Hinge length contributes to the phagocytic activity of HIV-specific IgG1 and IgG3 antibodies.
Antibody functions such as neutralization require recognition of antigen by the Fab region, while effector functions are additionally mediated by interactions of the Fc region with soluble factors and cellular receptors. The efficacy of individual antibodies varies based on Fab domain characteristics, such as affinity for antigen and epitope-specificity, and on Fc domain characteristics that include isotype, subclass, and glycosylation profile. Here, a series of HIV-specific antibody subclass and hinge variants were constructed and tested to define those properties associated with differential effector function. In the context of the broadly neutralizing CD4 binding site-specific antibody VRC01 and the variable loop (V3) binding antibody 447-52D, hinge truncation and extension had a considerable impact on the magnitude of phagocytic activity of both IgG1 and IgG3 subclasses. The improvement in phagocytic potency of antibodies with extended hinges could not be attributed to changes in either intrinsic antigen or antibody receptor affinity. This effect was specific to phagocytosis and was generalizable to different phagocytes, at different effector cell to target ratios, for target particles of different size and composition, and occurred across a range of antibody concentrations. Antibody dependent cellular cytotoxicity and neutralization were generally independent of hinge length, and complement deposition displayed variable local optima. In vivo stability testing showed that IgG molecules with altered hinges can exhibit similar biodistribution and pharmacokinetic profiles as IgG1. Overall, these results suggest that when high phagocytic activity is desirable, therapeutic antibodies may benefit from being formatted as human IgG3 or engineered IgG1 forms with elongated hinges.


Importance of dietary advice, nutritional supplements and compliance for maintaining body weight and body fat after hip fracture.
Poor nutritional status amongst elderly individuals with hip fractures is well documented. Studies have suggested that 30-50 % of patients admitted to orthopaedic departments suffer from protein-energy malnutrition (PEM). An 6 month intervention study. The study was conducted in Sweden between February 2005 and October 2006. Elderly patients with hip fractures (n=32). Evaluation of compliance with individual nutritional support and whether body weight and body fat (BF) could be maintained after six months. Evaluation of possible effects of nutritional supplements and dietary advice after hip fracture on BMI, BF, and Mini Nutritional Assessment (MNA). Overall compliance with supplement intake was 73%. After six months, BMI was unchanged. Women's BF had decreased (P < 0.01), although the mean calorie intake with nutritional support was 34 calories per kg body weight/day. Three groups could be identified: one group with increased body weight and BF, one with loss of body weight and BF, and one with increased body weight together with increased TBW and loss of BF. PARTICIPANTS who consumed 0-1 supplements daily lost more weight than those who consumed 2 supplements daily. There was a positive difference (p= < 0.001) for women between MNA values at baseline and after six months. In the present study compliance was satisfactory at the group level, and the energy and protein intake increased significantly. BMI was unchanged during the 6 months period. However, the women lost BF during the study period of with some had increasing total body water (TBW). MNA values for women changed in a positive direction.


A mechanically detachable coil for the treatment of aneurysms and occlusion of blood vessels.
To evaluate mechanically detachable coil designs capable of controlled and instantaneous release within an aneurysm or vascular space. Three mechanically detachable coil designs, clamped ball, looped ribbon, and interlocking cylinder, were evaluated using in vitro and in vivo testing to study reliability of coil release, retractability, and coil behavior in a microcatheters. In vitro tests were performed using a glass side-wall aneurysm model and conventional microcatheters. In vivo experiments in rabbits included aneurysm models (side-wall and bifurcation) and arterial occlusions (carotid and renal). All three designs deployed coils easily and were able to retract coils after partial deployment. Motion was seen in previously released coils and in the catheter when using the clamped ball and looped ribbon designs. The interlocking cylinder design did not cause similar motion. When compared with the other two designs, the interlocking cylinder had significantly greater separation forces between coil pusher and coil while in the catheter. Frictional forces within the catheter were lower for the interlocking cylinder mechanically detachable coil design than for a commercially available conventional coil and coil pusher system. During in vivo testing, the mechanically detachable coil design operated smoothly in the catheter, providing good release and retraction in aneurysms and straight vessels. The interlocking cylinder mechanically detachable coil design is superior to the other two tested designs. The mechanically detachable coil was reliably delivered and detached in in vivo testing for the treatment of aneurysms and for the occlusion of blood vessels.


Whole genome amplification and real-time PCR in forensic casework.
WGA (Whole Genome Amplification) in forensic genetics can eliminate the technical limitations arising from low amounts of genomic DNA (gDNA). However, it has not been used to date because any amplification bias generated may complicate the interpretation of results. Our aim in this paper was to assess the applicability of MDA to forensic SNP genotyping by performing a comparative analysis of genomic and amplified DNA samples. A 26-SNPs TaqMan panel specifically designed for low copy number (LCN) and/or severely degraded genomic DNA was typed on 100 genomic as well as amplified DNA samples. Aliquots containing 1, 0.1 and 0.01 ng each of 100 DNA samples were typed for a 26-SNPs panel. Similar aliquots of the same DNA samples underwent multiple displacement amplification (MDA) before being typed for the same panel. Genomic DNA samples showed 0% PCR failure rate for all three dilutions, whilst the PCR failure rate of the amplified DNA samples was 0% for the 1 ng and 0.1 ng dilutions and 0.077% for the 0.01 ng dilution. The genotyping results of both the amplified and genomic DNA samples were also compared with reference genotypes of the same samples obtained by direct sequencing. The genomic DNA samples showed genotype concordance rates of 100% for all three dilutions while the concordance rates of the amplified DNA samples were 100% for the 1 ng and 0.1 ng dilutions and 99.923% for the 0.01 ng dilution. Moreover, ten artificially-degraded DNA samples, which gave no results when analyzed by current forensic methods, were also amplified by MDA and genotyped with 100% concordance. We investigated the suitability of MDA material for forensic SNP typing. Comparative analysis of amplified and genomic DNA samples showed that a large number of SNPs could be accurately typed starting from just 0.01 ng of template. We found that the MDA genotyping call and accuracy rates were only slightly lower than those for genomic DNA. Indeed, when 10 pg of input DNA was used in MDA, we obtained 99.923% concordance, indicating a genotyping error rate of 1/1299 (7.7 x 10(-4)). This is quite similar to the genotyping error rate of STRs used in current forensic analysis. Such efficiency and accuracy of SNP typing of amplified DNA suggest that MDA can also generate large amounts of genome-equivalent DNA from a minimal amount of input DNA. These results show for the first time that MDA material is suitable for SNP-based forensic protocols and in general when samples fail to give interpretable STR results.


Multi-Omics Analysis to Characterize Cigarette Smoke Induced Molecular Alterations in Esophageal Cells.
Though smoking remains one of the established risk factors of esophageal squamous cell carcinoma, there is limited data on molecular alterations associated with cigarette smoke exposure in esophageal cells. To investigate molecular alterations associated with chronic exposure to cigarette smoke, non-neoplastic human esophageal epithelial cells were treated with cigarette smoke condensate (CSC) for up to 8 months. Chronic treatment with CSC increased cell proliferation and invasive ability of non-neoplastic esophageal cells. Whole exome sequence analysis of CSC treated cells revealed several mutations and copy number variations. This included loss of high mobility group nucleosomal binding domain 2 (HMGN2) and a missense variant in mediator complex subunit 1 (MED1). Both these genes play an important role in DNA repair. Global proteomic and phosphoproteomic profiling of CSC treated cells lead to the identification of 38 differentially expressed and 171 differentially phosphorylated proteins. Bioinformatics analysis of differentially expressed proteins and phosphoproteins revealed that most of these proteins are associated with DNA damage response pathway. Proteomics data revealed decreased expression of HMGN2 and hypophosphorylation of MED1. Exogenous expression of HMGN2 and MED1 lead to decreased proliferative and invasive ability of smoke exposed cells. Immunohistochemical labeling of HMGN2 in primary ESCC tumor tissue sections (from smokers) showed no detectable expression while strong to moderate staining of HMGN2 was observed in normal esophageal tissues. Our data suggests that cigarette smoke perturbs expression of proteins associated with DNA damage response pathways which might play a vital role in development of ESCC.


