TIGAR has a dual role in cancer cell survival through regulating apoptosis and autophagy.
The p53-induced glycolysis and apoptosis regulator (TIGAR) inhibits glycolysis, resulting in higher intracellular NADPH, lower reactive oxygen species (ROS) and autophagy activity. In this study, we investigated whether TIGAR might exert dual impacts on cancer cell survival based on its ability to inhibit both apoptosis and autophagy. In liver or lung cancer cells treated with the anticancer drug epirubicin, TIGAR levels increased in a dose- and time-dependent manner. TIGAR silencing enhanced epirubicin-induced elevations in ROS levels and apoptosis rates, in a manner that was blocked by ectopic addition of NADPH or N-acetyl cysteine. These findings were correlated with reduced tumorigenicity and increased chemosensitivity in mouse xenograft tumor assays. In parallel, TIGAR silencing also enhanced the epirubicin-induced activation of autophagy, in a manner that was also blocked by ectopic addition of NADPH. Notably, TIGAR silencing also licensed epirubicin-mediated inactivation of the mTOR pathway, suggesting TIGAR also exerted a negative impact on autophagy. However, genetic or pharmacologic inhibition of autophagy increased epirubicin-induced apoptosis in TIGAR-silenced cells. Overall, our results revealed that TIGAR inhibits both apoptosis and autophagy, resulting in a dual impact on tumor cell survival in response to tumor chemotherapy. Cancer Res; 74(18); 5127-38. ©2014 AACR.


Isolation of a novel herpesvirus from a Pacific white-sided dolphin.
During establishment of primary cell culture from the kidney of a dead Pacific white-sided dolphin (Lagenorhynchus obliquidens), a cytopathic effect was observed. Polymerase chain reaction with a set of herpesvirus consensus primers yielded a fragment of the expected size. Nucleotide sequencing of the product indicated that the isolated virus was closely related to an alphaherpesvirus detected in a bottlenose dolphin in the United States, but the sequence identity at the protein level was low (86.6 %). Phylogenetic analysis of the encoded sequence confirmed that the new isolate belonged to the subfamily Alphaherpesvirinae and clustered together with other cetacean alphaherpesviruses. The complete gene encoding glycoprotein B (2,757 bp) was amplified from the novel isolate; the encoded protein was compared with the corresponding protein of other herpesviruses, revealing that this virus belongs to the genus Varicellovirus. Taken together, these results suggest that this virus corresponds to a novel herpesvirus capable of infecting Pacific white-sided dolphins.


Age dependent differences in the kinetics of γδ T cells after influenza vaccination.
Immunosenescence is a hallmark of the aging immune system and is considered the main cause of a reduced vaccine efficacy in the elderly. Although γδ T cells can become activated by recombinant influenza hemagglutinin, their age-related immunocompetence during a virus-induced immune response has so far not been investigated. In this study we evaluate the kinetics of γδ T cells after vaccination with the trivalent 2011/2012 northern hemisphere seasonal influenza vaccine. We applied multi-parametric flow cytometry to a cohort of 21 young (19-30 years) and 23 elderly (53-67 years) healthy individuals. Activated and proliferating γδ T cells, as identified by CD38 and Ki67 expression, were quantified on the days 0, 3, 7, 10, 14, 17, and 21. We observed a significantly lower number of activated and proliferating γδ T cells at baseline and following vaccination in elderly as compared to young individuals. The kinetics changes of activated γδ T cells were much stronger in the young, while corresponding changes in the elderly occurred slower. In addition, we observed an association between day 21 HAI titers of influenza A and the frequencies of Ki67+ γδ T cells at day 7 in the young. In conclusion, aging induces alterations of the γδ T cell response that might have negative implications for vaccination efficacy.


MicroRNA let-7a represses chemoresistance and tumourigenicity in head and neck cancer via stem-like properties ablation.
Head and neck cancer (HNC) is a prevalent cancer worldwide. Let-7 has been shown to function as a tumour suppressor by regulating multiple oncogenic signalling pathways. However, the role of let-7 in head and neck cancer (HNC) and in HNC-associated tumour initiating cells (TIC) remains unclear. In this study, we first demonstrated that let-7a expression was significantly decreased but that Nanog/Oct4 expression was increased in HNC tissues as compared to adjacent normal cells. Expression of let-7a in recurrent HNC tissue and in regional metastatic lymph nodes of HNC patients was also significantly decreased, but Nanog/Oct4 expression was increased as compared to the expression levels in the parental tumours. Consistently, the stemness genes were significantly up-regulated and let-7a was down-regulated in HNC-ALDH1(+) cells relative to HNC-ALDH1(-) cells. Furthermore, lentiviral-mediated let-7a overexpression could significantly inhibit the stemness signature and the chemoresistant abilities of HNC-ALDH1(+) cells. Most importantly, overexpression of let-7 or knockdown of Nanog in ALDH1(+) cells effectively blocked tumour metastasis and significantly prolonged survival time in ALDH1(+)-transplanted immunocompromised mice. Overall, restoration of let-7a in HNC and HNC-TIC may be a new approach for the therapeutic treatment of HNC in the future. These results show that let-7a negatively modulates the expression of stemness genes and plays a role as a tumour suppressor in HNC by eliminating the putative HNC-TIC population.


State social capital and individual health status.
Recent studies have found that two state-level measures of social capital, average levels of civic participation and trust, are associated with improvements in individual health status. In this study we employ these measures, together with the Putnam index of state social capital, to examine several key aspects of the relationship between state social capital and individual health. We find that for all three measures, the association with health status persists after carefully adjusting for household income and that for two measures, mistrust and the Putnam index, the size of this association warrants further attention. Using the Putnam index, we find particular support for the hypothesis that social capital has a more pronounced salutary effect for the poor. Our findings generate both support for the social capital and health hypothesis and a number of implications for future research.


Stress response in postpartum women with and without obsessive-compulsive symptoms: an fMRI study.
During the postpartum period, some women might be under a considerable amount of stress and at increased risk for on-set or exacerbation of obsessive-compulsive disorder (OCD). Little is known about the stress response correlates during the postpartum period and in patients with OCD. This study aimed to examine the cerebral, psychologic and endocrine correlates of the stress response in patients with OCD and during the postpartum period. Women with postpartum OCD, healthy postpartum women and healthy mothers past the postpartum period underwent functional magnetic resonance imaging while facing a reliable psychosocial stressor (the Montreal Imaging Stress Task). Stress-related psychologic and endocrine responses (i.e., cortisol) were obtained. We enrolled 12 women with postpartum OCD, 16 healthy postpartum women and 11 healthy mothers past the postpartum period in our study. Compared with healthy postpartum counterparts, postpartum women with OCD had a heightened self-reported and endocrine stress response associated with a distinct brain activation pattern in response to psychosocial stress involving the orbitofrontal and temporal cortices. Moreover, compared with mothers assessed in a period of time beyond the postpartum period, healthy postpartum women did not differ in psychologic and cortisol response to stress, but recruited different brain regions, such as the dorsolateral prefrontal cortex and the anterior cingulate cortex, during exposure to stress. Potential confounding factors, such as medication use, breastfeeding, parity and personality factors, may have modulated the stress-related endocrine response and could not be assessed in this study. Obsessive-compulsive disorder and the postpartum period differentially influence the brain circuitry underlying psychosocial stress as well as the psychologic and endocrine responses.


A cross-sectional study on schistosomiasis and soil-transmitted helminths in Mbita district, western Kenya using different copromicroscopic techniques.
Identification of populations to be targeted for individual treatment and broad-spectrum therapy in schistosomiasis-endemic areas, assessment of therapy efficacy, morbidity, and evaluation of control strategies need to be based on reliable diagnostic tools. Kato-Katz is routinely used and remains the standard diagnostic technique for schistosomiasis, despite its many challenges. This study was conducted in Nyamanga village, Mbita, western Kenya, and evaluated the diagnostic performance of Kato-Katz, Mini-Parasep and modified Mini-FLOTAC techniques in detection of Schistosoma mansoni and soil-transmitted helminths (Ascaris lumbricoides, Trichuris trichiura and hookworm) ova. Stool samples from 132 individuals were screened for eggs of S. mansoni by the 3 techniques. Mini-Parasep faecal parasite concentrator (Apacor Ltd, England), a single-use diagnostic device with a built-in filter for faecal concentration of helminth eggs by sedimentation was employed on stool samples fixed in 10% formalin. A modified Mini-FLOTAC (University of Naples, Italy) was based on floatation of helminths eggs with two different solutions (FS2 and FS7) using a closed system (Fill-FLOTAC) with 5% formalin. Kato-Katz was performed following WHO recommendation. Prevalence of S. mansoni and STH, sensitivity and degree of agreement among the 3 techniques were determined. Prevalence of S. mansoni was 47.0%, 34.1% and 20.5% by Mini-Parasep, Kato-Katz and modified Mini-FLOTAC FS7 techniques, respectively. Prevalence of any STH infection was 6.1%, 3.0%, 6.1% and 6.8% by Mini-Parasep, Kato-Katz, modified Mini-FLOTAC FS2 and modified Mini-FLOTAC FS7 techniques, respectively. Considering the pooled results of the three methods (Mini-Parasep, Kato-Katz and modified Mini-FLOTAC FS7) as diagnostic 'gold' standard, the sensitivity of Mini-Parasep, Kato-Katz and modified Mini-FLOTAC FS7 for S. mansoni was 77.5%, 56.1%, and 33.8%, respectively. Mini-Parasep and modified Mini-FLOTAC FS7 techniques had moderate (κ = 0.46) and fairly good (κ = 0.25) agreements with Kato-Katz for S. mansoni, respectively. Mini-Parasep detected a higher proportion of light intensity S. mansoni infections compared to Kato-Katz, which detected high proportions of heavy infections. Mini-Parasep detected a similar mean number of S. mansoni eggs per gram (EPG) of stool compared to the standard Kato-Katz (62.9 vs 97.3; t (131) = -0.49, P = 0.6265) and significantly higher EPG compared to the modified Mini-FLOTAC FS7 (62.9 vs 34.6; t (131) = 5.39, P < 0.0001). The high sensitivity of Mini-Parasep suggests its promising potential as an alternative tool in enhancing diagnosis and in monitoring schistosomiasis transmission and determining endpoint of intervention programs, especially in low endemicity areas. Mini-Parasep is also easy to operate, safe and also permits work with fresh stool.


