isolates on nonheme-iron absorption was examined in 32 human subjects. Iron absorption was measured by using an extrinsic radioiron label in liquid-formula meals containing hydrolyzed corn starch, corn oil, and either egg white or one of a series of soy-protein isolates with different phytate contents. Iron absorption increased four- to fivefold when phytic acid was reduced from its native amount of 4.9-8.4 to less than 0.01 mg/g of isolate. Even relatively small quantities of residual phytate were strongly inhibitory and phytic acid had to be reduced to less than 0.3 mg/g of isolate (corresponding to less than 10 mg phytic acid/meal) before a meaningful increase in iron absorption was observed. However, even after removal of virtually all the phytic acid, iron absorption from the soy-protein meal was still only half that of the egg white control. It is concluded that phytic acid is a major inhibitory factor of iron absorption in soy-protein isolates but that other factors contribute to the poor bioavailability of iron from these products.


Omega-3 fatty acid EPA improves regenerative capacity of mouse skeletal muscle cells exposed to saturated fat and inflammation.
Sarcopenic obesity is characterised by high fat mass, low muscle mass and an elevated inflammatory environmental milieu. We therefore investigated the effects of elevated inflammatory cytokine TNF-α (aging/obesity) and saturated fatty acid, palmitate (obesity) on skeletal muscle cells in the presence/absence of EPA, a-3 polyunsaturated fatty acid with proposed anti-inflammatory, anti-obesity activities. In the present study we show that palmitate was lipotoxic, inducing high levels of cell death and blocking myotube formation. Cell death under these conditions was associated with increased caspase activity, suppression of differentiation, reductions in both creatine kinase activity and gene expression of myogenic factors; IGF-II, IGFBP-5, MyoD and myogenin. However, inhibition of caspase activity via administration of Z-VDVAD-FMK (caspase-2), Z-DEVD-FMK (caspase-3) and ZIETD-KMK (caspase 8) was without effect on cell death. By contrast, lipotoxicity associated with elevated palmitate was reduced with the MEK inhibitor PD98059, indicating palmitate induced cell death was MAPK mediated. These lipotoxic conditions were further exacerbated in the presence of inflammation via TNF-α co-administration. Addition of EPA under cytotoxic stress (TNF-α) was shown to partially rescue differentiation with enhanced myotube formation being associated with increased MyoD, myogenin, IGF-II and IGFBP-5 expression. EPA had little impact on the cell death phenotype observed in lipotoxic conditions but did show benefit in restoring differentiation under lipotoxic plus cytotoxic conditions. Under these conditions Id3 (inhibitor of differentiation) gene expression was inversely linked with survival rates, potentially indicating a novel role of EPA and Id3 in the regulation of apoptosis in lipotoxic/cytotoxic conditions. Additionally, signalling studies indicated the combination of lipo- and cyto-toxic effects on the muscle cells acted through ceramide, JNK and MAPK pathways and blocking these pathways using PD98059 (MEK inhibitor) and Fumonisin B1 (ceramide inhibitor) significantly reduced levels of cell death. These findings highlight novel pathways associated with in vitro models of lipotoxicity (palmitate-mediated) and cytotoxicity (inflammatory cytokine mediated) in the potential targeting of molecular modulators of sarcopenic obesity.


Role of P-glycoprotein in drug disposition.
P-glycoprotein (Pgp), which is coded by human MDR1 (multidrug resistance) gene, is an energy-dependent efflux pump that exports its substrates out of the cell. Human Pgp is present not only in tumor cells but also in normal tissues including the kidney, liver, small and large intestine, brain, testis, and adrenal gland, and the pregnant uterus. This tissue distribution indicates that Pgp plays a significant role in excreting xenobiotics and metabolites into urine and bile and into the intestinal lumen, and in preventing their accumulation in the brain. The roles of Pgp in drug disposition include a urinary excretion mechanism in the kidney, a biliary excretion mechanism in the liver, an absorption barrier and determinant of oral bioavailability, and the blood-brain barrier that limits the accumulation of drugs in the brain. The inhibition of the transporting function of Pgp can cause clinically significant drug interactions and can also increase the penetration of drugs into the brain and the accumulation of drugs in the brain. Digoxin is a typical substrate for Pgp, which regulates the renal tubular secretion and brain distribution of digoxin. At present, potent Pgp inhibitors are being investigated in clinical trials aimed at overcoming the intrinsic or acquired multidrug resistance of human cancers. The clinical application of these Pgp inhibitors should take into consideration the physiologic function of pgp.