Interferon therapy for hepatocellular carcinoma patients with low HCV-RNA levels.
Interferon-alfa is widely used for the treatment of chronic hepatitis C, and has been thought to have a preventive effect on the development of hepatocellular carcinoma. Hepatocellular carcinoma develops from chronic liver diseases such as chronic hepatitis C or liver cirrhosis. We studied the effect of interferon for liver cirrhosis with hepatocellular carcinoma after treating hepatocellular carcinoma itself. To evaluate the preventive effect of this drug on local recurrence and/or new development of primary tumor after clearance of hepatitis C virus, 46 patients with hepatocellular carcinoma with low HCV-RNA level were randomized to receive recombinant interferon-alfa 2b (n = 22) or not (n = 24) after being treated by transcatheter arterial chemoembolization and percutaneous ethanol injection therapy. In the interferon-treated group, patients received 3 million international units of interferon-alfa 2b intramuscularly three times a week for 4 months. In both groups, transcatheter arterial chemoembolization followed by percutaneous ethanol injection therapy was performed as an initial treatment and these therapies were repeated every 4-6 months. Serum HCV-RNA levels of all 46 patients were under 0.5 Meq/mL by branched DNA probe assay. In the interferon-treated group, 11 of the 22 (50%) patients were HCV-RNA negative at the 6 months after completing the course of interferon therapy. HCV-RNA was undetectable during the observation period in 2 of the 24 (9.5%) patients in the untreated group. The survival rate in the interferon-treated group was significantly higher than that in the untreated group (P = 0.01 by the log-rank test). Though there was no significant difference in the incidence of local recurrence in both groups, the incidence of secondary hepatocellular carcinoma was significantly lower in the interferon-treated group than that in the untreated group. Cox proportional hazards regression analysis validated interferon treatment as an independent predictor of hepatocellular carcinoma prognosis. We concluded that, if HCV-RNA level is low, interferon may be a therapy of choice in combination with transcatheter arterial chemoembolization and percutaneous ethanol injection therapy for the treatment of hepatocellular carcinoma.


Take the Money and Run: Psychopathic Behavior in the Trust Game.
We study the association among different sources of individual differences such as personality, cognitive ability and risk attitudes with trust and reciprocate behavior in an incentivized experimental binary trust game in a sample of 220 (138 females) undergraduate students. The game involves two players, player 1 (P1) and player 2 (P2). In the first stage, P1 decides whether to trust and let P2 decide, or to secure an egalitarian payoff for both players. If P1 trusts P2, the latter can choose between a symmetric payoff that is double than the secure alternative discarded by P1, and an asymmetric payoff in which P2 earns more than in any other case but makes P1 worse off. Before the main experiment, we obtained participants' scores for Abstract Reasoning (AR), risk attitudes, basic personality characteristics, and specific traits such as psychopathy and impulsivity. During the main experiment, we measured Heart Rate (HR) and ElectroDermal Activity (EDA) variation to account for emotional arousal caused by the decision and feedback processes. Our main findings indicate that, on one hand, P1 trust behavior associates to positive emotionality and, specifically, to the extraversion's warmth facet. In addition, the impulsivity facet of positive urgency also favors trust behavior. No relation to trusting behavior was found for either other major personality aspects or risk attitudes. The physiological results show that participants scoring high in psychopathy exhibit increased EDA and reduced evoked HR deceleration at the moment in which they are asked to decide whether or not to trust. Regarding P2, we find that AR ability and mainly low disagreeable disinhibition favor reciprocal behavior. Specifically, lack of reciprocity significantly relates with a psychopathic, highly disinhibited and impulsive personality. Thus, the present study suggests that personality characteristics would play a significant role in different behaviors underlying cooperation, with extraversion/positive emotionality being more relevant for initiating cooperation, and low disagreeable disinhibition for maintaining it.


After the DNR: Surrogates Who Persist in Requesting Cardiopulmonary Resuscitation.
Some health care organizations allow physicians to withhold cardiopulmonary resuscitation from a patient, despite patient or surrogate requests that it be provided, when they believe it will be more harmful than beneficial. Such cases usually involve patients with terminal diagnoses whose medical teams argue that aggressive treatments are medically inappropriate or likely to be harmful. Although there is state-to-state variability and a considerable judicial gray area about the conditions and mechanisms for refusals to perform CPR, medical teams typically follow a set of clearly defined procedures for these decisions. The procedures are based on the principle of nonmaleficence and typically include consultation with hospital ethics committees, reflecting the guidelines of relevant professional associations. Ethical debates about when CPR can and should be limited tend to rely more on discussions of theory, principles, and case studies than systematic empirical study of the situations in which such limitations are applied. Sociologists of bioethics call for empirical study, arguing that what ethicists and health professionals believe they are doing when they draft policies or invoke principles does not always mirror what is happening on the ground. In this article, we begin the task of modeling the empirical analyses sociologists call for, focusing on a cohort at Massachusetts General Hospital. We inductively analyzed ethics committee notes and medical records of nineteen patients whose surrogates did not accept the decision to withhold CPR.


Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status.
EphA2 is a transmembrane receptor tyrosine kinase that functions in the regulation of cell growth, survival, angiogenesis, and migration and EphA2 targeting has been proposed as a novel therapeutic strategy for neoplasms that overexpress this protein. EphA2 overexpression has been correlated with increased invasive and metastatic ability in pancreatic cancer cell lines. However, the patterns of EphA2 expression in human pancreatic cancers and associated metastases is unknown, as are the genetics of EphA2 in this tumor type. We collected clinicopathologic data and paraffin-embedded materials from 98 patients with primary and/or metastatic pancreatic cancer and performed immunohistochemical labeling for EphA2 protein. EphA2 protein immunolabeling was found in 207 of 219 samples (95%). The expression was predominantly cytoplasmic, although predominant membranous staining was observed in a minority of cases. When evaluated specifically for labeling intensity, primary and metastatic carcinomas were more strongly positive compared to benign ducts and PanIN lesions (P < 0.00001 and P < 0.01, respectively) and poorly differentiated carcinomas were more strongly positive for EphA2 than well and moderately differentiated tumors (P < 0.005). When primary carcinomas without metastatic disease were specifically compared to carcinomas with associated metastatic disease, the advanced carcinomas showed relatively less strong positive labeling for EphA2 (P < 0.008). Moreover, decreased EphA2 labeling was more commonly found in liver (P < 0.002), lung (P < 0.004) or peritoneal metastases (P < 0.01) as compared to distant lymph node metastases (P < 0.01). Genetic sequencing of the tyrosine kinase domain of EPHA2 in 22 samples of xenograft enriched pancreatic cancer did not reveal any inactivating mutations. However, EPHA2 amplification was found in 1 of 33 pancreatic cancers corresponding to a lymph node metastasis, indicating EPHA2 genomic amplification may underlie EphA2 overexpression in a minority of patients. Our data confirms that EphA2 is overexpressed in pancreatic cancer, but suggests a relative loss of EphA2 in co-existent pancreatic cancer metastases as well as a role for EPHA2 in organ specific metastasis.