Chromosome looping in yeast: telomere pairing and coordinated movement reflect anchoring efficiency and territorial organization.
Long-range chromosome organization is known to influence nuclear function. Budding yeast centromeres cluster near the spindle pole body, whereas telomeres are grouped in five to eight perinuclear foci. Using live microscopy, we examine the relative positions of right and left telomeres of several yeast chromosomes. Integrated lac and tet operator arrays are visualized by their respective repressor fused to CFP and YFP in interphase yeast cells. The two ends of chromosomes 3 and 6 interact significantly but transiently, forming whole chromosome loops. For chromosomes 5 and 14, end-to-end interaction is less frequent, yet telomeres are closer to each other than to the centromere, suggesting that yeast chromosomes fold in a Rabl-like conformation. Disruption of telomere anchoring by deletions of YKU70 or SIR4 significantly compromises contact between two linked telomeres. These mutations do not, however, eliminate coordinated movement of telomere (Tel) 6R and Tel6L, which we propose stems from the territorial organization of yeast chromosomes.


Navigating Into the Future or Driven by the Past.
Prospection (Gilbert & Wilson, 2007), the representation of possible futures, is a ubiquitous feature of the human mind. Much psychological theory and practice, in contrast, has understood human action as determined by the past and viewed any such teleology (selection of action in light of goals) as a violation of natural law because the future cannot act on the present. Prospection involves no backward causation; rather, it is guidance not by the future itself but by present, evaluative representations of possible future states. These representations can be understood minimally as "If X, then Y" conditionals, and the process of prospection can be understood as the generation and evaluation of these conditionals. We review the history of the attempt to cast teleology out of science, culminating in the failures of behaviorism and psychoanalysis to account adequately for action without teleology. A wide range of evidence suggests that prospection is a central organizing feature of perception, cognition, affect, memory, motivation, and action. The authors speculate that prospection casts new light on why subjectivity is part of consciousness, what is "free" and "willing" in "free will," and on mental disorders and their treatment. Viewing behavior as driven by the past was a powerful framework that helped create scientific psychology, but accumulating evidence in a wide range of areas of research suggests a shift in framework, in which navigation into the future is seen as a core organizing principle of animal and human behavior.


HLA-DQB1*0201 homozygosis predisposes to severe intestinal damage in celiac disease.
Celiac disease (CD) is a T-lymphocyte-mediated small intestinal enteropathy triggered and maintained by dietary gluten, with a strong genetic component mapping to the HLA genes encoding for the class II DQ(alpha1*0501, beta1*02) molecule. Damage of the small intestine may cause a variety of clinical signs ranging from isolated long-standing iron-deficiency anemia refractory to iron supplementation to forms of severe malnutrition that may become life threatening. However, patients carrying the typical intestinal lesions of CD and presenting no symptoms at all (silent CD) are also a common clinical observation. Since it is commonly assumed that clinical signs and symptoms tend to correlate with the severity of the intestinal damage, the purpose of this study was to investigate whether particular HLA class II genotypes might also influence the extent of intestinal damage and consequently the clinical presentation of the disease. We retrospectively compared histological grading of celiac disease intestinal biopsies with HLA haplotype, age at onset of disease and clinical signs and symptoms. Our findings showed that homozygosis for the DQB1*0201 allele is associated with a higher severity of the histological score (p<0.008). Of note for the clinician, this work also suggests that the same type 3c of intestinal damage causes a different clinical syndrome, depending on the patient's age. The genetic predisposition at the HLA-DQB1 locus influences the severity of the mucosal damage in a dose-dependent manner, but not the clinical presentation, of celiac disease.


Cardiac beta-adrenergic responsiveness is well preserved in moderate protein calorie malnutrition from semistarvation.
Twenty-one dogs underwent instrumentation of the left ventricle with ultrasonic dimension to study the effects of acute protein-calorie malnutrition on the adrenergic responsiveness of the heart. This study allowed a chronic and dynamic measurement of the major cardiac axes and the ventricular wall thickness, which in turn can be used to derive sophisticated measurements of global and intrinsic left ventricular function. Of the 21 dogs, 11 received a protein- and calorie-deficient diet designed to achieve a mean weight loss from a baseline of 20-25% over a 4-week period. The other 10 dogs received a normal diet. Dogs were also randomized to receive either acute propranolol beta-receptor blockade (n = 9) or acute isoproterenol beta-receptor stimulation (n = 12) during their baseline studies. Of the nine dogs given propranolol, five were subsequently malnourished and four served as controls. Of the 12 given isoproterenol, six were rendered malnourished and six were controls. All dogs were studied at both baseline and 4 weeks and received drugs in an identical fashion during both studies. The significant changes with malnutrition consisted of decreases in heart rate, cardiac mass, and left ventricular wall thickness. The degree of change in stroke volume, ejection fraction, cardiac output, dp/dt, and Emax (index of left ventricular contractility), with the administration of propranolol or isoproterenol was unaltered by malnutrition. These data support the contention that moderate protein-calorie malnutrition is well tolerated in instrumented, unstessed dogs and that the left ventricle's capacity to respond to beta-stimulation and to tolerate beta-blockade is largely unimpaired.


Spatial prediction of naturally occurring gamma radiation in Great Britain.
Gamma radiation from natural sources is an important component of background radiation, and correlates with childhood leukaemia risk in Great Britain. The geographic variation of indoor gamma radiation dose-rates in Great Britain is explored using various geo-statistical methods. A multi-resolution Gaussian-process model using radial basis functions with 2, 4, or 8 components, is fitted via maximum likelihood, and a non-spatial model is also used, fitted by ordinary least squares. Because of the dataset size (N = 10,199), four other parametric spatial models are fitted by variogram-fitting. A randomly selected 70:30 split is used for fitting:validation. The models are evaluated based on their predictive performance as measured by Mean Absolute Error, Mean Squared Error, as well as Pearson correlation and rank-correlation between predicted and actual dose-rates. Each of the four parametric models (Matérn, Gaussian, Bessel, Spherical) fitted the empirical variogram well, and yielded similar predictions at >50 km separation, although with more substantial differences in predicted variograms at <50 km. The multi-resolution Gaussian-process model with 8 components had the best predictive accuracy among the models considered. The Spherical, Bessel, Matérn, Gaussian and ordinary least squares models had progressively worse predictive performance, the ordinary least squares model being particularly poor in this respect.


TRP Channels Localize to Subdomains of the Apical Plasma Membrane in Human Fetal Retinal Pigment Epithelium.
Calcium regulates many functions of the RPE. Its concentration in the subretinal space and RPE cytoplasm is closely regulated. Transient receptor potential (TRP) channels are a superfamily of ion channels that are moderately calcium-selective. This study investigates the subcellular localization and potential functions of TRP channels in a first-passage culture model of human fetal RPE (hfRPE). The RPE isolated from 15- to 16-week gestation fetuses were maintained in serum-free media. Cultures were treated with barium chloride (BaCl2) in the absence and presence of TRP channel inhibitors and monitored by the transepithelial electrical resistance (TER). The expression of TRP channels was determined using quantitative RT-PCR, immunoblotting, and immunofluorescence confocal microscopy. Barium chloride substantially decreased TER and disrupted cell-cell contacts when added to the apical surface of RPE, but not when added to the basolateral surface. The effect could be partially blocked by the general TRP inhibitor, lanthanum chloride (LaCl3, ~75%), or an inhibitor of calpain (~25%). Family member-specific inhibitors, ML204 (TRPC4) and HC-067047 (TRPV4), had no effect on basal channel activity. Expression of TRPC4, TRPM1, TRPM3, TRPM7, and TRPV4 was detected by RT-PCR and immunoblotting. The TRPM3 localized to the base of the primary cilium, and TRPC4 and TRPM3 localized to apical tight junctions. The TRPV4 localized to apical microvilli in a small subset of cells. The TRP channels localized to subdomains of the apical membrane, and BaCl2 was only able to dissociate tight junctions when presented to the apical membrane. The data suggest a potential role for TRP channels as sensors of [Ca(2+)] in the subretinal space.


Analysis of factors affecting repeat microdissection testicular sperm extraction outcomes in infertile men.
There is no clear consensus on which patients and how many of microscopic testicular sperm extraction (mTESE) procedures will be successful. In this study, we aimed to evaluate the sperm retrieval rates and factors affecting these rates in men who underwent repeat mTESEs. A total of 346 patients who underwent mTESE for sperm retrieval were included in the study. Patients were divided into groups according to the number of mTESE operations. Patients' karyotype, follicle-stimulating hormone (FSH) and testosterone levels, varicocele presence, and testis volumes were recorded from patient files. The sperm retrieval rates were compared between groups, and predicting factors for successful sperm retrieval were evaluated. Microscopic TESE was applied for the first time in 244 patients, 1-2 times in 73 patients, and 3-4 times in 29 patients. There was a significant difference between groups in preoperative FSH values and postoperative testicular histopathology (p=0.004 and p<0.001). The sperm retrieval rate in the group of patients who had not undergone previous TESE was higher than the group of patients that had undergone TESE for 1-2 times and 3-4 times (p=0.028). In addition, testicular volume, histology, karyotype, and Y-chromosome microdeletion were predicting factors for successful sperm retrieval (p=0.011, p=0.039, p=0.002, and p<0.001, respectively). Our results confirm the necessity for repeat mTESE operations to be performed by experienced surgeons in reference centers to optimize the chance of reduced sperm retrieval rates with recurrent biopsies.