The structure and function relationship in glaucoma: implications for detection of progression and measurement of rates of change.
To evaluate the relationship between change in estimated retinal ganglion cell (RGC) counts and change in measures of functional and structural damage in glaucoma, from cross-sectional data. The study included 397 eyes of 397 patients with glaucoma, suspects, and healthy individuals. All eyes underwent testing with standard automated perimetry (SAP) and spectral-domain optical coherence tomography (SD-OCT). Estimates of retinal ganglion cell (RGC) counts were obtained from SAP and SD-OCT using a previously derived algorithm. Smoothing spline curves were fitted to investigate the relationship between functional/structural parameters and RGC counts. The first derivatives (i.e., slopes) of these curves were obtained to investigate the relationship between changes in these measures. A nonlinear relationship was observed between SAP mean deviation (MD) and RGC counts. The same amount of RGC loss corresponded to largely different amounts of MD change depending on the stage of the disease. For SDOCT average retinal nerve fiber layer (RNFL) thickness, a linear relationship was seen with RGC counts throughout most of the spectrum of disease, but reaching a plateau in advanced glaucoma. Changes in RGC counts for eyes with early damage corresponded to small changes in MD, but to relatively larger changes in RNFL thickness. For eyes with advanced disease, changes in RGC counts produced relatively larger changes in MD but only small or no changes in average RNFL thickness. The analysis and interpretation of rates of SAP and SD-OCT change, as indicators of the velocity of neural damage in glaucoma, should take into account the severity of the disease.


Enrichments/Derichments of Root-Associated Bacteria Related to Plant Growth and Nutrition Caused by the Growth of an EPSPS-Transgenic Maize Line in the Field.
During the past decades, the effects of the transgenic crops on soil microbial communities have aroused widespread interest of scientists, which was mainly related to the health and growth of plants. In this study, the maize root-associated bacterial communities of 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) transgenic glyphosate-tolerant (GT) maize line CC-2 (CC2) and its recipient variety Zhengdan958 (Z958) were compared at the tasseling and flowering stages by high-throughput sequencing of V3-V4 hypervariable regions of 16S rRNA gene (16S rDNA) amplicons via Illumina MiSeq. In addition, real-time quantitative PCR (qPCR) was also performed to analyze the nifH gene abundance between CC2 and Z958. Our results showed no significant difference in alpha/beta diversity of root-associated bacterial communities at the tasseling or flowering stage between CC2 and Z958 under field growth conditions. The relative abundances of the genera Bradyrhizobium and Bacillus including species B. cereus and B. muralis were significantly lower in the roots of CC2 than that of Z985 under field conditions. Both these species are regarded as plant growth promoting bacteria (PGPB), as they belong to both nitrogen-fixing and phosphate-solubilizing bacterial genera. The comparison of the relative abundance of nitrogen-fixing/phosphate-solubilizing bacteria at the class, order or family levels indicated that only one class Bacilli, one order Bacillales and one family Bacillaceae were found to be significantly lower in the roots of CC2 than that of Z985. These bacteria were also enriched in the roots and rhizospheric soil than in the surrounding soil at both two stages. Furthermore, the class Betaproteobacteria, the order Burkholderiales, the family Comamonadaceae, and the genus Acidovorax were significantly higher in the roots of CC2 than that of Z985 at the tasseling stage, meanwhile the order Burkholderiales and the family Comamonadaceae were also enriched in the roots than in the rhizospheric soil at both stages. Additionally, the nifH gene abundance at the tasseling stage in the rhizosphere soil also showed significant difference. The relative abundance of nifH gene was higher in the root samples and lower in the surrounding soil, which implicated that the roots of maize tend to be enriched in nitrogen-fixing bacteria.


Chest CT Findings in Coronavirus Disease-19 (COVID-19): Relationship to Duration of Infection.
In this retrospective study, chest CTs of 121 symptomatic patients infected with coronavirus disease-19 (COVID-19) from four centers in China from January 18, 2020 to February 2, 2020 were reviewed for common CT findings in relationship to the time between symptom onset and the initial CT scan (i.e. early, 0-2 days (36 patients), intermediate 3-5 days (33 patients), late 6-12 days (25 patients)). The hallmarks of COVID-19 infection on imaging were bilateral and peripheral ground-glass and consolidative pulmonary opacities. Notably, 20/36 (56%) of early patients had a normal CT. With a longer time after the onset of symptoms, CT findings were more frequent, including consolidation, bilateral and peripheral disease, greater total lung involvement, linear opacities, "crazy-paving" pattern and the "reverse halo" sign. Bilateral lung involvement was observed in 10/36 early patients (28%), 25/33 intermediate patients (76%), and 22/25 late patients (88%).