Resistance to chloroquine by Plasmodium vivax at Alor in the Lesser Sundas Archipelago in eastern Indonesia.
The therapeutic response to standard chloroquine therapy against Plasmodium vivax was evaluated in 36 subjects living at Alor in the Lesser Sundas Archipelago of eastern Indonesia. Chloroquine level were measured on 32 individuals, and showed evidence of adequate absorption of standard chloroquine therapy. Three subjects failed treatment by Day 2 or 3, with evidence of rising asexual parasitemia, and two others had stable parasitemia to Day 7. Ten more subjects had recurrent parasitemia by Day 14, two by Day 21, and another one by Day 28. Three subjects had recurrent parasitemia on Days 14 and 28, but with chloroquine < 100 ng/mL. Eleven subjects cleared parasitemia by Day 3 and had no recurrences up to Day 28. In summary, 28-day cumulative incidence of confirmed resistance to chloroquine was 56% of infections evaluated. Chloroquine should not be considered adequate for treatment of acute vivax malaria acquired in this region.


The scheduled squeeze on children's programs: tracking the implications of projected federal spending patterns.
Federal programs for children are under increasing budgetary pressure. According to current federal law or any budget alternative being offered by the president or congressional leaders, spending on children would decline as a share of the budget and of the national economy. This article summarizes past, current, and projected budgets for children's programs. It traces significant historical expansions of means-tested programs, such as the Supplemental Nutrition Assistance Program; depicts fairly significant declines in more universal supports, such as the income tax exemption for dependents; and shows the future squeeze on children's programs brought about by automatic growth in health, retirement, and tax subsidy programs, along with the failure of revenues to keep pace with the overall growth in spending. Federal programs for health care have been a mixed blessing for children: Medicaid has grown to be the largest federal support for children, but overall federal health care costs eat away at the share of the budgetary pie left for anything else.


A proposed guideline for vagus nerve stimulator handling in palliative care and after death.
Vagus nerve stimulation (VNS) is often used for patients with drug-resistant epilepsy. Although this intervention may improve seizure control and mood, a number of factors must be considered when patients with VNS near end of life. We reviewed relevant literature to create a proposed guideline for management of patients with VNS in palliative care and after death. VNS has multiple possible side effects, including cough and swallowing difficulties. For patients with neurologic disease in palliative care, such adverse effects can severely affect quality of life and increase the risk for complications such as aspiration pneumonia. Patients with VNS should be screened regularly for such side effects, and VNS parameters should be adjusted if they are identified. If a patient requires urgent cardiac resuscitation involving external defibrillation, the VNS should be interrogated immediately afterwards to evaluate its function. During defibrillation, paddles should be placed perpendicular to the VNS, and as far as possible away from it. The VNS can be acutely turned off by taping the magnet to the patient's chest, thereby preventing any possible interference with restoration of a normal heart rhythm. After death, any staff involved with handling the body should be notified that a VNS is in place. The device must be removed prior to cremation, as it can explode with high heat. If the cause of death is unclear, a full postmortem examination should be undertaken, per sudden unexpected death in epilepsy guidelines. If there is concern about device malfunction, the device should be returned to the manufacturer for evaluation.


Efficacy of benzimidazole anthelmintics in goats and sheep in the Philippines using a larval development assay.
The negative effects of nematodes in small ruminants can be reduced by use of dewormers but their effectiveness is increasingly limited by the emergence of anthelmintic resistance. The efficacy of benzimidazole (BZ) anthelmintics in the Philippines was estimated by an in vitro larval development assay using worm eggs recovered from faeces collected from goats and sheep. Two hundred and eighteen farms were selected to represent areas of the country with high goat and sheep populations and the full range of farm sizes, from smallholders with just a few animals to commercial and institutional farms with several hundred. Initial surveys of worm control advisers indicated that BZs have been in continuous widespread use for up to 20 years with little use of other chemical groups. A larval development assay (LDA: DrenchRite) was modified for use with BZs alone to allow up to five samples to be analysed on a single microtitre plate. The assay was validated by comparison with the faecal egg count reduction test (FECRT). The dominant nematode genera were Haemonchus and Trichostrongylus with small numbers of Oesophagostomum. The range of BZ efficacy estimated from the LDA results was 0-100% and the distribution of efficacy levels was continuous, with mean efficacy of 82 and 64% for goats and sheep, respectively. There were significant associations between efficacy and parameters measured to characterize the sampled farms: size of animal management group, FEC of sample, recent importation of stock and no access to common grazing were all correlated with decreased efficacy. Likewise, low efficacy was associated with reported frequency and number of years that BZ drenches had been used. The LDA was found to be highly suited to estimate efficacy in nematode populations from small farms where performance of a FECRT for even one chemical would be impractical. Using a larval development assay, we have demonstrated a wide efficacy range for BZs against nematodes from all sizes of goat and sheep farms in the tropics.


The role of topical corticosteroids in the management of Acanthamoeba keratitis.
To clarify the role of topical corticosteroids in the management of Acanthamoeba keratitis. The records of 38 patients diagnosed with Acanthamoeba keratitis at three institutions were retrospectively reviewed. After medical therapy alone, patients diagnosed within 1 month of symptom onset had an increased likelihood of being cured (p = 0.02) and attaining visual acuity of 20/60 or better (p < 0.01). Fourteen (73.7%) of 19 patients treated with topical corticosteroids at any time were cured after antiamoebal therapy alone, whereas five (26.3%) patients required penetrating keratoplasty for either persistent infection (n = 3) or perforation (n = 2). The mean antiamoebal therapy duration, excluding duration after keratoplasty if applicable, was 38.5 weeks. Thirteen (76.5%) of 17 patients treated with antiamoebal therapy without topical corticosteroids were medically cured, whereas four (23.5%) required penetrating keratoplasty for either persistent infection (n = 2) or perforation (n = 2). The mean antiamoebal therapy duration was 20 weeks. Although the mean antiamoebal therapy duration in the steroid-treated group was significantly longer than that in the non-steroid-treated group (p = 0.02), outcome after medical therapy between the groups was not significantly different. Topical corticosteroids were not associated with a higher rate of medical treatment failure in patients with Acanthamoeba keratitis. Rather, poor outcome was significantly related to diagnostic delays. Therefore prudent use of corticosteroids in selected patients with severe pain not responsive to analgesics or severe corneal or anterior chamber inflammation appears justified.