Pro-gonadotropin-releasing hormone (ProGnRH) and GnRH content in the preoptic area and the basal hypothalamus of anterior medial preoptic nucleus/suprachiasmatic nucleus-lesioned persistent estrous rats.
The content of GnRH and its precursor peptide were quantified in female rats bearing lesions in the anterior medial preoptic nucleus (AMPO) and the suprachiasmatic nucleus (SCN), and the effects of the lesions on the synthetic activity of the GnRH neurons were evaluated. Electrolytic lesions which induced persistent estrous (PE), or irregular estrous cycles, were produced by passing 5-10 microA of direct current into the AMPO or the SCN of female rats which exhibited regular 4 days estrous cycles before the lesions. Approximately 5 weeks after lesion placement, blood samples were withdrawn from catheterized, freely moving animals and plasma LH, PRL, estrogen, and progesterone were determined by RIA. The preovulatory surges of LH and PRL were eliminated in AMPO- or SCN-lesioned PE rats. Moreover, the LH surge was eliminated and the PRL surge significantly attenuated after estrogen and progesterone treatment of rats bearing complete lesions, irrespective of the presence of ovaries. Irregular cycling animals with incomplete AMPO or SCN lesions, exhibited attenuated LH surge and PRL surge similar to proestrous controls. In one incidence this occurred spontaneously, and could also be induced by sequential estrogen and progesterone injections. After ovariectomy, plasma LH levels were significantly lower in the lesioned animals as compared to sham operated rats (P less than 0.05). Similar secretory patterns of LH and PRL were obtained from a second series of sham-operated rats during the different stages of the estrous cycle or from AMPO- or SCN-lesioned rats during persistent estrus. After 2 months the animals were killed between 0830 and 0930 h, and the preoptic area and the basal hypothalamus were microdissected from the brain sections. After extraction and purification, proGnRH and GnRH levels were measured by RIA. ProGnRH levels in the preoptic area were significantly reduced in AMPO- or in SCN-lesioned rats, compared to proestrous controls (P less than 0.01). In contrast, GnRH levels in either area did not differ in AMPO- or in SCN-lesioned animals compared to sham-operated, proestrous controls. Therefore, lesions of the AMPO or the SCN produce PE and reduce proGnRH without reducing GnRH levels. These data would suggest that the AMPO and the SCN participate in the control of the estrous cycle and are necessary for preovulatory surges of PRL and LH to occur and that the AMPO and the SCN form part of the neural circuit that regulates GnRH synthesis and/or release.


Evidence for a Strong Topological Insulator Phase in ZrTe_{5}.
The complex electronic properties of ZrTe_{5} have recently stimulated in-depth investigations that assigned this material to either a topological insulator or a 3D Dirac semimetal phase. Here we report a comprehensive experimental and theoretical study of both electronic and structural properties of ZrTe_{5}, revealing that the bulk material is a strong topological insulator (STI). By means of angle-resolved photoelectron spectroscopy, we identify at the top of the valence band both a surface and a bulk state. The dispersion of these bands is well captured by ab initio calculations for the STI case, for the specific interlayer distance measured in our x-ray diffraction study. Furthermore, these findings are supported by scanning tunneling spectroscopy revealing the metallic character of the sample surface, thus confirming the strong topological nature of ZrTe_{5}.


Biofouling of inlet pipes affects water quality in running seawater aquaria and compromises sponge cell proliferation.
Marine organism are often kept, cultured, and experimented on in running seawater aquaria. However, surprisingly little attention is given to the nutrient composition of the water flowing through these systems, which is generally assumed to equal in situ conditions, but may change due to the presence of biofouling organisms. Significantly lower bacterial abundances and higher inorganic nitrogen species (nitrate, nitrite, and ammonium) were measured in aquarium water when biofouling organisms were present within a 7-year old inlet pipe feeding a tropical reef running seawater aquaria system, compared with aquarium water fed by a new, biofouling-free inlet pipe. These water quality changes are indicative of the feeding activity and waste production of the suspension- and filter-feeding communities found in the old pipe, which included sponges, bivalves, barnacles, and ascidians. To illustrate the physiological consequences of these water quality changes on a model organism kept in the aquaria system, we investigated the influence of the presence and absence of the biofouling community on the functioning of the filter-feeding sponge Halisarca caerulea, by determining its choanocyte (filter cell) proliferation rates. We found a 34% increase in choanocyte proliferation rates following the replacement of the inlet pipe (i.e., removal of the biofouling community). This indicates that the physiological functioning of the sponge was compromised due to suboptimal food conditions within the aquarium resulting from the presence of the biofouling organisms in the inlet pipe. This study has implications for the husbandry and performance of experiments with marine organisms in running seawater aquaria systems. Inlet pipes should be checked regularly, and replaced if necessary, in order to avoid excessive biofouling and to approach in situ water quality.


Estimating the bias field of MR images.
We propose a modification of Wells et al. technique for bias field estimation and segmentation of magnetic resonance (MR) images. We show that replacing the class other, which includes all tissue not modeled explicitly by Gaussians with small variance, by a uniform probability density, and amending the expectation-maximization (EM) algorithm appropriately, gives significantly better results. We next consider the estimation and filtering of high-frequency information in MR images, comprising noise, intertissue boundaries, and within tissue microstructures. We conclude that post-filtering is preferable to the prefiltering that has been proposed previously. We observe that the performance of any segmentation algorithm, in particular that of Wells et al. (and our refinements of it) is affected substantially by the number and selection of the tissue classes that are modeled explicitly, the corresponding defining parameters and, critically, the spatial distribution of tissues in the image. We present an initial exploration to choose automatically the number of classes and the associated parameters that give the best output. This requires us to define what is meant by "best output" and for this we propose the application of minimum entropy. The methods developed have been implemented and are illustrated throughout on simulated and real data (brain and breast MR).


Measuring the visual salience of alignments by their non-accidentalness.
Quantitative approaches are part of the understanding of contour integration and the Gestalt law of good continuation. The present study introduces a new quantitative approach based on the a contrario theory, which formalizes the non-accidentalness principle for good continuation. This model yields an ideal observer algorithm, able to detect non-accidental alignments in Gabor patterns. More precisely, this parameterless algorithm associates with each candidate percept a measure, the Number of False Alarms (NFA), quantifying its degree of masking. To evaluate the approach, we compared this ideal observer with the human attentive performance on three experiments of straight contours detection in arrays of Gabor patches. The experiments showed a strong correlation between the detectability of the target stimuli and their degree of non-accidentalness, as measured by our model. What is more, the algorithm's detection curves were very similar to the ones of human subjects. This fact seems to validate our proposed measurement method as a convenient way to predict the visibility of alignments. This framework could be generalized to other Gestalts.


Mineralogy and petrology of comet 81P/Wild 2 nucleus samples.
The bulk of the comet 81P/Wild 2 (hereafter Wild 2) samples returned to Earth by the Stardust spacecraft appear to be weakly constructed mixtures of nanometer-scale grains, with occasional much larger (over 1 micrometer) ferromagnesian silicates, Fe-Ni sulfides, Fe-Ni metal, and accessory phases. The very wide range of olivine and low-Ca pyroxene compositions in comet Wild 2 requires a wide range of formation conditions, probably reflecting very different formation locations in the protoplanetary disk. The restricted compositional ranges of Fe-Ni sulfides, the wide range for silicates, and the absence of hydrous phases indicate that comet Wild 2 experienced little or no aqueous alteration. Less abundant Wild 2 materials include a refractory particle, whose presence appears to require radial transport in the early protoplanetary disk.


Age-related differences in the response of the brain to dietary melatonin.
The aged brain is prone to excessive levels of immune activity, not initiated by an acute response to an extrinsic agent. While dietary melatonin is reported to attenuate the extent of expression of proinflammatory genes, little is known about the extent to which these changes can be translated into altered levels of corresponding proteins. The baseline levels of the proinflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-1 alpha, were greater in older (~29 months old) compared to younger (~7 months old) mouse brains. Acute (3 h) exposure to lipopolysaccharide (LPS) induced activation of nuclear factor kappa B (NF-κB), but not inflammatory cytokines in the brain. The serum level of TNF-α was increased after LPS injection, indicating a systemic immune response to the bacterial cell wall component. Dietary melatonin (40 ppm for 9.3 weeks) did not prevent LPS-induced changes in younger animals but caused an increased systemic TNF-α response in older mice. Melatonin did reduce markers of carbonyl formation in brain proteins of young animals and nitrosylative damage to peptide-bound amino acid residues, in the brains of older animals. Acute LPS challenge did not significantly affect these oxidative markers. Thus, despite lack of clear evidence of attenuation of the NF-κB-cytokine inflammatory trajectory within the CNS by melatonin, this agent did show a protective effect against free radical-initiated injury to amino acid residues within proteins. The results illustrate that previously reported changes in gene expression following melatonin treatment need not be closely paralleled by corresponding changes in protein content.


Self-assembled monolayers of rigid thiols.
The preparation, structure, properties and applications of self-assembled monolayers (SAMs) of rigid 4-mercapto-biphenyls are briefly reviewed. The rigid character of the biphenyl moiety results in a molecular dipole moment that affects both the adsorption kinetics on gold surfaces, as well as the equilibrium structure of mixed SAMs. Due to repulsive intermolecular interaction, the Langmuir isotherm model does not fit the adsorption kinetics of these biphenyl thiols, and a new Ising model was developed to fit the kinetics data. The equilibrium structures of SAMs and mixed SAMs depend on the polarity of the solution from which they were assembled. Infrared spectroscopy suggests that biphenyl moieties in SAMs on gold have small tilt angles with respect to the surfaces normal. Wetting studies shows that surfaces of these SAMs are stable for months, thus providing stable model surfaces that can be engineered at the molecular level. Such molecular engineering is important for nucleation and growth studies. The morphology of glycine crystals grown on SAM surfaces depends on the structure of the nucleating glycine layer, which, in turn, depends on the H-bonding of these molecules with the SAM surface. Finally, the adhesion of PDMS cross-linked networks to SAM surfaces depends on the concentration of interfacial H-bonding. This non-linear relationship suggests that the polymeric nature of the elastomer results in a collective H-bonding effect.