Transcription factor interplay during Drosophila haematopoiesis.
Transcription factors play a key role in regulating blood cell fate choice and differentiation. In this review, we examine current knowledge of the function and mode of action of the transcription factors implicated in haematopoiesis in Drosophila. We particularly emphasize regulation by transcription factors and cofactors, such as GATA, FOG and RUNX, whose homologues in mammals also control blood cell formation and we discuss the cross talks between these transcriptional regulators at the different stages of haematopoietic cell fate decision.


Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome.
To resolve the genetic heterogeneity within pediatric high-risk B-precursor acute lymphoblastic leukemia (ALL), a clinically defined poor-risk group with few known recurring cytogenetic abnormalities, we performed gene expression profiling in a cohort of 207 uniformly treated children with high-risk ALL. Expression profiles were correlated with genome-wide DNA copy number abnormalities and clinical and outcome features. Unsupervised clustering of gene expression profiling data revealed 8 unique cluster groups within these high-risk ALL patients, 2 of which were associated with known chromosomal translocations (t(1;19)(TCF3-PBX1) or MLL), and 6 of which lacked any previously known cytogenetic lesion. One unique cluster was characterized by high expression of distinct outlier genes AGAP1, CCNJ, CHST2/7, CLEC12A/B, and PTPRM; ERG DNA deletions; and 4-year relapse-free survival of 94.7% ± 5.1%, compared with 63.5% ± 3.7% for the cohort (P = .01). A second cluster, characterized by high expression of BMPR1B, CRLF2, GPR110, and MUC4; frequent deletion of EBF1, IKZF1, RAG1-2, and IL3RA-CSF2RA; JAK mutations and CRLF2 rearrangements (P < .0001); and Hispanic ethnicity (P < .001) had a very poor 4-year relapse-free survival (21.0% ± 9.5%; P < .001). These studies reveal striking clinical and genetic heterogeneity in high-risk ALL and point to novel genes that may serve as new targets for diagnosis, risk classification, and therapy.


Oscillatory Dynamics of Perceptual to Conceptual Transformations in the Ventral Visual Pathway.
Object recognition requires dynamic transformations of low-level visual inputs to complex semantic representations. Although this process depends on the ventral visual pathway, we lack an incremental account from low-level inputs to semantic representations and the mechanistic details of these dynamics. Here we combine computational models of vision with semantics and test the output of the incremental model against patterns of neural oscillations recorded with magnetoencephalography in humans. Representational similarity analysis showed visual information was represented in low-frequency activity throughout the ventral visual pathway, and semantic information was represented in theta activity. Furthermore, directed connectivity showed visual information travels through feedforward connections, whereas visual information is transformed into semantic representations through feedforward and feedback activity, centered on the anterior temporal lobe. Our research highlights that the complex transformations between visual and semantic information is driven by feedforward and recurrent dynamics resulting in object-specific semantics.


[Melatonin, synthetic analogs, and the sleep/wake rhythm].
Melatonin, a widespread hormone in the animal kingdom, is produced by several organs and tissues besides the pineal gland. Whilst extrapineal melatonin behaves as a cytoprotective molecule, the pineal produces the hormone in a rhythmic manner. The discovery of melatonin in 1958, and the characterization of its synthesis somewhat later, let to the description of its photoperiodic regulation and its relationship with the biological rhythms such as the sleep/wake rhythm. The suprachiasmatic nuclei are the anatomical seat of the biological clock, represented by the clock genes, which code for the period and frequency of the rhythms. The photoperiod synchronizes the activity of the auprachiasmatic biological clock, which in turn induces the melatonin's rhythm. The rhythm of melatonin, peaking at 2-3 am, acts as an endogenous synchronizer that translates the environmental photoperiodic signal in chemical information for the cells. The sleep/wake cycle is a typical biological rhythm synchronized by melatonin, and the sleep/wake cycle alterations of chronobiological origin, are very sensitive to melatonin treatment. Taking advantage of the chronobiotic and antidepressive properties of melatonin, a series of synthetic analogs of this hormone, with high interest in insomnia, are now available. Melatonin is a highly effective chronobiotic in the treatment of chronobiological alterations of the sleep/wake cycle. From a pharmacokinetic point of view, the synthetic drugs derived from melatonin are interesting tools in the therapy of these alterations.