Age and gender differences in self-esteem-A cross-cultural window.
Research and theorizing on gender and age differences in self-esteem have played a prominent role in psychology over the past 20 years. However, virtually all empirical research has been undertaken in the United States or other Western industrialized countries, providing a narrow empirical base from which to draw conclusions and develop theory. To broaden the empirical base, the present research uses a large Internet sample (N = 985,937) to provide the first large-scale systematic cross-cultural examination of gender and age differences in self-esteem. Across 48 nations, and consistent with previous research, we found age-related increases in self-esteem from late adolescence to middle adulthood and significant gender gaps, with males consistently reporting higher self-esteem than females. Despite these broad cross-cultural similarities, the cultures differed significantly in the magnitude of gender, age, and Gender × Age effects on self-esteem. These differences were associated with cultural differences in socioeconomic, sociodemographic, gender-equality, and cultural value indicators. Discussion focuses on the theoretical implications of cross-cultural research on self-esteem. (PsycINFO Database Record


Mini Nutritional Assessment Scores Indicate Higher Risk for Prospective Mortality and Contrasting Correlation With Age-Related Epigenetic Biomarkers.
The plasticity of the individual epigenetic landscape that goes to countless rearrangements throughout life is closely the reflection of environmental factors such as chemical exposure, socio-economic status and nutrient intakes both early and late in life. The Mini Nutritional Assessment (MNA) is a well-validated tool for assessing malnutrition in old people. It includes 6 (MNA-SF) or 18 (MNA-LF) self-reported questions derived from general, anthropometric, dietary, and self- assessment. We evaluated the association between the nutritional status, as measured by MNA, and methylation biomarkers we previously demonstrated to be associated with chronological and biological age in human. We found that malnutrition is positively correlated with DNA methylation status at the global level, in line with our previous reports. On the contrary, most of the sites located within specific genes, which were previously reported to be correlated with chronological and biological aging, showed to be not affected by malnutrition, or even to have correlations with malnutrition opposite to those previously reported with frailty. These results may suggest that malnutrition is among the first effects of disability and other age- related problems and a generalized non-specific epigenetic remodeling may be the initial response of the organism. By contrast, the fine remodeling of specific genomic sites is scarcely affected by malnutrition and may respond to a more complex interaction of different factors. Therefore, although malnutrition in the elderly is certainly a risk factor for survival, this is partially independent of the aging process of the organism which leads to the methylation remodeling previously described to measure chronological and biological aging.


Structure-immunogenicity relationship of kresoxim-methyl regioisomeric haptens.
Kresoxim-methyl was one of the two first strobilurins to be discovered, and nowadays it is widely used as an antifungal agent in crop protection. Because of its low molecular weight and negligible structural complexity, the generation of antibodies to kresoxim-methyl noticeably requires the preparation of functionalized haptens. In this study, the introduction of a hydrocarbon spacer arm at the aromatic moieties of the target molecule was carried out by a convergent strategy based on the Sonogashira cross-coupling reaction, and functionalized linkers of the same length were also tethered to the aliphatic toxophore group by the O-alkylation reaction. Evaluation of the immune response, in terms of antibody affinity, showed a differential behavior among five synthesized haptens whose sole dissimilarity was the derivatization site. The characteristic (methoxyimino)acetate moiety of strobilurins was revealed as the optimum linker position for high-affinity polyclonal and monoclonal antibody production. However, good monoclonal antibodies were isolated from mice immunized with a hapten carrying the linker at an opposite site, which otherwise generated a poor polyclonal response in rabbits. Site-heterology was confirmed as a feasible approach for the improvement of the apparent affinity, particularly with polyclonal antibodies. Several of the monoclonal antibodies generated in the context of this project could be proper binders for kresoxim-methyl immunosensing over different analytical platforms.


Onychomycosis in patients with psoriasis--a multicentre study.
1-3% of human population is affected by psoriasis. Nail disorders are reported in 10-80% of patients with psoriasis. Nail deformations vary according to their degree of severity but are mainly represented by pitting, Beau's lines, hyperkeratosis, onycholysis, leuconychia or oil drops. Onychomycosis is a fungal infection of the nails, caused by dermatophytes, yeast and moulds. In this study, 228 patients with psoriasis aged between 18 and 72 were examined (48 - from Plovdiv, Bulgaria; 145 - from Pleven, Bulgaria and 35 - from Thessaloniki, Greece); 145 of them were male and 83 of them were female. The examination of the nail material was performed via direct microscopy with 20% KOH and nail samples plated out on Sabouraud agar methodology. The severity of the nail disorders was determined according to the Nail Psoriasis Severity Index (NAPSI). Positive mycological cultures were obtained from 62% of the patients with psoriasis (52%- Plovdiv, Bulgaria; 70%- Pleven, Bulgaria and 43%- Thessaloniki, Greece). In 67% of the cases, the infection was caused by dermatophytes, in 24% by yeast, in 6% by moulds and in 3% by a combination of causes. All patients with psoriasis were identified with high levels of NAPSI, whereas the ones with isolated Candida had even higher levels. Seventeen percentage of the patients have been treated with methotrexate, 6% have been diagnosed with diabetes and 22% have been reported with onychomycosis and tinea pedis within the family. An increased prevalence of onychomycosis among the patients with psoriasis was found. Dystrophic nails in psoriasis patients are more predisposed to fungal infections. The mycological examination of all psoriasis patients with nail deformations is considered obligatory because of the great number of psoriasis patients diagnosed with onychomycosis.


Absorption and metabolism of chlorogenic acids in cultured gastric epithelial monolayers.
Gastric absorption of feruloylquinic acid and di-O-caffeoylquinic acid analogs has never been investigated despite their potential contribution to the proposed beneficial health effects leading to reduced risk of type 2 diabetes. Using a cultured gastric epithelial model, with an acidic apical pH, the relative permeability coefficients (P(app)) and metabolic fate of a series of chlorogenic acids (CGAs) were investigated. Mechanistic studies were performed in the apical to basal direction and demonstrated differential rates of absorption for different CGA subgroups. For the first time, we show intact absorption of feruloylquinic acids and caffeoylquinic acid lactones across the gastric epithelium (P(app) ∼ 0.2 cm/s). Transport seemed to be mainly by passive diffusion, because good linearity was observed over the incubation period and test concentrations, and we speculate that a potential carrier-mediated component may be involved in uptake of certain 4-acyl CGA isomers. In contrast, absorption of intact di-O-caffeoylquinic acids was rapid (P(app) ∼ 2-10 cm/s) but nonlinear with respect to time and concentration dependence, which was potentially limited by interaction with an efflux transporter and/or pH gradient dependence. For the first time, methylation is shown in gastric mucosa. Furthermore, isoferulic acid, dimethoxycinnamic acid, and ferulic acid were identified as novel gastric metabolites of CGA biotransformation. We propose that the stomach is the first location for the release of hydroxycinnamic acids, which could explain their early detection after coffee consumption.


Initiation of autoimmune diabetes in NOD/Lt mice is MHC class I-dependent.
MHC class II alleles clearly contribute a primary genetic component of susceptibility to autoimmune insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. However, IDDM does not occur in NOD mice made MHC class I-deficient by a functionally inactivated beta2-microglobulin allele (beta2m(null)). In the present study the beta2m(null) mutation was used to examine the relative contributions of MHC class I and class II-dependent T cell responses for initiating autoimmune pancreatic beta cell destruction in NOD mice. Splenocytes from diabetic NOD donors transferred IDDM to both lymphocyte-deficient NOD-scid (class I+) and NOD-scid.beta2m(null) mice (class I-). In contrast, splenocytes from young prediabetic NOD donors only transferred IDDM to class I+, but not class I- NOD-scid recipients. However, splenocytes from prediabetic NOD donors did transfer IDDM to NOD-scid.beta2m(null) recipients previously engrafted with class I+, but not class I-, pancreatic islets. CD4+ T cell lines reactive against some syngeneic class I+ targets could be isolated from NOD.beta2m(null) mice. However, NOD.beta2m(null) T cells underwent activation-driven deletion when transferred into class I+ NOD-scid recipients. Hence, the class I autoreactive T cells present in NOD.beta2m(null) donors did not elicit IDDM when transferred into class I+ NOD-scid recipients. Collectively, these results show that autoimmune IDDM in NOD mice is initiated by MHC class I-dependent T cell responses, but this leads to the subsequent activation of additional T cell populations that can mediate pancreatic beta cell destruction in a MHC class I-independent manner.