Renoprotective effect of hydroalcoholic extract of Rheum ribes root in diabetic female rats.
Medical plants, as rich sources of natural antioxidants with antidiabetic effects, are used worldwide to diminish a variety of symptoms and many diseases. R. ribes L., which belongs to the family of polygonaceae, can provide symptomatic relief and assist in the prevention of the secondary complications of the diabetes. 36 female adult rats were randomly divided into 6 groups of 6. Normal Control groups treated with normal saline. Positive control groups treated with hydroalcohlic extract of R. ribes root (150 mg/kg) daily by gavages for 4 consecutive weeks. Diabetes was inducedby injection of 120 mg/kg alloxan monohydrate intraperitoneally. Two diabetic groups were treated with different doses of R. ribes root extract. The sixth diabetic groups were treated with glibenclamide (0.6 mg/kg). At the end of 28 days, blood samples were collected and their kidney tissues were processed for light microscopy. The results showed that hydro-alcoholic extract of R. ribes decreased the level of glucose, cholesterol, triglyceride, urea and creatinine in diabetic rats (p<0.05) in compared with diabetic rats, while the level of HDL increased at the same group (p<0.05). Histopathological changes of kidney samples were comparable with respective control. In diabetic rats, kidney sections showed atrophy of glomerular capillaries with increased Bowman's space and acute tubular necrosis. The groups that were treated with R. ribes root were improved towards normal condition. It is interesting to note that hydroalcohlic extract of R. ribes root improves renal dysfunction in alloxan-induced diabetic rats through controlling blood glucose and renal protective effects.


Modulation of the tumor suppressor protein alpha-catenin by ischemic microenvironment.
Dysregulation or mislocalization of cell adhesion molecules and their regulators, such as E-cadherin, beta-catenin, and alpha-catenin, usually correlates with loss of polarity, dedifferentiation, invasive tumor growth, and metastasis. A subpopulation of alpha-catenin-negative cells within the DLD-1 colorectal carcinoma cell line causes it to display a heterogeneous morphological makeup, thus providing an excellent model system in which to investigate the role of alpha-catenin in tumorigenesis. We re-established expression of alpha-catenin protein in an alpha-catenin-deficient subpopulation of the DLD-1 cell line and used it to demonstrate that loss of alpha-catenin resulted in increased in vitro tumorigenic characteristics (increased soft agarose colony formation, clonogenic survival after suspension, and survival in suspension). When the cells were used to form tumor xenografts, those lacking alpha-catenin showed faster growth rates because of increased cellular cycling but not increased tumor microvascular recruitment. alpha-Catenin-expressing cells were preferentially located in well perfused areas of xenografts when tumors were formed from mixed alpha-catenin-positive and -negative cells. We therefore evaluated the role of the ischemic tumor microenvironment on alpha-catenin expression and demonstrated that cells lose expression of alpha-catenin after prolonged exposure in vitro to hypoglycemic conditions. Our findings illustrate that the tumor microenvironment is a potent modulator of tumor suppressor expression, which has implications for localized nutrient deficiency and ischemia-induced cancer progression.


The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease.
Aggression, agitation or psychosis occur in the majority of people with dementia at some point in the illness. There have been a number of trials of atypical antipsychotics to treat these symptoms over the last five years, and a systematic review is needed to evaluate the evidence in a balanced way. To determine whether evidence supports the use of atypical antipsychotics for the treatment of aggression, agitation and psychosis in people with Alzheimer's disease. The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 7 December 2004 using the terms olanzapine, quetiapine, risperidone, clozapine, amisulpride, sertindole, zotepine, aripiprazole, ziprasidone. This Register contains articles from all major healthcare databases and many ongoing trials databases and is updated regularly. Randomised, placebo-controlled trials, with concealed allocation, where dementia and psychosis and/or aggression were assessed. 1. Two reviewers extracted data from included trials2. Data were pooled where possible, and analysed using appropriate statistical methods3. Analysis included patients treated with an atypical antipsychotic, compared with placebo Sixteen placebo controlled trials have been completed with atypical antipsychotics although only nine had sufficient data to contribute to a meta-analysis and only five have been published in full in peer reviewed journals. No trials of amisulpiride, sertindole or zotepine were identified which met the criteria for inclusion. The included trials led to the following results:1. There was a significant improvement in aggression with risperidone and olanzapine treatment compared to placebo.2. There was a significant improvement in psychosis amongst risperidone treated patients.3. Risperidone and olanzpaine treated patients had a significantly higher incidence of serious adverse cerebrovascular events (including stroke), extra-pyramidal side effects and other important adverse outcomes.4. There was a significant increase in drop-outs in risperidone (2 mg) and olanzapine (5-10 mg) treated patients.5. The data were insufficient to examine impact upon cognitive function. Evidence suggests that risperidone and olanzapine are useful in reducing aggression and risperidone reduces psychosis, but both are associated with serious adverse cerebrovascular events and extra-pyramidal symptoms. Despite the modest efficacy, the significant increase in adverse events confirms that neither risperidone nor olanzapine should be used routinely to treat dementia patients with aggression or psychosis unless there is marked risk or severe distress. Although insufficient data were available from the considered trials, a meta-analysis of seventeen placebo controlled trials of atypical neuroleptics for the treatment of behavioural symptoms in people with dementia conducted by the Food and Drug Administration (using data not in the public domain) suggested a significant increase in mortality (OR 1.7).


The Parent Trauma Response Questionnaire (PTRQ): development and preliminary validation.
Background: Following a child's experience of trauma, parental response is thought to play an important role in either facilitating or hindering their psychological adjustment. However, the ability to investigate the role of parenting responses in the post-trauma period has been hampered by a lack of valid and reliable measures. Objectives: The aim of this study was to design, and provide a preliminary validation of, the Parent Trauma Response Questionnaire (PTRQ), a self-report measure of parental appraisals and support for children's coping, in the aftermath of child trauma. Methods: We administered an initial set of 78 items to 365 parents whose children, aged 2-19 years, had experienced a traumatic event. We conducted principal axis factoring and then assessed the validity of the reduced measure against a standardized general measure of parental overprotection and via the measure's association with child post-trauma mental health. Results: Factor analysis generated three factors assessing parental maladaptive appraisals: (i) permanent change/damage, (ii) preoccupation with child's vulnerability, and (iii) self-blame. In addition, five factors were identified that assess parental support for child coping: (i) behavioural avoidance, (ii) cognitive avoidance, (iii) overprotection, (iv) maintaining pre-trauma routines, and (v) approach coping. Good validity was evidenced against the measure of parental overprotection and child post-traumatic stress symptoms. Good test-retest reliability of the measure was also demonstrated. Conclusions: The PTRQ is a valid and reliable self-report assessment of parenting cognitions and coping in the aftermath of child trauma.


Simulations of the observation of clouds and aerosols with the Experimental Lidar in Space Equipment system.
We carried out a simulation study for the observation of clouds and aerosols with the Japanese Experimental Lidar in Space Equipment (ELISE), which is a two-wavelength backscatter lidar with three detection channels. The National Space Development Agency of Japan plans to launch the ELISE on the Mission Demonstrate Satellite 2 (MDS-2). In the simulations, the lidar return signals for the ELISE are calculated for an artificial, two-dimensional atmospheric model including different types of clouds and aerosols. The signal detection processes are simulated realistically by inclusion of various sources of noise. The lidar signals that are generated are then used as input for simulations of data analysis with inversion algorithms to investigate retrieval of the optical properties of clouds and aerosols. The results demonstrate that the ELISE can provide global data on the structures and optical properties of clouds and aerosols. We also conducted an analysis of the effects of cloud inhomogeneity on retrievals from averaged lidar profiles. We show that the effects are significant for space lidar observations of optically thick broken clouds.


Pulmonary Circulation in Obesity, Diabetes, and Metabolic Syndrome.
Obesity, diabetes mellitus, and the metabolic syndrome are important risk factors for the development of cardiovascular disease, with significant impact on human morbidity and mortality. Several decades of research have accumulated considerable knowledge about the mechanisms by which metabolic conditions precipitate systemic cardiovascular diseases. In short, these mechanisms are thought to involve changes in the external environment of vascular cells, which are mediated by the pro-inflammatory effects of adipokines, free fatty acids, and hyperglycemia. Thus, it has been hypothesized that the pulmonary circulation, witnessing similar insults as the systemic circulation, may be equally vulnerable to the development of vascular disease. Accordingly, recent attention has focused on exploring the mechanistic and epidemiological relationships among obesity, type 2 diabetes mellitus, metabolic syndrome, and pulmonary vascular diseases. In this article, we discuss in detail the preclinical evidence showing a modest but perceivable impact of metabolic disorders on the pulmonary circulation. In addition, we review the existing epidemiological studies examining the relationship among cardiovascular risk factors and pulmonary vascular diseases, using the acute respiratory distress syndrome and pulmonary arterial hypertension as examples. We conclude by discussing areas of limitations in the field and by suggesting future directions for investigation, including the notion that the pulmonary circulation may, in fact, be a resilient entity in the setting of some metabolic perturbations. © 2020 American Physiological Society. Compr Physiol 10:297-316, 2020.


Evaluation and environmental correction of ambient CO2 measurements from a low-cost NDIR sensor.
Non-dispersive infrared (NDIR) sensors are a low-cost way to observe carbon dioxide concentrations in air, but their specified accuracy and precision are not sufficient for some scientific applications. An initial evaluation of six SenseAir K30 carbon dioxide NDIR sensors in a lab setting showed that without any calibration or correction, the sensors have an individual root mean square error (RMSE) between ~5 and 21 parts per million (ppm) compared to a research-grade greenhouse gas analyzer using cavity enhanced laser absorption spectroscopy. Through further evaluation, after correcting for environmental variables with coefficients determined through a multivariate linear regression analysis, the calculated difference between the each of six individual K30 NDIR sensors and the higher-precision instrument had an RMSE of between 1.7 and 4.3 ppm for 1 min data. The median RMSE improved from 9.6 for off-the-shelf sensors to 1.9 ppm after correction and calibration, demonstrating the potential to provide useful information for ambient air monitoring.


Predicting treatment outcome on three measures for post-traumatic stress disorder.
The aim of the present study was to investigate predictors of treatment outcome for Posttraumatic Stress Disorder (PTSD) after treatment completion and at 15-months follow-up (n = 48), in a trial of Eye Movement Desensitisation and Reprocessing (EMDR) versus Imaginal Exposure and Cognitive Restructuring (E+CR). Factors associated with treatment outcome were investigated using regression analyses with the mean change scores in three assessor and self-rated PTSD symptomatology measures, including the Clinician-Administered PTSD Scale (CAPS), the Impact of Events Scale (IES) and the PTSD Symptom Checklist (PCL) from pre- to post-treatment and pre-treatment to follow-up as the dependent variables and demographics, trauma, clinical and personality measures as independent variables. Irrespective to outcome measures and assessment points it was found that four variables were able to predict significantly treatment outcome. These included baseline PTSD symptomatology, number of sessions, gender and therapy type. Overall, our results showed that it is difficult to use pre-treatment variables as a powerful and reliable tool for predicting treatment outcome, as significant predictors were found to be sample-specific and outcome measure-specific. Clinical relevance of the present results and directions for future research are discussed.