What is the optimal treatment of large brain metastases? An argument for a multidisciplinary approach.
Single-modality treatment of large brain metastases (>2 cm) with whole-brain irradiation, stereotactic radiosurgery (SRS) alone, or surgery alone is not effective, with local failure (LF) rates of 50% to 90%. Our goal was to improve local control (LC) by using multimodality therapy of surgery and adjuvant SRS targeting the resection cavity. We retrospectively evaluated 97 patients with brain metastases >2 cm in diameter treated with surgery and cavity SRS. Local and distant brain failure (DF) rates were analyzed with competing risk analysis, with death as a competing risk. The overall survival rate was calculated by the Kaplain-Meier product-limit method. The median imaging follow-up duration for all patients was 10 months (range, 1-80 months). The 12-month cumulative incidence rates of LF, with death as a competing risk, were 9.3% (95% confidence interval [CI], 4.5%-16.1%), and the median time to LF was 6 months (range, 3-17 months). The 12-month cumulative incidence rate of DF, with death as a competing risk, was 53% (95% CI, 43%-63%). The median survival time for all patients was 15.6 months. The median survival times for recursive partitioning analysis classes 1, 2, and 3 were 33.8, 13.7, and 9.0 months, respectively (p = 0.022). On multivariate analysis, Karnofsky Performance Status (≥80 vs. <80; hazard ratio 0.54; 95% CI 0.31-0.94; p = 0.029) and maximum preoperative tumor diameter (hazard ratio 1.41; 95% CI 1.08-1.85; p = 0.013) were associated with survival. Five patients (5%) required intervention for Common Terminology Criteria for Adverse Events v4.02 grade 2 and 3 toxicity. Surgery and adjuvant resection cavity SRS yields excellent LC of large brain metastases. Compared with other multimodality treatment options, this approach allows patients to avoid or delay whole-brain irradiation without compromising LC.


Universal two-point interaction of mediator KIX with 9aaTAD activation domains.
The nine-amino-acid activation domain (9aaTAD) is defined by a short amino acid pattern including two hydrophobic regions (positions p3-4 and p6-7). The KIX domain of mediator transcription CBP interacts with the 9aaTAD domains of transcription factors MLL, E2A, NF-kB, and p53. In this study, we analyzed the 9aaTADs-KIX interactions by nuclear magnetic resonance. The positions of three KIX helixes α1-α2-α3 are influenced by sterically-associated hydrophobic I611, L628, and I660 residues that are exposed to solvent. The positions of two rigid KIX helixes α1 and α2 generate conditions for structural folding in the flexible KIX-L12-G2 regions localized between them. The three KIX I611, L628, and I660 residues interact with two 9aaTAD hydrophobic residues in positions p3 and p4 and together build a hydrophobic core of five residues (5R). Numerous residues in 9aaTAD position p3 and p4 could provide this interaction. Following binding of the 9aaTAD to KIX, the hydrophobic I611, L628, and I660 residues are no longer exposed to solvent and their position changes inside the hydrophobic core together with position of KIX α1-α2-α3 helixes. The new positions of the KIX helixes α1 and α2 allow the KIX-L12-G2 enhanced formation. The second hydrophobic region of the 9aaTAD (positions p6 and p7) provides strong binding with the KIX-L12-G2 region. Similarly, multiple residues in 9aaTAD position p6 and p7 could provide this interaction. In conclusion, both 9aaTAD regions p3, p4 and p6, p7 provide co-operative and highly universal binding to mediator KIX. The hydrophobic core 5R formation allows new positions of the rigid KIX α-helixes and enables the enhanced formation of the KIX-L12-G2 region. This contributes to free energy and is the key for the KIX-9aaTAD binding. Therefore, the 9aaTAD-KIX interactions do not operate under the rigid key-and-lock mechanism what explains the 9aaTAD natural variability.