CD160 is essential for NK-mediated IFN-γ production.
NK-derived cytokines play important roles for natural killer (NK) function, but how the cytokines are regulated is poorly understood. CD160 is expressed on activated NK or T cells in humans but its function is unknown. We generated CD160-deficient mice to probe its function. Although CD160(-/-) mice showed no abnormalities in lymphocyte development, the control of NK-sensitive tumors was severely compromised in CD160(-/-) mice. Surprisingly, the cytotoxicity of NK cells was not impaired, but interferon-γ (IFN-γ) secretion by NK cells was markedly reduced in CD160(-/-) mice. Functionally targeting CD160 signaling with a soluble CD160-Ig also impaired tumor control and IFN-γ production, suggesting an active role of CD160 signaling. Using reciprocal bone marrow transfer and cell culture, we have identified the intrinsic role of CD160 on NK cells, as well as its receptor on non-NK cells, for regulating cytokine production. To demonstrate sufficiency of the CD160(+) NK cell subset in controlling NK-dependent tumor growth, intratumoral transfer of the CD160(+) NK fraction led to tumor regression in CD160(-/-) tumor-bearing mice, indicating demonstrable therapeutic potential for controlling early tumors. Therefore, CD160 is not only an important biomarker but also functionally controls cytokine production by NK cells.


Serum soluble bone turnover biomarkers in psoriatic arthritis and psoriatic spondyloarthropathy.
Because psoriatic arthritis (PsA) is an inflammatory disease of joints, serum soluble biomarkers specific for chronic joint and bone inflammation may predict future disease severity and response to therapy, thereby informing stratified medicine approaches. The objectives of our systematic review were to determine whether serum soluble bone and cartilage turnover biomarkers are (1) associated with PsA or psoriatic spondyloarthropathy; and (2) associated with disease activity, disease severity, or clinical phenotype. Ten studies met eligibility criteria. Matrix metalloproteinase (MMP)-3, Dickkopf (DKK)-1, macrophage colony-stimulating factor (M-CSF), crosslinked telopeptide of collagen-1, and tumor necrosis factor-related apoptosis-inducing ligand were associated with PsA, with equivocal results for osteoprotegerin (OPG) and bone alkaline phosphatase (ALP). MMP-3, DKK-1, M-CSF, CPII:C2C (ratio of cartilage degradation vs byproduct formation), and possibly OPG were associated with PsA independently of psoriasis. C1-2C (a neoepitope released when type 2 cartilage is degraded by collagenases) was associated with both tender and swollen joint counts, and bone morphogenetic protein-4 with patient global assessment of disease, pain score, and the Bath Ankylosing Spondylitis Disease Activity Index. Bone ALP was associated with disease activity. M-CSF and receptor activator of nuclear factor-κB ligand were associated with several plain radiographic features. No studies have investigated biomarker associations specifically with axial PsA.


The ebb and flow of attention: Between-subject variation in intrinsic connectivity and cognition associated with the dynamics of ongoing experience.
Cognition is dynamic, allowing us the flexibility to shift focus from different aspects of the environment, or between internally- and externally-oriented trains of thought. Although we understand how individuals switch attention across different tasks, the neurocognitive processes that underpin the dynamics of less constrained elements of cognition are less well understood. To explore this issue, we developed a paradigm in which participants intermittently responded to external events across two conditions that systematically vary in their need for updating working memory based on information in the external environment. This paradigm distinguishes the influences on cognition that emerge because of demands placed by the task (sustained) from changes that result from the time elapsed since the last task response (transient). We used experience sampling to identify dynamic changes in ongoing cognition in this paradigm, and related between subject variation in these measures to variations in the intrinsic organisation of large-scale brain networks. We found systems important for attention were involved in the regulation of off-task thought. Coupling between the ventral attention network and regions of primary motor cortex was stronger for individuals who were able to regulate off-task thought in line with the demands of the task. This pattern of coupling was linked to greater task-related thought when environmental demands were high and elevated off-task thought when demands were low. In contrast, the coupling of the dorsal attention network with a region of lateral visual cortex was stronger for individuals for whom off-task thoughts transiently increased with the time since responding to the external world . This pattern is consistent with a role for this system in the time-limited top-down biasing of visual processing to increase behavioural efficiency. Unlike the attention networks, coupling between regions of the default mode network and dorsal occipital cortex was weaker for individuals for whom the level of detail decreased with the passage of time when the external task did not require continuous monitoring of external information. These data provide novel evidence for how neural systems vary across subjects and may underpin individual variation in the dynamics of thought, linking attention systems to the maintenance of task-relevant information, and the default mode network to supporting experiences with vivid detail.


Transcutaneous Vagal Nerve Stimulation in Treatment-Resistant Depression: A Feasibility Study.
Major depression (MD) contributes significantly to the global burden of disease with up to one-third of patients being treatment resistant. Therefore, the development of new treatment options for treatment-resistant depression (TRD) is needed. Vagus nerve stimulation (VNS) has shown mood improvements in patients with TRD. However, due to high costs related to the implantation and the invasive nature of VNS, an application with transcutaneous VNS (t-VNS) has been developed stimulating a vagal nerve branch in the earlobe (Arnold's nerve). A few studies with t-VNS in MD have shown a possible antidepressant effect, but feasibility is poorly described and patients with TRD have not been investigated. As the full antidepressant effect of t-VNS takes months we wanted to assess feasibility and side effects of daily treatments. Single-arm feasibility trial assessing compliance, usability, side effects, cognitive speed, and depression in a four-week period with a recommended t-VNS stimulation duration of four hours per day in patients with TRD. The primary outcome was compliance with 80% of the recommended daily treatment time. Compliance threshold was reached for 80.0% of the 20 included participants. Usability was acceptable. Side effects were few, mild or moderate, mostly as local effects at the contact point in the ear. The device was difficult to use for some participants. A statistically significant reduction in depression severity and an increase in cognitive speed were seen with unchanged suicidal ideation and sleep. We would recommend larger long-term randomized studies of t-VNS to access any antidepressant effect in TRD. The design of the device might be improved for higher usability.


The absence of JC virus antigens in Indian children with medulloblastomas.
The human polyoma virus, also known as the JC virus (JCV), replicates predominantly in the oligodendrocytes, the myelin producing cells in the central nervous system and results in the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) especially in immunosuppressed patients with AIDS. Several investigators have also documented the presence of the viral genome and early and late antigens in a variety of brain tumors particularly in medulloblastomas, gliomas and ependymomas. Reports also indicate the presence of JCV in patients with colon cancer. The T antigen of JCV has been postulated to have oncogenic potential as substantiated by animal experiments. Although JCV infects 80% of the population, there are scant epidemiological studies regarding JCV from India. There are also reports of the low prevalence of PML in patients with AIDS from India and Africa. This study was undertaken to investigate if Indian children with medulloblastomas also show evidence of JCV. Twenty-two consecutive cases of medulloblastomas were investigated for the presence of T antigen and agnoprotein of JCV in biopsy specimens by immunohistochemistry. Antibodies to the agnoprotein antigen raised in rabbits and a monoclonal antibody against SV40 T antigen raised in mice that cross-reacts with JCV T antigen were used. Out of 22 patients, 4 had desmoplastic tumors while the rest had classical tumors. All children were below the age of 10. Results indicate that while PML tissues showed consistent immunostaining both with antibody to T antigen and agnoprotein antibody, none of the tumors showed any positive staining for JC viral antigens. JCV antigens could not be detected by immunohistochemistry in the tumor tissues of Indian children with medulloblastomas.