Preventing Post-ERCP Pancreatitis: The Role of Prophylactic Pancreatic Duct Stenting in the Rectal NSAID Era.
Rectal non-steroidal anti-inflammatory drug at endoscopic retrograde cholangiopancreatography is now the standard of care to reduce the risk of post-ERCP pancreatitis. Pancreatic duct stenting also reduces the risk of post- ERCP pancreatitis in high-risk patients, but failed pancreatic duct stenting carries an increased PEP rate (up to 35%). To assess the impact on post-ERCP pancreatitis of successful and unsuccessful pancreatic duct stent placement in the setting of universal rectal non-steroidal anti-inflammatory drug use. Between 2013-2015, all patients undergoing endoscopic retrograde cholangiopancreatographys in our tertiary referral centre (where rectal non-steroidal anti-inflammatory drugs are used routinely) were included. The electronic patient's records were reviewed and the following parameters were analysed: indication for pancreatic duct stenting; deployment success; and adverse events. A total of 1633 endoscopic retrograde cholangiopancreatographys were performed, and pancreatic duct stenting was attempted in 324 cases (20%), with successful placement in 307 patients (95%). Contra-indications to non-steroidal anti-inflammatory drugs were found in 106 (6.5%) patients. Prophylactic stenting failed in 12 of 213 patients; of whom one patient developed post-ERCP pancreatitis (8%). Eighteen (9%) patients with prophylactic pancreatic duct stents developed post-ERCP pancreatitis compared to 1.4% without prophylactic stents (RR 8.4, p=0.04). A lack of difference in post-ERCP pancreatitis in those who underwent successful, and unsuccessful, pancreatic duct stent placement may reflect the protective effect of non-steroidal anti-inflammatory drugs. This data adds to evidence suggesting that pancreatic duct stenting may be less important, even in high-risk patients, with the widespread use of non-steroidal anti-inflammatory drugs.


Neurodevelopmental trajectories of the human cerebral cortex.
Understanding the organization of the cerebral cortex remains a central focus of neuroscience. Cortical maps have relied almost exclusively on the examination of postmortem tissue to construct structural, architectonic maps. These maps have invariably distinguished between areas with fewer discernable layers, which have a less complex overall pattern of lamination and lack an internal granular layer, and those with more complex laminar architecture. The former includes several agranular limbic areas, and the latter includes the homotypical and granular areas of association and sensory cortex. Here, we relate these traditional maps to developmental data from noninvasive neuroimaging. Changes in cortical thickness were determined in vivo from 764 neuroanatomic magnetic resonance images acquired longitudinally from 375 typically developing children and young adults. We find differing levels of complexity of cortical growth across the cerebrum, which align closely with established architectonic maps. Cortical regions with simple laminar architecture, including most limbic areas, predominantly show simpler growth trajectories. These areas have clearly identified homologues in all mammalian brains and thus likely evolved in early mammals. In contrast, polysensory and high-order association areas of cortex, the most complex areas in terms of their laminar architecture, also have the most complex developmental trajectories. Some of these areas are unique to, or dramatically expanded in primates, lending an evolutionary significance to the findings. Furthermore, by mapping a key characteristic of these development trajectories (the age of attaining peak cortical thickness) we document the dynamic, heterochronous maturation of the cerebral cortex through time lapse sequences ("movies").


Association of folic acid supplementation during pregnancy and infant bronchiolitis.
Viral bronchiolitis affects 20%-30% of infants; because there is no known effective treatment, it is important to identify risk factors that contribute to its pathogenesis. Although adequate folate intake during the periconceptional period prevents neural tube defects, animal data suggest that higher supplementation may be a risk factor for child respiratory diseases. Using a population-based retrospective cohort of 167,333 women and infants, born in 1995-2007 and enrolled in the Tennessee Medicaid program, we investigated the association between the filling of folic acid-containing prescriptions and infant bronchiolitis. We categorized women into the following 4 groups in relation to the first trimester: "none" (no prescription filled), "first trimester only," "after first trimester," and "both" (prescriptions filled both during and after the first trimester). Overall, 21% of infants had a bronchiolitis diagnosis, and 5% were hospitalized. Most women filled their first prescriptions after the fifth to sixth weeks of pregnancy, and most prescriptions contained 1,000 µg of folic acid. Compared with infants born to women in the "none" group, infants born to women in the "first trimester only" group had higher relative odds of bronchiolitis diagnosis (adjusted odds ratio = 1.17, 95% confidence interval: 1.11, 1.22) and greater severity (adjusted odds ratio = 1.16, 95% confidence interval: 1.11, 1.22). This study's findings contribute to an understanding of the implications of prenatal nutritional supplement recommendations for infant bronchiolitis.


Large-scale replication study reveals a limit on probabilistic prediction in language comprehension.
Do people routinely pre-activate the meaning and even the phonological form of upcoming words? The most acclaimed evidence for phonological prediction comes from a 2005 Nature Neuroscience publication by DeLong, Urbach and Kutas, who observed a graded modulation of electrical brain potentials (N400) to nouns and preceding articles by the probability that people use a word to continue the sentence fragment ('cloze'). In our direct replication study spanning 9 laboratories (N=334), pre-registered replication-analyses and exploratory Bayes factor analyses successfully replicated the noun-results but, crucially, not the article-results. Pre-registered single-trial analyses also yielded a statistically significant effect for the nouns but not the articles. Exploratory Bayesian single-trial analyses showed that the article-effect may be non-zero but is likely far smaller than originally reported and too small to observe without very large sample sizes. Our results do not support the view that readers routinely pre-activate the phonological form of predictable words.


Protecting people against radiation exposure in the event of a radiological attack. A report of The International Commission on Radiological Protection.
This report responds to a widely perceived need for professional advice on radiological protection measures to be undertaken in the event of a radiological attack. The report, which is mainly concerned with possible attacks involving 'radioactive dispersion devices', re-affirms the applicability of existing ICRP recommendations to such situations, should they ever occur. Many aspects of the emergency scenarios expected to arise in the event of a radiological attack may be similar to those that experience has shown can arise from radiological accidents, but there may also be important differences. For instance, a radiological attack would probably be targeted at a public area, possibly in an urban environment, where the presence of radiation is not anticipated and the dispersion conditions commonly assumed for a nuclear or radiological emergency, such as at a nuclear installation, may not be applicable. First responders to a radiological attack and other rescuers need to be adequately trained and to have the proper equipment for identifying radiation and radioactive contamination, and specialists in radiological protection must be available to provide advice. It may be prudent to assume that radiological, chemical, and/or biological agents are involved in an attack until it is proven otherwise. This calls for an 'all-hazard' approach to the response. In the aftermath of an attack, the main aim of radiological protection must be to prevent the occurrence of acute health effects attributable to radiation exposure (termed 'deterministic' effects) and to restrict the likelihood of late health effects (termed 'stochastic' effects) such as cancers and some hereditable diseases. A supplementary aim is to minimise environmental contamination from radioactive residues and the subsequent general disruption of daily life. The report notes that action taken to avert exposures is a much more effective protective measure than protective measure the provision of medical treatment after exposure has occurred. Responders involved in recovery, remediation and eventual restoration should be subject to the usual international standards for occupational radiological protection, which are based on ICRP recommendations, including the relevant requirements for occupational dose limitation established in such standards. These restrictions may be relaxed for informed volunteers undertaking urgent rescue operations, and they are not applicable for voluntary life-saving actions. However, specific protection measures are recommended for female workers who may be pregnant or nursing an infant. The immediate countermeasures to protect the public in the rescue phase are primarily caring for people with traumatic injuries and controlling access. Subsequent actions include respiratory protection, personal decontamination, sheltering, iodine prophylaxis (if radio-iodines are involved), and temporary evacuation. In the recovery phase, the relocation and resettlement of people may be needed in extreme cases. This phase may require remedial action, including cleanup, management of the resulting radioactive waste, management of any human remains containing significant amounts of radioactive substances, and dealing with remaining radioactive residues. The guidance given in relation to public protection is based solely on radiological protection considerations and should be seen as a decision-aiding tool to prepare for the aftermath of a radiological attack. It is expected to serve as input to a final decision-making process that may include other societal concerns, consideration of lessons learned in the past (especially these involving the public perception of the risks posed by radioactive contamination) and the participation of interested parties. A radiological attack could also be the cause of radioactive contamination of water, food, and other widely consumed commodities. This possible outcome is considered unlikely to lead to significant internal contamination of a large number of people owing to the large amounts of radioactive material that would be required to cause high levels of contamination of water, food, and other commodities. Nonetheless, the report recommends radiological criteria for restricting the use of commodities under such circumstances. The report concludes by re-iterating that the response to radiological attacks should be planned beforehand following the customary processes for optimisation of radiological protection recommended by ICRP, and that optimised measures should be prepared in advance. Such plans should result in a systematic approach that can be modified if necessary to take into account the prevailing conditions and to invoke actions as warranted by the circumstances. Many potential scenarios clearly cannot induce immediate severe radiation injuries. Therefore, in order to prevent over-reaction, response measures prepared in advance should reflect the real expected gravity of the various possible scenarios.


Variability of the pullout strength of cancellous bone screws with cement augmentation.
Orthopaedic surgeons often face clinical situations where improved screw holding power in cancellous bone is needed. Injectable calcium phosphate cements are one option to enhance fixation. Paired screw pullout tests were undertaken in which human cadaver bone was augmented with calcium phosphate cement. A finite element model was used to investigate sensitivity to screw positional placement. Statistical analysis of the data concluded that the pullout strength was generally increased by cement augmentation in the in vitro human cadaver tests. However, when comparing the individual paired samples there were surprising results with lower strength than anticipated after augmentation, in apparent contradiction to the generally expected conclusion. Investigation using the finite element model showed that these strength reductions could be accounted for by small screw positional changes. A change of 0.5mm might result in predicted pullout force changes of up to 28%. Small changes in screw position might lead to significant changes in pullout strength sufficient to explain the lower than expected individual pullout values in augmented cancellous bone. Consequently whilst the addition of cement at a position of low strength would increase the pullout strength at that point, it might not reach the pullout strength of the un-augmented paired test site. However, the overall effect of cement augmentation produces a significant improvement at whatever point in the bone the screw is placed. The use of polymeric bone-substitute materials for tests may not reveal the natural variation encountered in tests using real bone structures.