Immediate responses to backpack carriage on postural angles in young adults: A crossover randomized self-controlled study with repeated measures.
Heavy backpacks have been associated with various postural changes and consequently musculoskeletal disorders. We evaluated the immediate responses of varying backpack loads on cranio-vertebral angle (CVA), sagittal shoulder angle (SSA) and trunk forward lean (TFL) of young adults between the ages of 18-25 years. This was a 3×3 cross over randomized controlled study with repeated measures among a convenience sample of young adults (n = 30; 50% male, 50% female). Each participant in a standing posture was assessed at four different loads: no backpack, carrying backpack of 5%, 10%, and 15% of body weight (BW). A sagittal photograph was taken of the area of the body corresponding to spinal angle during each of these test conditions to allow for later analysis of postural deviations. Comparisons of the mean deviations of the different postural angles from baseline and between test conditions were made using ANOVA at p≤0.05. Generally, there was a trend toward a decrease in the CVA and TFL with increasing backpack loads. Specifically, a significant decrease was seen for TFL at10% and 15% BW loads when compared with no load condition. In contrast, the decrease in CVA was only significant between no load condition and 15% body weight load. The SSA remained unchanged with backpack weight within 15% BW. Whereas the SSA of young adults may not be upset by an acute loading with a backpack within 15% of body weight, a 15% BW backpack led to more forward posture of the head on the neck. In addition, backpack load as low as 10% BW is enough to cause an immediate forward lean of the trunk.


The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway.
Transient induction of p53 can cause reversible quiescence and irreversible senescence. Using nutlin-3a (a small molecule that activates p53 without causing DNA damage), we have previously identified cell lines in which nutlin-3a caused quiescence. Importantly, nutlin-3a caused quiescence by actively suppressing the senescence program (while still causing cell cycle arrest). Noteworthy, in these cells nutlin-3a inhibited the mTOR (mammalian Target of Rapamycin) pathway, which is known to be involved in the senescence program. Here we showed that shRNA-mediated knockdown of TSC2, a negative regulator of mTOR, partially converted quiescence into senescence in these nutlin-arrested cells. In accord, in melanoma cell lines and mouse embryo fibroblasts, which easily undergo senescence in response to p53 activation, nutlin-3a failed to inhibit mTOR. In these senescence-prone cells, the mTOR inhibitor rapamycin converted nutlin-3a-induced senescence into quiescence. We conclude that status of the mTOR pathway can determine, at least in part, the choice between senescence and quiescence in p53-arrested cells.


Peutz-Jeghers syndrome and duodeno-jejunal adenocarcinoma--therapeutic implications.
The Peutz-Jeghers syndrome (PJS) is an autosomal dominant hamartomatous poliposis describred in 1921. Hemminki in 1997 described the presence of LKB-1 mutation tumor-suppressor gen.The patients with PJS develop a higher cumulative incidence of gastrointestinal, pancreas and extraintestinal tumors, being occasion of a renew interest on hamartomatous polyposis syndromes regarding the clinical care, cancer surveillance treatment and long term follow-up.We report the case of a 38 years old male, diagnosed of PJS who developed a multiple adenocarcinoma in duodenum and yeyunum. Surgically treated and with a long-term free disease survival of 11 years represents the sixth case reported in the spanish literature of PJS associated with a gastrointestinal tumor.A critical review, molecular alterations and the established criteria of tumor screening and surveillance are reviewed.


Non-invasively differentiating extent of liver fibrosis by visualizing hepatic integrin αvβ3 expression with an MRI modality in mice.
To explore the potential of a dendrimer nanoprobe labeled with cyclic arginine-glycine-aspartic acid pentapeptide (cRGDyK) as a magnetic resonance imaging (MRI) tracer to non-invasively differentiate the extent of liver fibrosis. Synthetic dendrimer nanoprobes were labeled with cRGDyK (Den-RGD) to form a formulation of hepatic stellate cell (HSC)-specific MRI tracer. An MRI modality was employed to visualize hepatic Den-RGD deposition in a mouse model of liver fibrosis caused by thioacetamide treatment. Den-RGD bound to activated HSCs via integrin αvβ3 receptors. The labeling of nanoprobes with cRGDyK increased their affinity to and accelerated their uptake by activated HSCs. Most of intravenously administrated Den-RGD nanoprobes deposited in the fibrotic areas, and the deposited amount was paralleled with the severity of liver fibrosis. Majority of cells taking-up Den-RGD was found to be activated HSCs in fibrotic livers. An MRI modality using Den-RGD as a tracer demonstrated that the relative hepatic T1-weighed MR signal value was increased in parallel with the severity of liver fibrosis. The extent of Den-RGD deposition reflects integrin αvβ3 expression in activated HSCs, and Den-RGD appears to be a useful formulation of MRI tracer and may non-invasively and quantitatively assess the extent of liver fibrosis.