Reproducibility of dynamic cerebral autoregulation parameters: a multi-centre, multi-method study.
Different methods to calculate dynamic cerebral autoregulation (dCA) parameters are available. However, most of these methods demonstrate poor reproducibility that limit their reliability for clinical use. Inter-centre differences in study protocols, modelling approaches and default parameter settings have all led to a lack of standardisation and comparability between studies. We evaluated reproducibility of dCA parameters by assessing systematic errors in surrogate data resulting from different modelling techniques. Fourteen centres analysed 22 datasets consisting of two repeated physiological blood pressure measurements with surrogate cerebral blood flow velocity signals, generated using Tiecks curves (autoregulation index, ARI 0-9) and added noise. For reproducibility, dCA methods were grouped in three broad categories: 1. Transfer function analysis (TFA)-like output; 2. ARI-like output; 3. Correlation coefficient-like output. For all methods, reproducibility was determined by one-way intraclass correlation coefficient analysis (ICC). For TFA-like methods the mean (SD; [range]) ICC gain was 0.71 (0.10; [0.49-0.86]) and 0.80 (0.17; [0.36-0.94]) for VLF and LF (p = 0.003) respectively. For phase, ICC values were 0.53 (0.21; [0.09-0.80]) for VLF, and 0.92 (0.13; [0.44-1.00]) for LF (p < 0.001). Finally, ICC for ARI-like methods was equal to 0.84 (0.19; [0.41-0.94]), and for correlation-like methods, ICC was 0.21 (0.21; [0.056-0.35]). When applied to realistic surrogate data, free from the additional exogenous influences of physiological variability on cerebral blood flow, most methods of dCA modelling showed ICC values considerably higher than what has been reported for physiological data. This finding suggests that the poor reproducibility reported by previous studies may be mainly due to the inherent physiological variability of cerebral blood flow regulatory mechanisms rather than related to (stationary) random noise and the signal analysis methods.


An epidemiological analysis of Stenotrophomonas maltophilia strains in a university hospital.
The aim of this investigation was to evaluate the epidemiology of Stenotrophomonas maltophilia in a university hospital of Turkey. From June 2000 to December 2001, S. maltophilia strains were collected, clinical presentations were noted, and MIC determinations were performed by means of E-test. Enterobacterial repetitive intergenic consensus sequences-PCR (ERIC-PCR) was used for molecular typing of the strains. Forty-four strains of S. maltophilia were isolated from 41 hospitalized patients in a teaching hospital. The majority of specimens were from the blood and respiratory tract. Antimicrobial sensitivities of these strains were as follows: 97.7 % trimethoprim-sulfamethoxazole, 15.9% ticarcillin, and 95.4% ticarcillin- clavulanate. The strains were evaluated using the ERIC-PCR method. It was of interest to note that epidemiological typing revealed three small outbreaks that were caused by a total of 12 strains. The remaining isolates generated singular DNA patterns. DNA amplification was possible in 38 isolates and yielded 26 different patterns in a period of 20 months, leading to the suggestion that commensal bacteria becomes selected in the presence of a suitable host.


Dual RNA-Sequencing to Elucidate the Plant-Pathogen Duel.
RNA-sequencing technology has been widely adopted to investigate host responses during infection with pathogens. Dual RNA-sequencing (RNA-seq) allows the simultaneous capture of pathogen specific transcripts during infection, providing a more complete view of the interaction. In this review, we focus on the design of dual RNA-seq experiments and the application of downstream data analysis to gain biological insight into both sides of the interaction. Recent literature in this area demonstrates the power of the dual RNA-seq approach and shows that it is not limited to model systems where genomic resources are available. A reduction in sequencing cost and single cell transcriptomics coupled with protein and metabolite level dual approaches are set to enhance our understanding of plant-pathogen interactions. Sequencing costs continue to decrease and single cell transcriptomics is becoming more feasible. In combination with proteomics and metabolomics studies, these technological advances are likely to contribute to our understanding of the temporal and spatial aspects of dynamic plant-pathogen interactions.


[Remission criteria in schizophrenia].
Recent research shows that there is a considerable variation in the incidence and course of schizophrenia. The illness therefore can best be defined in terms of changeability and plasticity. An internationally accepted standard definition of symptomatic remission. Two international panels of experts have wrestled with the problem of whether or how symptomatic remission in persons diagnosed with schizophrenia can be defined. A draft definition was published recently. The proposed definition is conceptually viable and can be incorporated easily into both clinical practice and clinical research. Acceptance of the remission concept can raise expectations about treatment outcome to a higher level than is possible when a patient is merely defined as being 'stable', can improve the quality of treatment documentation and facilitate the dialogue concerning treatment expectations. The availability of validated outcome measures based on remission should enhance the reporting and the comparability of clinical research and should facilitate the design and interpretation of new research into the relation between symptomatic remission and functional outcomes. The introduction of standard remission criteria can create many opportunities for clinical practice, clinical research and cumulative records of results; at the same time it can facilitate a dialogue with patients and help to clarify the diagnosis of schizophrenia.


Swedish experience of the Dialock.
To study the patency and complications associated with the Dialock, an access device for haemodialysis. The records of seven Swedish patients who were treated with the Dialock access device between 2000 and 2004 were studied retrospectively. A total of 10 Dialock devices were used in seven patients. The mean period of patency was 16.3+/-13.8 months. Major complications observed were bleeding in the dose pocket in three patients and infection in four. Three patients experienced no complications. The 1-year patency was similar to that of a newly created arteriovenous fistula used in our unit. In spite of the associated complications, the Dialock is an acceptable access device for haemodialysis patients with vascular access problems. Although the Dialock is no longer available on the market, similar access devices may be of importance in the future.


Characterization of fus1 of Schizosaccharomyces pombe: a developmentally controlled function needed for conjugation.
In Schizosaccharomyces pombe, the fus1 mutation blocks conjugation at a point after cell contact and agglutination. The cell walls separating the mating partners are not degraded, which prevents cytoplasmic fusion. In order to investigate the molecular mechanism of conjugation, we cloned the fus1 gene and found that it is capable of encoding a 1,372-amino-acid protein with no significant similarities to other known proteins. Expression of the fus1 gene is regulated by the developmental state of the cells. Transcription is induced by nitrogen starvation and requires a pheromone signal in both P and M cell types. Consequently, mutants defective in the pheromone response pathway fail to induce fus1 expression. The ste11 gene, which encodes a transcription factor controlling expression of many genes involved in sexual differentiation, is also required for transcription of fus1. Furthermore, deletion of two potential Ste11 recognition sites in the fus1 promoter region abolished transcription, and expression could be restored when we inserted a different Ste11 site from the mat1-P promoter. Since this element was inverted relative to the fus1 element, we conclude that activation of transcription by Ste11 is independent of orientation. Although the fus1 mutant has a phenotype very similar to that of Saccharomyces cerevisiae fus1 mutants, the two proteins appear to have different roles in the process of cell fusion. Budding yeast Fus1 is a typical membrane protein and contains an SH3 domain. Fission yeast Fus1 has no features of a membrane protein, yet it appears to localize to the projection tip. A characteristic proline-rich potential SH3 binding site may mediate interaction with other proteins.