DC-SIGN (CD209) Promoter -336 A/G polymorphism is associated with dengue hemorrhagic fever and correlated to DC-SIGN expression and immune augmentation.
the C-type lectin DC-SIGN (CD209) is known to be the major dengue receptor on human dendritic cells, and a single nucleotide polymorphism (SNP) in the promoter region of CD209 (-336 A/G; rs4804803) is susceptible to many infectious diseases. We reason that variations in the DC-SIGN gene might have a broad influence on viral replication and host immune responses. we studied whether the rs4804803 SNP was associated with a susceptibility to dengue fever (DF) and/or dengue hemorrhagic fever (DHF) through genotyping analysis in a Taiwanese cohort. We generated monocyte-derived dendritic cells (MDDCs) from individuals with AA or AG genotype of rs4804803 to study the viral replication and immune responses for functional validation. A total of 574 DNA samples were genotyped, including 176 DF, 135 DHF, 143 other non-dengue febrile illnesses (OFI) and 120 population controls. A strong association between GG/AG genotypes of rs4804803 and risk of DHF was found when compared among DF, OFI and controls (p = 0.004, 3×10(-5) and 0.001, respectively). The AA genotype was associated with protection against dengue infection compared with OFI and controls (p = 0.002 and 0.020, respectively). Moreover, MDDCs from individuals with AG genotype with a higher cell surface DC-SIGN expression had a significantly higher TNFα, IL-12p40, and IP-10 production than those with AA genotype in response to dengue infection. However, the viral replication in MDDCs with AG genotype was significantly lower than those with AA genotype. With both genotypes, MDDCs revealed an increase in viral replication following the addition of anti-IP-10 neutralizing antibody. the rs4804803 SNP in the CD209 promoter contributed to susceptibility to dengue infection and complication of DHF. This SNP with AG genotype affects the cell surface DC-SIGN expression related to immune augmentation and less viral replication.


2019-nCoV (Wuhan virus), a novel Coronavirus: human-to-human transmission, travel-related cases, and vaccine readiness.
On 31 December 2019 the Wuhan Health Commission reported a cluster of atypical pneumonia cases that was linked to a wet market in the city of Wuhan, China. The first patients began experiencing symptoms of illness in mid-December 2019. Clinical isolates were found to contain a novel coronavirus with similarity to bat coronaviruses. As of 28 January 2020, there are in excess of 4,500 laboratory-confirmed cases, with > 100 known deaths. As with the SARS-CoV, infections in children appear to be rare. Travel-related cases have been confirmed in multiple countries and regions outside mainland China including Germany, France, Thailand, Japan, South Korea, Vietnam, Canada, and the United States, as well as Hong Kong and Taiwan. Domestically in China, the virus has also been noted in several cities and provinces with cases in all but one provinence. While zoonotic transmission appears to be the original source of infections, the most alarming development is that human-to-human transmission is now prevelant. Of particular concern is that many healthcare workers have been infected in the current epidemic. There are several critical clinical questions that need to be resolved, including how efficient is human-to-human transmission? What is the animal reservoir? Is there an intermediate animal reservoir? Do the vaccines generated to the SARS-CoV or MERS-CoV or their proteins offer protection against 2019-nCoV? We offer a research perspective on the next steps for the generation of vaccines. We also present data on the use of in silico docking in gaining insight into 2019-nCoV Spike-receptor binding to aid in therapeutic development. Diagnostic PCR protocols can be found at https://www.who.int/health-topics/coronavirus/laboratory-diagnostics-for-novel-coronavirus.


Ocular developmental abnormalities and glaucoma associated with interstitial 6p25 duplications and deletions.
Mutations in the forkhead transcription factor gene FOXC1 on 6p25 cause a range of ocular developmental abnormalities, with associated glaucoma. However, FOXC1 mutations have not been found in all similarly affected pedigrees mapping to this interval. This study was undertaken to investigate the potential role of 6p25 rearrangements in causing such phenotypes. Two large families with autosomal dominant iris hypoplasia and early-onset glaucoma, 21 probands with Axenfeld-Rieger phenotypes not attributable to PITX2 mutations, and 7 individuals with documented 6p25 cytogenetic rearrangements, were investigated by genotyping and fluorescence in situ hybridization, with markers and probes from the 6p25 region. Interstitial 6p25 duplications were present in the unrelated families with iris hypoplasia, whereas an interstitial 6p25 deletion was identified in one Axenfeld-Rieger pedigree. Larger cytogenetic rearrangements, leading to trisomy or monosomy of the 6p25 region, resulted in microcornea and Rieger syndrome phenotypes, respectively. All the rearrangements encompassed FOXC1, increasing or decreasing the number of FOXC1 copies present, and appeared to correlate with the phenotypes observed. These findings represent the first example of both interstitial duplications and deletions cosegregating with a human developmental disorder that is attributable to altered dose of transcription factor. The data presented provide additional evidence for the pathogenicity of altered gene dosage of FOXC1 and suggest that a common mechanism is responsible for rearrangements of 6p25.


Preparing the health care workforce to care for adults with Alzheimer's disease and related dementias.
In the United States, one in nine people ages sixty-five and older and one-third of people ages eighty-five and older have Alzheimer's disease. The number of cases of Alzheimer's disease is projected to triple by 2050, from 5.0 million in 2013 to 13.8 million. This will challenge the health care workforce, which is already inadequate in both size and training. We assessed what is likely to be an increasing shortage of physicians, nurses, and social workers with specialized training in geriatrics and, more specifically, in the care of people with dementia. We highlight the limited training of health care professionals in best practices of dementia care and chronic disease management. To address these shortfalls, we recommend the dissemination of team-based models of care that integrate health and social services; expansion of education loan forgiveness and faculty development programs to attract students into clinician-educator careers focusing on Alzheimer's disease; inclusion of curricula specific to the disease in all health professions training; expansion of federal programs to train existing workers; and increased compensation for the direct care workforce.


Chimeras taking shape: potential functions of proteins encoded by chimeric RNA transcripts.
Chimeric RNAs comprise exons from two or more different genes and have the potential to encode novel proteins that alter cellular phenotypes. To date, numerous putative chimeric transcripts have been identified among the ESTs isolated from several organisms and using high throughput RNA sequencing. The few corresponding protein products that have been characterized mostly result from chromosomal translocations and are associated with cancer. Here, we systematically establish that some of the putative chimeric transcripts are genuinely expressed in human cells. Using high throughput RNA sequencing, mass spectrometry experimental data, and functional annotation, we studied 7424 putative human chimeric RNAs. We confirmed the expression of 175 chimeric RNAs in 16 human tissues, with an abundance varying from 0.06 to 17 RPKM (Reads Per Kilobase per Million mapped reads). We show that these chimeric RNAs are significantly more tissue-specific than non-chimeric transcripts. Moreover, we present evidence that chimeras tend to incorporate highly expressed genes. Despite the low expression level of most chimeric RNAs, we show that 12 novel chimeras are translated into proteins detectable in multiple shotgun mass spectrometry experiments. Furthermore, we confirm the expression of three novel chimeric proteins using targeted mass spectrometry. Finally, based on our functional annotation of exon organization and preserved domains, we discuss the potential features of chimeric proteins with illustrative examples and suggest that chimeras significantly exploit signal peptides and transmembrane domains, which can alter the cellular localization of cognate proteins. Taken together, these findings establish that some chimeric RNAs are translated into potentially functional proteins in humans.


Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination.
Although present in both humans and chimpanzees, recombination hotspots, at which meiotic crossover events cluster, differ markedly in their genomic location between the species. We report that a 13-base pair sequence motif previously associated with the activity of 40% of human hotspots does not function in chimpanzees and is being removed by self-destructive drive in the human lineage. Multiple lines of evidence suggest that the rapidly evolving zinc-finger protein PRDM9 binds to this motif and that sequence changes in the protein may be responsible for hotspot differences between species. The involvement of PRDM9, which causes histone H3 lysine 4 trimethylation, implies that there is a common mechanism for recombination hotspots in eukaryotes but raises questions about what forces have driven such rapid change.


3D structure and allosteric modulation of the transmembrane domain of pentameric ligand-gated ion channels.
Pentameric ligand-gated ion channels mediate rapid chemo-electric signal transduction in animals. The active site of this family of proteins is their ion channel pore, which is located at the center of the transmembrane domain. The opening/closing motions of the channel pore are governed by the binding of neurotransmitter to the extracellular domain, but also by allosteric effectors acting within the transmembrane domain. Here, we review the structure of the transmembrane domain as well as its role in the allosteric modulation of pentameric ligand-gated ion channel function. We focus on two examples: the interactions of nicotinic ACh receptors with lipids, for which a novel "uncoupled" state has been proposed, and the interactions of GABA(A) and Glycine receptors with allosteric modulators, such as general anesthetics, ethanol and neurosteroids. We revisit these data in light of the recently solved X-ray structures of bacterial members of the family, which provide atomic-resolution insight into the structures of both the transmembrane domain and associated lipids.


Role of cardiac T1 mapping and extracellular volume in the assessment of myocardial infarction.
Although late gadolinium enhancement on cardiac magnetic resonance imaging remains the reference standard for scar assessment, it does not provide quantitative information about the extent of pathophysiological changes within the scar tissue. T1 mapping and extracellular volume (ECV) mapping are steadily becoming diagnostic and prognostically useful tests for in vivo myocardial histology, influencing clinical decision-making. Quantitative native T1 maps (acquired without a contrast agent) represent the longitudinal relaxation time within the myocardium and changes with myocardial extracellular water (edema, focal, or diffuse fibrosis), fat, iron, and amyloid protein content. Post-contrast ECV maps estimate the size of the extracellular space and have sensitivity in the identification of interstitial disease. Both pre- and post-contrast T1 mapping are emerging as comprehensive tools for the assessment of numerous conditions including ischemic scarring that occurs post myocardial infarction (MI). This review outlines the current evidence and potential future role of T1 mapping in MI. We conclude by highlighting some of the remaining challenges such as quality control, standardization of image acquisition for clinical practice, and automated methods for quantifying infarct size, area at risk, and myocardial salvage post MI.