TH1 cell-inducing Escherichia coli strain identified from the small intestinal mucosa of patients with Crohn's disease.
Dysbiotic microbiota contributes to the pathogenesis of Crohn's disease (CD) by regulating the immune system. Although pro-inflammatory microbes are probably enriched in the small intestinal (SI) mucosa, most studies have focused on fecal microbiota. This study aimed to examine jejunal and ileal mucosal specimens from patients with CD via double-balloon enteroscopy. Comparative microbiome analysis revealed that the microbiota composition of CD SI mucosa differs from that of non-CD controls, with an increased population of several families, including Enterobacteriaceae, Ruminococcaceae, and Bacteroidaceae. Upon anaerobic culturing of the CD SI mucosa, 80 bacterial strains were isolated, from which 9 strains representing 9 distinct species (Escherichia coli, Ruminococcus gnavus, Klebsiella pneumoniae, Erysipelatoclostridium ramosum, Bacteroides dorei, B. fragilis, B. uniformis, Parabacteroides distasonis, and Streptococcus pasteurianus) were selected on the basis of their significant association with CD. The colonization of germ-free (GF) mice with the 9 strains enhanced the accumulation of TH1 cells and, to a lesser extent, TH17 cells in the intestine, among which an E. coli strain displayed high potential to induce TH1 cells and intestinal inflammation in a strain-specific manner. The present results indicate that the CD SI mucosa harbors unique pro-inflammatory microbiota, including TH1 cell-inducing E. coli, which could be a potential therapeutic target.


Telogen effluvium following bivalent human papillomavirus vaccine administration: a report of two cases.
We describe two cases of telogen effluvium occurring in two 11-year-old children following bivalent human papillomavirus (HPV) vaccine administration. The two children began to lose their hair following the second HPV vaccine dose. Alopecia worsened following the third vaccine dose and then resolved spontaneously within a few months. In both cases, laboratory analysis and psychiatric evaluation excluded causes other than anti-HPV vaccine. Social discomfort and isolation were associated with alopecia in the two children. The clinical presentation was consistent with a pattern of telogen effluvium. The identification of specific vaccine components responsible for triggering the adverse event remains difficult. In similar cases, suspension of immunization is not recommended, as it provides health benefits that overcome the possible adverse effect of transient telogen effluvium. Caregivers should ensure psychiatric support to their patients to manage the social and emotional distress that might be associated with hair loss.


Natural locomotion based on a reduced set of inertial sensors: Decoupling body and head directions indoors.
Inertial sensors offer the potential for integration into wireless virtual reality systems that allow the users to walk freely through virtual environments. However, owing to drift errors, inertial sensors cannot accurately estimate head and body orientations in the long run, and when walking indoors, this error cannot be corrected by magnetometers, due to the magnetic field distortion created by ferromagnetic materials present in buildings. This paper proposes a technique, called EHBD (Equalization of Head and Body Directions), to address this problem using two head- and shoulder-located magnetometers. Due to their proximity, their distortions are assumed to be similar and the magnetometer measurements are used to detect when the user is looking straight forward. Then, the system corrects the discrepancies between the estimated directions of the head and the shoulder, which are provided by gyroscopes and consequently are affected by drift errors. An experiment is conducted to evaluate the performance of this technique in two tasks (navigation and navigation plus exploration) and using two different locomotion techniques: (1) gaze-directed mode (GD) in which the walking direction is forced to be the same as the head direction, and (2) decoupled direction mode (DD) in which the walking direction can be different from the viewing direction. The obtained results show that both locomotion modes show similar matching of the target path during the navigation task, while DD's path matches the target path more closely than GD in the navigation plus exploration task. These results validate the EHBD technique especially when allowing different walking and viewing directions in the navigation plus exploration tasks, as expected. While the proposed method does not reach the accuracy of optical tracking (ideal case), it is an acceptable and satisfactory solution for users and is much more compact, portable and economical.