A novel quantitative immunoassay system for p53 using antibodies selected for optimum designation of p53 status.
To develop a highly sensitive and specific enzyme linked immunosorbent assay (ELISA) system for analysis of p53 protein in cancer lysates. The anti-p53 monoclonal antibodies DO7, 1801, BP53.12, and 421, and anti-p53 polyclonal antiserum CM1 were assessed by immunohistochemistry and western blot analysis to identify those most suitable for determining p53 status of cancer cells. Antibodies with desired characteristics were used to develop a non-competitive sandwich type ELISA system for analysis of p53 expression in cancer cytosols. Using the ELISA, p53 protein concentrations were measured in a small series of breast cancers, and the quantitative values compared with p53 immunohistochemical data of the same cancers. DO7 and 1801 gave the most specific and reliable results on immunohistochemistry and western blot analysis. Using these two antibodies, a non-competitive sandwich type ELISA system was developed to analyse p53 quantitatively. Analysis of the breast cancer series showed a good correlation between immunohistochemistry and the ELISA-tumours were generally positive using both techniques. Discrepancies were noted however: some cancers were immunohistochemically negative but ELISA positive. One explanation for this may be that the ELISA is more sensitive than immunohistochemistry. The p53 ELISA system is a non-competitive double monoclonal antibody sandwich method, using DO7 and 1801 which have been shown to be highly specific for p53 protein by immunohistochemistry and western blot analysis. The lower threshold of the assay is 0.1 ng/ml analyte in an enriched recombinant p53 preparation. As p53 is now regarded as a protein associated with prognosis in breast and other cancers, the assay may have clinical applications.


Power output in the jump squat in adolescent male athletes.
The load that maximizes power output in the jump squat (JS) in college-aged athletic males has been reported to be 0% of 1 repetition maximum [1RM] squat strength) or in other words body mass. No data exist concerning adolescent athletic males. In addition, strength levels have been theorized to possibly affect the load that maximizes power output in the JS. The purpose of this investigation was to identify the load that maximizes power output in the JS in adolescent athletic men, and concurrently describe their strength level and its effect on the load that maximizes power output. Eleven high-school male athletes were tested on 2 occasions, first determining their 1RM in the squat (1RM = 141.14 ± 28.08 kg; squat 1RM-to-body mass ratio = 1.76 ± 0.15) and then performing JS testing at loads equal to 0% (body mass), 20, 40, 60, and 80% of squat 1RM. Peak power (PP), peak force, peak velocity (PV), and peak displacement were measured at each load. Jump squat at the 0% load produced significantly (p ≤ 0.05) higher PP, PV, and peak displacement in comparison with the 40, 60, and 80% loading conditions. It was concluded that the load that maximizes power output in the JS is 0% of 1RM in adolescent athletic men, the same as found in college-aged athletic men. In addition, strength level relative to body mass did not affect the load that maximized power output. Practically, when devising a training program to increase PP, it is important to include JSs at body mass along with traditional strength training at heavier loads to increase power output across the entire loading spectrum.


UK research expenditure on dementia, heart disease, stroke and cancer: are levels of spending related to disease burden?
A UK government review recommended that the impact of disease on the population and economy should be assessed to inform health research priorities. This study aims to quantify UK governmental and charity research funding for dementia, cancer, coronary heart disease (CHD) and stroke in 2007/08 and assess whether the levels of research expenditure are aligned with disease and economic burden. We identified UK governmental agencies and charities providing health research funding and determined their levels of funding for dementia, cancer, CHD and stroke. Research funding levels were compared to the number of cases, disability-adjusted life years (DALYs) and economic burden. Economic costs were estimated using data on morbidity, mortality, health and social care use, private costs and other related indicators. Research funding to the four diseases was £833 million, of which £590 million (71%) was devoted to cancer, £169 million (20%) to CHD, £50 million (6%) to dementia and £23 million (4%) to stroke. Cancer received £482 in research funding per 1000 DALYs lost, CHD received £266, dementia received £166, with stroke receiving £71. In terms of economic burden, for every £1 million of health and social care costs attributable to each disease, cancer received £129 269 in research funding, CHD received £73 153, stroke received £8745 and dementia received £4882. Most health research funding in the UK is currently directed towards cancer. When compared to their burden, our analysis suggests that research spending on dementia and stroke is severely underfunded in comparison with cancer and CHD.


Structure and function of histone acetyltransferases.
Histone acetyltranferase (HAT) enzymes are the catalytic subunit of large multisubunit HAT complexes that acetylate the epsilon-amino group of specific lysine residues on histone tails to promote transcriptional activation. Recent structural and functional studies on the divergent HAT enzymes Gcn5/PCAF, Esa1 and Hat1 have provided new insights into the underlying mechanism of histone binding and acetylation by HAT proteins. The three HAT enzymes contain a structurally conserved core domain that plays a functionally conserved role in binding the coenzyme A cofactor and in harboring the putative general base for catalysis. Structurally variable N- and C-terminal domains appear to contain a related scaffold that mediates histone substrate binding. These data provide a framework for understanding the structure and function of other more divergent HAT proteins such as TAF(II)250 and CBP/p300, and provides a starting point for understanding how HAT proteins may cooperate with other factors within in vivo HAT complexes to promote transcriptional activation.


Brain activity response to cues during gait in Parkinson's disease: A study protocol.
Various cueing strategies (internal and external) have been used to alleviate gait deficits in Parkinson's disease (PD). However, it remains unclear which type of cueing strategy is most effective at different disease stages or with more severe walking impairment, such as freezing of gait (FOG). The underlying neural mechanisms of response to cueing are also unknown. This trial aims to: (i) determine brain activity response to cue stimulus (internal, visual, auditory or tactile) when walking in PD and; (ii) examine changes in brain activity to cues at different stages of PD. This ongoing single-site study uses an exploratory observational design, with laboratory application of cues for gait deficit. A total of 80 people with PD who meet the inclusion criteria will be enrolled. Participants are split into groups dependent on their disease stage (classified with the Hoehn and Yahr (H&Y) scale); n = 20 H&YI; n = 30 H&YII; n = 30 H&YIII. Within the H&Y stage II and III groups, we will also ensure recruitment of a sub-group of 15 individuals with FOG within each group. Participants perform walking tasks under several conditions: baseline walking without cues; randomized cued walking conditions [internal and external (visual, auditory and tactile) cues]. A combined functional near-infrared spectroscopy and electroencephalography system quantifies cortical brain activity while walking. Inertial sensors are used to assess gait. Primary outcome measures are cue-related changes in cortical brain activity while walking, including the relative change in cortical HbO2 and the power spectral densities at alpha (8-13Hz), beta (13-30Hz), delta (0.5-4Hz), theta (4-8Hz) and gamma (30-40Hz) frequency bandwidths. Secondary outcome measures are cue-related changes in spatiotemporal gait characteristics. Findings will enhance our understanding about the cortical responses to different cueing strategies and how they are influenced by PD progression and FOG status. This trial is registered at clinicaltrials.gov (NCT04863560; April 28, 2021, https://clinicaltrials.gov/ct2/show/NCT04863560).


Virtual experiments in megastudies: A case study of language and emotion.
A recent dramatic increase in the number and scope of chronometric and norming lexical megastudies offers the ability to conduct virtual experiments-that is, to draw samples of items with properties that vary in critical linguistic dimensions. This paper introduces a bootstrapping approach, which enables testing of research hypotheses against a range of samples selected in a uniform, principled manner and evaluates how likely a theoretically motivated pattern is in a broad distribution of possible outcome patterns. We apply this approach to conflicting theoretical and empirical accounts of the relationship between the psychological valence (positivity) of a word and its speed of recognition. To this end, we conduct three sets of multiple virtual experiments with a factorial and a regression design, drawing data from two lexical decision megastudies. We discuss the influence that criteria for stimuli selection, statistical power, collinearity, and the choice of dataset have on the efficacy and outcomes of the bootstrapping procedure.