Genetic Variability in Phosphorus Responses of Rice Root Phenotypes.
Low phosphorus availability is a major factor limiting rice productivity. Since root traits determine phosphorus acquisition efficiency, they are logical selection targets for breeding rice with higher productivity in low phosphorus soils. Before using these traits for breeding, it is necessary to identify genetic variation and to assess the plasticity of each trait in response to the environment. In this study, we measured phenotypic variation and effect of phosphorus deficiency on root architectural, morphological and anatomical traits in 15 rice (Oryza sativa) genotypes. Rice plants were grown with diffusion-limited phosphorus using solid-phase buffered phosphorus to mimic realistic phosphorus availability conditions. Shoot dry weight, tiller number, plant height, number of nodal roots and shoot phosphorus content were reduced under low phosphorus availability. Phosphorus deficiency significantly reduced large lateral root density and small and large lateral root length in all genotypes, though the degree of plasticity and relative allocation of root length between the two root classes varied among genotypes. Root hair length and density increased in all genotypes in response to low phosphorus. Nodal root cross-sectional area was significantly less under low phosphorus availability, and reduced cortical area was disproportionately responsible for this decline. Phosphorus deficiency caused a 20 % increase in the percent cortical area converted to aerenchyma. Total stele area and meta-xylem vessel area responses to low phosphorus differed significantly among genotypes. Phosphorus treatment did not significantly affect theoretical water conductance overall, but increased or reduced it in a few genotypes. All genotypes had restricted water conductance at the base of the nodal root compared to other positions along the root axis. There was substantial genetic variation for all root traits investigated. Low phosphorus availability significantly affected most traits, often to an extent that varied with the genotype. With the exception of stele and meta-xylem vessel area, root responses to low phosphorus were in the same direction for all genotypes tested. Therefore, phenotypic evaluations conducted with adequate fertility should be useful for genetic mapping studies and identifying potential sources of trait variation, but these should be confirmed in low-phosphorus environments.


Origin and fate of nitrate runoff in an agricultural catchment: Haean, South Korea - Comparison of two extremely different monsoon seasons.
The monsoon season in South Korea has great influences on biogeochemical and hydrological processes in the entire country, but is specifically of concern in the Soyang lake watershed, the main drinking water reservoir for the 20-million-people metropolis Seoul. Therefore, water quality and nitrate concentration control in Lake Soyang is of high public priority. The Haean catchment is the most prominent agriculture-dominated sub-catchment of the Soyang lake watershed. It is a complex terrain influenced by extreme rain events and non-point nitrate sources. In this investigation we used input-output calculations and a stable isotope approach to quantify and determinate the origin of nitrate inputs into the rivers that later flow into the lake. During pre-monsoon and monsoon seasons in 2013 and 2014 we measured daily rainfall and river water discharge within the Haean catchment and collected rain, river water and groundwater samples in order to analyze nitrate concentrations and nitrate nitrogen and oxygen isotope abundances. Furthermore, we collected nitrogen fertilizers as applied in the catchment. Heavy monsoon events, as in 2013, were the most pronounced drivers of nitrate leaching being responsible for >80% of the nitrate output in the river runoff. On the other hand, an almost missing summer monsoon in 2014 drove the nitrate runoff in a different manner, being responsible for only 0.4% of the total nitrate nitrogen river discharge in the previous year. Results of nitrate nitrogen and oxygen isotope abundance analyses suggest soil microbial nitrification as the most important contributor to the nitrate in the river runoff. In addition, nitrate from groundwater partially affected by microbial denitrification contributed to the nitrate in the runoff due to river-aquifer exchange fluxes during the monsoon season. Direct leaching of nitrate from mineral fertilizers and atmospheric nitrate deposition were obviously only minor contributors to the nitrate in the runoff.


The biotic ligand model can successfully predict the uptake of a trivalent ion by a unicellular alga below pH 6.50 but not above: possible role of hydroxo-species.
In many reported cases, the biotic ligand model (BLM) has been shown to predict the bioavailability of divalent metals toward aquatic biota successfully. However, studies on the bioavailability of nonessential trivalent metals, including aluminum (Al), are relatively scarce. In the present study, short-term scandium (Sc) internalization fluxes (Jint) were measured in Chlamydomonas reinhardtii in order to explore the applicability of the BLM to trivalent metals. Scandium was selected for its chemical similarities with Al and for its convenient radio-isotope (Sc-46). Apparent affinity constants of Sc(3+) with membrane transport sites (KSc-Rcell app) were surprisingly high, ranging from 10(8.08) M(-1) to 10(13.95) M(-1) over the pH range from 4.50 to 7.90. The competition of H(+) for binding with Sc(3+) transport sites explained this trend within the pH range of 4.50 to 6.00, but not from pH 6.50-7.90. In this latter pH range, predicted fluxes were smaller than observed fluxes and this divergence increased with pH, from a factor of 4 to approximately 1000. Above pH 6.50, the calculated supply of Sc(3+) to the biointerface by physical diffusion of the free Sc(3+) ion and by the dissociation of its hydroxo-complexes (ScOH(2+), Sc(OH)2(+) and Sc(OH)3) was insufficient to support the high observed internalization fluxes. We speculate that this failure of the BLM could be due to the transmembrane transport of undissociated Sc hydroxo-complexes. Scandium uptake could be modeled reasonably well using a simple semiempirical equation considering equal contributions from Sc(3+), ScOH(2+), Sc(OH)2(+), and Sc(OH)3 and no H(+) competition. Our work highlights the importance of studying the possible role of hydroxo-species in trace metal uptake.


Anticarcinoma activity of a novel drug, 3-ethyl-3'-methyl-thiatelluracarbocyanine iodide (Te), a tellurium-containing cyanine targeted at mitochondria.
Lipophilic cationic compounds such as rhodamine 123, AA1, and dequalinium chloride have been reported to constitute a new class of anticarcinoma agents based on their selective localization, accumulation, and retention within the mitochondria of certain carcinoma cells. After screening more than 1000 lipophilic cationic compounds in clonogenic assays, we found that a tellurium-containing cyanine, 3-ethyl-3'-methyl-thiatelluracarbocyanine iodide (Te), exhibits significant anticarcinoma activity. In vitro testing showed that Te was 64-fold more toxic to the carcinoma cell line CX-1 than to the normal epithelial cell line CV-1. In vivo testing showed that Te significantly prolonged the survival of mice implanted with tumors. For C57BL x DBA/2 F1 mice implanted with the mouse bladder carcinoma cell line MB49, the treated:control (T:C) ratio ranged from 250 to 268%. For Swiss nu/nu mice implanted with the human melanoma cell line LOX, the T:C ratio ranged from 176 to 270%. For Swiss nu/nu mice implanted with the human ovarian tumor cell line OVCA-III, the T:C ratio was 344%. These anticarcinoma activities warrant further investigation of Te as a potential anticarcinoma agent.


Stable Isotopic Evidence for a Pedogenic Origin of Carbonates in Trench 14 near Yucca Mountain, Nevada.
Layered carbonate and silica encrust fault fractures exposed in Trench 14 near Yucca Mountain, site of the proposed high-level nuclear waste repository in southern Nevada. Comparison of the stable carbon and oxygen isotopic compositions of the fracture carbonates with those of modern soil carbonates in the area shows that the fracture carbonates are pedogenic in origin and that they likely formed in the presence of vegetation and rainfall typical of a glacial climate. Their isotopic composition differs markedly from that of carbonate associated with nearby springs. The regional water table therefore remained below the level of Trench 14 during the time that the carbonates and silica precipitated, a period probably covering parts of at least the last 300,000 years.


The impact of Chiari malformation on daily activities: A report from the national Conquer Chiari Patient Registry database.
Chiari malformation (CM) is characterized by herniation of the cerebellar tonsils into the cervical spine. While ample literature on CM exists for clinical and procedural aspects of the disease, few studies have measured the impact CM has on daily activities. The objective of this study was to measure the impact that CM has on daily living activities. Data was analyzed from 798 CM patients gathered by the national Conquer Chiari Patient Registry database. Results indicate CM is associated with negative impact on daily living and physical activities for patients, even those exhibiting mild symptoms. Participants with severe symptoms experience the greatest deficit with regards to daily living such as difficulty walking, driving, housecleaning and food preparation. As 96.1% of CM patients report impact in one or more areas of daily living, CM is classified as a disability according to 42 U.S. CODE § 12101 (Americans with Disabilities Act). The degree of self-reported CM symptom severity is strongly related to the frequency and extent of limitations in both physical and daily activities.


Morbid obesity resulting from inactivation of the ciliary protein CEP19 in humans and mice.
Obesity is a major public health concern, and complementary research strategies have been directed toward the identification of the underlying causative gene mutations that affect the normal pathways and networks that regulate energy balance. Here, we describe an autosomal-recessive morbid-obesity syndrome and identify the disease-causing gene defect. The average body mass index of affected family members was 48.7 (range = 36.7-61.0), and all had features of the metabolic syndrome. Homozygosity mapping localized the disease locus to a region in 3q29; we designated this region the morbid obesity 1 (MO1) locus. Sequence analysis identified a homozygous nonsense mutation in CEP19, the gene encoding the ciliary protein CEP19, in all affected family members. CEP19 is highly conserved in vertebrates and invertebrates, is expressed in multiple tissues, and localizes to the centrosome and primary cilia. Homozygous Cep19-knockout mice were morbidly obese, hyperphagic, glucose intolerant, and insulin resistant. Thus, loss of the ciliary protein CEP19 in humans and mice causes morbid obesity and defines a target for investigating the molecular pathogenesis of this disease and potential treatments for obesity and malnutrition.