Encapsulation of Adenovirus BMP2-Transduced Cells with PEGDA Hydrogels Allows Bone Formation in the Presence of Immune Response.
Gene therapy approaches have been difficult to implement due to pre-existing immunity against the virus used for delivery. To circumvent this problem, a cell-based approach was developed that avoided the use of free virus within the animal. However, even cells transduced in vitro with E1- to E3-deleted adenovirus encoding bone morphogenetic protein 2 (AdBMP2) resulted in the production of virus-neutralizing antibodies in mice. Furthermore, when mice received an intramuscular injection of nonencoding adenovirus (AdEmpty)-transduced cells, AdBMP2-transduced cells were unable to launch bone formation when an intramuscular injection of these BMP2-producing cells was delivered 1 week later. This phenomenon was not observed in NOD/SCID mice, and could be overcome in C57BL/6 mice by encapsulating the adenovirus-transduced cells in a nondegradable hydrogel poly(ethylene glycol) diacrylate (PEGDA). Data collectively suggest that PEGDA hydrogel encapsulation of AdBMP2-transduced cells prevents pre-existing immunity from suppressing BMP2-induced bone formation.


Risks Posed by Reston, the Forgotten Ebolavirus.
Out of the five members of the Ebolavirus family, four cause life-threatening disease, whereas the fifth, Reston virus (RESTV), is nonpathogenic in humans. The reasons for this discrepancy remain unclear. In this review, we analyze the currently available information to provide a state-of-the-art summary of the factors that determine the human pathogenicity of Ebolaviruses. RESTV causes sporadic infections in cynomolgus monkeys and is found in domestic pigs throughout the Philippines and China. Phylogenetic analyses revealed that RESTV is most closely related to the Sudan virus, which causes a high mortality rate in humans. Amino acid sequence differences between RESTV and the other Ebolaviruses are found in all nine Ebolavirus proteins, though no one residue appears sufficient to confer pathogenicity. Changes in the glycoprotein contribute to differences in Ebolavirus pathogenicity but are not sufficient to confer pathogenicity on their own. Similarly, differences in VP24 and VP35 affect viral immune evasion and are associated with changes in human pathogenicity. A recent in silico analysis systematically determined the functional consequences of sequence variations between RESTV and human-pathogenic Ebolaviruses. Multiple positions in VP24 were differently conserved between RESTV and the other Ebolaviruses and may alter human pathogenicity. In conclusion, the factors that determine the pathogenicity of Ebolaviruses in humans remain insufficiently understood. An improved understanding of these pathogenicity-determining factors is of crucial importance for disease prevention and for the early detection of emergent and potentially human-pathogenic RESTVs.


Estimation of leaf traits from reflectance measurements: comparison between methods based on vegetation indices and several versions of the PROSPECT model.
Leaf biochemical composition corresponds to traits related to the plant state and its functioning. This study puts the emphasis on the main leaf absorbers: chlorophyll a and b ([Formula: see text]), carotenoids ([Formula: see text]), water ([Formula: see text]) and dry mater ([Formula: see text]) contents. Two main approaches were used to estimate [[Formula: see text] [Formula: see text], [Formula: see text], [Formula: see text]] in a non-destructive way using spectral measurements. The first one consists in building empirical relationships from experimental datasets using either the raw reflectances or their combination into vegetation indices (VI). The second one relies on the inversion of physically based models of leaf optical properties. Although the first approach is commonly used, the calibration of the empirical relationships is generally conducted over a limited dataset. Consequently, poor predictions may be observed when applying them on cases that are not represented in the training dataset, i.e. when dealing with different species, genotypes or under contrasted environmental conditions. The retrieval performances of the selected VIs were thus compared to the ones of four PROSPECT model versions based on reflectance data acquired at two phenological stages, over six wheat genotypes grown under three different nitrogen fertilizations and two sowing density modalities. Leaf reflectance was measured in the lab with a spectrophotometer equipped with an integrating sphere, the leaf being placed in front of a white Teflon background to increase the sensitivity to leaf biochemical composition. Destructive measurements of [[Formula: see text] [Formula: see text], [Formula: see text], [Formula: see text]] were performed concurrently. The destructive measurements demonstrated that the carotenoid, [Formula: see text], and chlorophyll, [Formula: see text], contents were strongly correlated (r2 = 0.91). The sum of [Formula: see text] and [Formula: see text], i.e. the total chlorophyllian pigment content, [Formula: see text], was therefore used in this study. When inverting the PROSPECT model, accounting for the brown pigment content, [Formula: see text], was necessary when leaves started to senesce. The values of [Formula: see text] and [Formula: see text] were well estimated (r2 = 0.81 and r2 = 0.88 respectively) while the dry matter content, [Formula: see text], was poorly estimated (r2 = 0.00). Retrieval of [Formula: see text] from PROSPECT versions was only slightly biased, while substantial overestimation of [Formula: see text] was observed. The ranking between estimated values of [Formula: see text] and [Formula: see text] from the several PROSPECT versions and that derived using the VIs were similar to the ranking observed over the destructively measured values of [Formula: see text] and [Formula: see text]. PROSPECT model inversion and empirical VI approach provide similar retrieval performances and are useful methods to estimate leaf biochemical composition from spectral measurements. However, the PROSPECT model inversion gives potential access to additional traits on surface reflectivity and leaf internal structure. This study suggests that non-destructive estimation of leaf chlorophyll and water contents is a relevant method to provide leaf traits with relatively high throughput.