Evaluation of high efficiency gene knockout strategies for Trypanosoma cruzi.
Trypanosoma cruzi, a kinetoplastid protozoan parasite that causes Chagas disease, infects approximately 15 million people in Central and South America. In contrast to the substantial in silico studies of the T. cruzi genome, transcriptome, and proteome, only a few genes have been experimentally characterized and validated, mainly due to the lack of facile methods for gene manipulation needed for reverse genetic studies. Current strategies for gene disruption in T. cruzi are tedious and time consuming. In this study we have compared the conventional multi-step cloning technique with two knockout strategies that have been proven to work in other organisms, one-step-PCR- and Multisite Gateway-based systems. While the one-step-PCR strategy was found to be the fastest method for production of knockout constructs, it does not efficiently target genes of interest using gene-specific sequences of less than 80 nucleotides. Alternatively, the Multisite Gateway based approach is less time-consuming than conventional methods and is able to efficiently and reproducibly delete target genes. Using the Multisite Gateway strategy, we have rapidly produced constructs that successfully produce specific gene deletions in epimastigotes of T. cruzi. This methodology should greatly facilitate reverse genetic studies in T. cruzi.


Mobilization of 45Ca from insulin-producing RINm5F cells attached to microcarriers.
A technique was designed allowing studies of 45Ca efflux from insulin-releasing cells of a clonal cell line (RINm5F) attached to fibronectin-coated plastic beads. Supporting the existence of Ca2+-Ca2+ and Na+-Ca2+ exchange mechanisms, the efflux of 45Ca in a Ca2+-deficient perifusion medium was increased after introduction of Ca2+ and decreased after removal of Na+. The washout of radioactivity was similar to that from pancreatic islets in also being inhibited by glucose in the presence of low concentrations of extracellular Ca2+. During perifusion with a medium containing 2.56 mM Ca2+, increasing the K+ concentration resulted in an increased 45Ca efflux, a process counteracted by D-600. Also, exposure to tolbutamide resulted in a distinct stimulatory peak. Glucose was a poor stimulator of 45Ca efflux, suggesting that this sugar lacks the ability to depolarize the RINm5F cells sufficiently to induce normal opening of the voltage-dependent channels in the plasma membrane. Such a defect might well explain why the RINm5F cells do not respond to glucose with stimulation of insulin release.


Spatial correlation between hyperpigmentary changes on color fundus photography and hyperreflective foci on SDOCT in intermediate AMD.
Macular hyperpigmentation is associated with progression from intermediate to advanced age-related macular degeneration (AMD). The purpose of this study was to accurately correlate hyperpigmentary changes with spectral domain optical coherence tomography (SDOCT) hyperreflective foci in eyes with non-advanced AMD. A prospective cross-sectional analysis of 314 eyes (314 subjects) with intermediate AMD was performed in the multicenter Age-Related Eye Disease Study 2 (AREDS2) Ancillary SDOCT Study to correlate hyperpigmentary changes on color fundus photographs (CFP) with abnormal morphology on SDOCT. Spatial coregistration was performed with an automated algorithm in two nonoverlapping subsets of 20 study eyes, which permitted double-masked CFP and SDOCT grading by certified investigators. Macular CFP hyperpigmentation was significantly associated with SDOCT intraretinal hyperreflective foci in the 314 study eyes (P < 0.001). In a substudy of 40 eyes, automated intermodality spatial coregistration was successfully achieved in all 136 (100%) retinal regions selected for CFP and SDOCT grading. In one subset of 20 study eyes, 28 of 39 (71.8%) retinal CFP regions with hyperpigmentation were correlated with focal hyperreflectivity on SDOCT, versus seven of 39 (17.9%) control regions (P < 0.001). In another subset of 20 eyes, 21 of 29 (72.4%) SDOCT regions with hyperreflective foci were correlated with hyperpigmentary changes on CFP, versus two of 29 (6.9%) control regions (P < 0.001). A novel algorithm achieves automated intermodality spatial coregistration for masked grading of regions selected on CFP and SDOCT. In intermediate AMD, macular hyperpigmentation has high spatial correlation to SDOCT hyperreflective foci and often represents the same anatomical lesion. (ClinicalTrials.gov number, NCT00734487.).


Role of ionic interactions in the deformation and fracture behavior of perfluorosulfonic-acid membranes.
The stability of ion-conductive membranes, such as perfluorosulfonic-acid (PFSA) membranes, as a solid-electrolyte separator in energy devices is strongly linked to their mechanical properties, the characterization of which presents challenges, especially in the presence of ionic interactions. Ionomer membranes' elastic properties are affected by cations; however, their influence on deformation at small and large strains is relatively unexplored. In this paper, we report the stress-strain response and fracture behavior of Nafion membranes exchanged with various cations examined in three deformation regimes. In the small-strain regime, the Young's modulus is strongly dependent on cation size, due to the reduced mobility and local stiffening of polymer chains. The Young's modulus, yield limit and strain-hardening modulus all increase with monovalent cation size in the order H+ < Li+ < Na+ < K+ < Cs+, but with varying dependence. In the failure regime, however, the break strain and fracture energy of the membrane decrease in the presence of larger cations, which promote deformation instability while decreasing plastic dissipation energy during crack propagation, thereby leading to more brittle fracture. These results not only demonstrate the trade-off between strength and fracture toughness, but also reveal how it is altered by the ionic interactions, which also dictate the inverse relationship between stretchability and stiffness. Moreover, the measured stress-strain data are reproduced by the constitutive relations to extract parameters that are correlated to the fracture energy through craze instability. Such relationships provide insight into how parameters extracted from tensile testing can be used to assess membrane stability and the role of ionic interactions.


Raman evidence for specific substrate-induced structural changes in the heme pocket of human cytochrome P450 aromatase during the three consecutive oxygen activation steps.
Specific substrate-induced structural changes in the heme pocket are proposed for human cytochrome P450 aromatase (P450arom) which undergoes three consecutive oxygen activation steps. We have experimentally investigated this heme environment by resonance Raman spectra of both substrate-free and substrate-bound forms of the purified enzyme. The Fe-CO stretching mode (nu(Fe)(-)(CO)) of the CO complex and Fe(3+)-S stretching mode (nu(Fe)(-)(S)) of the oxidized form were monitored as a structural marker of the distal and proximal sides of the heme, respectively. The nu(Fe)(-)(CO) mode was upshifted from 477 to 485 and to 490 cm(-)(1) by the binding of androstenedione and 19-aldehyde-androstenedione, substrates for the first and third steps, respectively, whereas nu(Fe)(-)(CO) was not observed for P450arom with 19-hydroxyandrostenedione, a substrate for the second step, indicating that the heme distal site is very flexible and changes its structure depending on the substrate. The 19-aldehyde-androstenedione binding could reduce the electron donation from the axial thiolate, which was evident from the low-frequency shift of nu(Fe)(-)(S) by 5 cm(-)(1) compared to that of androstenedione-bound P450arom. Changes in the environment in the heme distal site and the reduced electron donation from the axial thiolate upon 19-aldehyde-androstenedione binding might stabilize the ferric peroxo species, an active intermediate for the third step, with the suppression of the formation of compound I (Fe(4+)=O porphyrin(+)(*)) that is the active species for the first and second steps. We, therefore, propose that the substrates can regulate the formation of alternative reaction intermediates by modulating the structure on both the heme distal and proximal sites in P450arom.


Comparative analysis of peak-detection techniques for comprehensive two-dimensional chromatography.
Comprehensive two-dimensional gas chromatography (GC×GC) is a powerful technology for separating complex samples. The typical goal of GC×GC peak detection is to aggregate data points of analyte peaks based on their retention times and intensities. Two techniques commonly used for two-dimensional peak detection are the two-step algorithm and the watershed algorithm. A recent study [4] compared the performance of the two-step and watershed algorithms for GC×GC data with retention-time shifts in the second-column separations. In that analysis, the peak retention-time shifts were corrected while applying the two-step algorithm but the watershed algorithm was applied without shift correction. The results indicated that the watershed algorithm has a higher probability of erroneously splitting a single two-dimensional peak than the two-step approach. This paper reconsiders the analysis by comparing peak-detection performance for resolved peaks after correcting retention-time shifts for both the two-step and watershed algorithms. Simulations with wide-ranging conditions indicate that when shift correction is employed with both algorithms, the watershed algorithm detects resolved peaks with greater accuracy than the two-step method.


HIV-1 disease progression and mortality before the introduction of highly active antiretroviral therapy in rural Uganda.
To provide estimates of survival and progression to different HIV disease endpoints after HIV infection among adults in a rural Ugandan setting. A prospective population-based cohort study. Eligible individuals at least 15 years of age with documented HIV seroconversion were recruited from a general population cohort in rural Uganda, along with a randomly selected proportion of HIV-prevalent and HIV-negative individuals. All participants were followed up every 3 months, and CD4 cell counts taken every 6 months in HIV-positive participants. Life tables and Kaplan-Meier functions were used to estimate survival patterns for all endpoints [death, time to World Health Organization (WHO) stage 2, 3, AIDS and CD4 cell count < 200 cells/mul]. Analysis of follow-up time was truncated when antiretroviral therapy (ART) became available in the area in January 2004. We recruited 240 HIV incident cases, 108 prevalent cases and 257 HIV-negative controls. Crude mortality rates were 70.0 per 1000 person-years in HIV-positive, and 12.1 per 1000 person-years in HIV-negative individuals. The median time from seroconversion to death was 9.0 years (N = 240) and 6.2 years to a CD4 cell count less than 200 cells/mul or WHO stage 4 (N = 229). The median time from ART eligibility (CD4 cell count < 200 cells/mul, < 350 cells/mul and WHO stage 3, or WHO stage 4) to death was 34.7 months. Older age at seroconversion was a risk factor for faster progression to death and ART eligibility. HIV progression in this African cohort is similar to that reported in industrialized countries before the widespread introduction of ART.


Sex determination: why so many ways of doing it?
Sexual reproduction is an ancient feature of life on earth, and the familiar X and Y chromosomes in humans and other model species have led to the impression that sex determination mechanisms are old and conserved. In fact, males and females are determined by diverse mechanisms that evolve rapidly in many taxa. Yet this diversity in primary sex-determining signals is coupled with conserved molecular pathways that trigger male or female development. Conflicting selection on different parts of the genome and on the two sexes may drive many of these transitions, but few systems with rapid turnover of sex determination mechanisms have been rigorously studied. Here we survey our current understanding of how and why sex determination evolves in animals and plants and identify important gaps in our knowledge that present exciting research opportunities to characterize the evolutionary forces and molecular pathways underlying the evolution of sex determination.