Synthesis and electrokinetics of cationic spherical nanoparticles in salt-free non-polar media.
Cationic diblock copolymer nanoparticles have been prepared in n-dodecane via polymerization-induced self-assembly (PISA). A previously reported poly(stearyl methacrylate)-poly(benzyl methacrylate) (PSMA-PBzMA) PISA formulation (Chem. Sci. 2016, 7, 5078-5090) was modified by statistically copolymerizing an oil-soluble cationic methacrylic monomer, (2-(methacryloyloxy)ethyl)trimethylammonium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, with either SMA or BzMA, to produce either charged shell or charged core nanoparticles. The electrokinetics were studied as a function of many variables (function of volume function, particle size, solvent viscosity, and number of ions per chain). These data are consistent with electrophoresis controlled by counterion condensation, which is typically observed in salt-free media. However, there are several interesting and unexpected features of interest. In particular, charged shell nanoparticles have a lower electrophoretic mobility than the equivalent charged core nanoparticles, and the magnitude of the electrophoretic mobility increases as the fraction of cationic stabilizer chains in the shell layer is reduced. These results show that cationic PSMA-PBzMA spheres provide an interesting new example of electrophoretic nanoparticles in non-polar solvents. Moreover, they should provide an ideal model system to evaluate new electrokinetic theories.


Photosensitive microgels containing azobenzene surfactants of different charges.
We report on light sensitive microgel particles that can change their volume reversibly in response to illumination with light of different wavelengths. To make the anionic microgels photosensitive we add surfactants with a positively charged polyamine head group and an azobenzene containing tail. Upon illumination, azobenzene undergoes a reversible photo-isomerization reaction from a trans- to a cis-state accompanied by a change in the hydrophobicity of the surfactant. Depending on the isomerization state, the surfactant molecules are either accommodated within the microgel (trans-state) resulting in its shrinkage or desorbed back into water (cis-isomer) letting the microgel swell. We have studied three surfactants differing in the number of amino groups, so that the number of charges of the surfactant head varies between 1 and 3. We have found experimentally and theoretically that the surfactant concentration needed for microgel compaction increases with decreasing number of charges of the head group. Utilization of polyamine azobenzene containing surfactants for the light triggered remote control of the microgel size opens up a possibility for applications of light responsive microgels as drug carriers in biology and medicine.


Why the debate over minimal risk needs to be reconsidered.
Minimal risk is a central concept in the ethical analysis of research with children. It is defined as the risks ". . . ordinarily encountered in daily life . . . ." But the question arises: who is the referent for minimal risk? Commentators in the research ethics literature often answer this question by endorsing one of two possible interpretations: the uniform interpretation (which is also known as the absolute interpretation) or the relative interpretation of minimal risk. We argue that describing the debate over minimal risk as a disagreement between the uniform and the relative interpretation impedes progress on the identification of a justifiable referent for minimal risk. There are two main problems with this approach: (1) constructing the debate over minimal risk as a disagreement between a uniform and a relative interpretation misconstrues the main difference between competing interpretations and (2) neither the uniform nor the relative interpretation identifies one unique and consistent group of children as the referent for minimal risk. We conclude that progress on the debate over minimal risk requires that we abandon the uniform and relative interpretations and address the main moral problem at stake: whether healthy children or the subjects of the research should be the referent for minimal risk.