Exercise and asthma: an overview.
The terms 'exercise-induced asthma' (EIA) and 'exercise-induced bronchoconstriction' (EIB) are often used interchangeably to describe symptoms of asthma such as cough, wheeze, or dyspnoea provoked by vigorous physical activity. In this review, we refer to EIB as the bronchoconstrictive response and to EIA when bronchoconstriction is associated with asthma symptoms. EIB is a common occurrence for most of the asthmatic patients, but it also affects more than 10% of otherwise healthy individuals as shown by epidemiological studies. EIA and EIB have a high prevalence also in elite athletes, especially within endurance type of sports, and an athlete's asthma phenotype has been described. However, the occurrence in elite athletes shows that EIA/EIB, if correctly managed, may not impair physical activity and top sports performance. The pathogenic mechanisms of EIA/EIB classically involve both osmolar and vascular changes in the airways in addition to cooling of the airways with parasympathetic stimulation. Airways inflammation plays a fundamental role in EIA/EIB. Diagnosis and pharmacological management must be carefully performed, with particular consideration of current anti-doping regulations, when caring for athletes. Based on the demonstration that the inhaled asthma drugs do not improve performance in healthy athletes, the doping regulations are presently much less strict than previously. Some sports are at a higher asthma risk than others, probably due to a high environmental exposure while performing the sport, with swimming and chlorine exposure during swimming as one example. It is considered very important for the asthmatic child and adolescent to master EIA/EIB to be able to participate in physical activity on an equal level with their peers, and a precise early diagnosis with optimal treatment follow-up is vital in this aspect. In addition, surprising recent preliminary evidences offer new perspectives for moderate exercise as a potential therapeutic tool for asthmatics.


Identification of messenger ribonucleic acids and proteins synthesized by the bacteriocinogenic factor Clo DF13 in purified minicells of Escherichia coli.
It has previously been shown that the cloacinogenic factor Clo DF13 (Clo DF13) segregates into minicells of strain Escherichia coli P678-54 that harbors Clo DF13 and that this Clo DF13 factor is the only deoxyribonucleic acid (DNA) present in these otherwise chromosomeless minicells. The study reported here shows that minicells prepared from P678-54(Clo DF13) are able to incorporate radioactive precursors into ribonucleic acid (RNA) and protein. The RNA synthesized in these purified minicells is Clo DF13 specific, as shown by RNA-DNA hybridization experiments. The results indicate that all the de novo synthesized gene products in Clo DF13 minicells are Clo DF13 specific. Polyacrylamide gel electrophoretic patterns show that in these minicells at least three polypeptides (molecular weight about 70,000, 20,000, and 11,000) and one major species of messenger RNA (mRNA) (S value about 21.3) are synthesized. To investigate the factor in its induced state, we isolated a Clo DF13 mutant with an enhanced level of cloacin production. Minicells harboring this Clo DF13 mutant produce five additional polypeptides (molecular weight about 58,000, 44,000, 28,000, 16,000, and 14,000). Three additional mRNA species (S value about 19.5, 14, and 12) could be distinguished. The total molecular weight of the eight polypeptides corresponds to 85% of the total coding capacity of the mRNAs (303,000). The total molecular weight of the four mRNAs is 2.55 x 10(6), which covers 85% of the Clo DF13 DNA (molecular weight 6 x 10(6)).


Streptococcus pyogenes in human plasma: adaptive mechanisms analyzed by mass spectrometry-based proteomics.
Streptococcus pyogenes is a major bacterial pathogen and a potent inducer of inflammation causing plasma leakage at the site of infection. A combination of label-free quantitative mass spectrometry-based proteomics strategies were used to measure how the intracellular proteome homeostasis of S. pyogenes is influenced by the presence of human plasma, identifying and quantifying 842 proteins. In plasma the bacterium modifies its production of 213 proteins, and the most pronounced change was the complete down-regulation of proteins required for fatty acid biosynthesis. Fatty acids are transported by albumin (HSA) in plasma. S. pyogenes expresses HSA-binding surface proteins, and HSA carrying fatty acids reduced the amount of fatty acid biosynthesis proteins to the same extent as plasma. The results clarify the function of HSA-binding proteins in S. pyogenes and underline the power of the quantitative mass spectrometry strategy used here to investigate bacterial adaptation to a given environment.


Blood volume: its adaptation to endurance training.
Expansion of blood volume (hypervolemia) has been well documented in both cross-sectional and longitudinal studies as a consequence of endurance exercise training. Plasma volume expansion can account for nearly all of the exercise-induced hypervolemia up to 2-4 wk; after this time expansion may be distributed equally between plasma and red cell volumes. The exercise stimulus for hypervolemia has both thermal and nonthermal components that increase total circulating plasma levels of electrolytes and proteins. Although protein and fluid shifts from the extravascular to intravascular space may provide a mechanism for rapid hypervolemia immediately after exercise, evidence supports the notion that chronic hypervolemia associated with exercise training represents a net expansion of total body water and solutes. This net increase of body fluids with exercise training is associated with increased water intake and decreased urine volume output. The mechanism of reduced urine output appears to be increased renal tubular reabsorption of sodium through a more sensitive aldosterone action in man. Exercise training-induced hypervolemia appears to be universal among most animal species, although the mechanisms may be quite different. The hypervolemia may provide advantages of greater body fluid for heat dissipation and thermoregulatory stability as well as larger vascular volume and filling pressure for greater cardiac stroke volume and lower heart rates during exercise.


Neonatal Seizures and Future Epilepsy: Predictive Value of Perinatal Risk Factors, Electroencephalography, and Imaging.
There are limited data in the literature about the relationship between neonatal seizures and subsequent epilepsy. This study aimed to identify the predictive value of perinatal factors, etiologies, electroencephalography (EEG), and cranial ultrasonography (USG) for future epilepsy after neonatal seizures. A total of 92 children with epilepsy who had seizures during their neonatal period were retrospectively evaluated whether the contribution of perinatal, natal, and postnatal risk factors confining clinical, laboratory, EEG, and imaging to subsequent epilepsy. Chi-square, uni, and multivariate logistic regression were applied to find out predictive factors for subsequent epilepsy. The rate of epilepsy was 57.6 % during 1-6 years follow-up. Birth weight, Apgar scores at first and fifth minutes, resuscitation history, abnormal neurological examination, etiology, response to the treatment, abnormal EEG, or USG findings were the most important risk factors for future epilepsy in univariate analysis (P < 0.05). Furthermore, asphyxia, fifth minute Apgar scores, response to the treatment, USG, and EEG were independent predictors (P < 0.05) for subsequent epilepsy in multivariate logistic regression. No relationship was found between subsequent epilepsy and mode of delivery, seizure onset time, and seizure types (P > 0.05). Although there are recent promising and advanced techniques in neonatal intensive care units, asphyxia is still one of the most important risk factors for not only poor neurological conditions but also for future epilepsy after neonatal seizures. Apgar scores, treatment with multiple antiepileptic drugs, poor background EEG activity, and abnormal neuroimaging seem to have strong predictive values for developing subsequent epilepsy. Therefore, patients with a history of neonatal seizures should be closely followed up to decrease the risk of long-term outcomes and early detection of epilepsy.


Glutamine reduces postprandial glycemia and augments the glucagon-like peptide-1 response in type 2 diabetes patients.
Impaired glucagon-like peptide (GLP-1) secretion or response may contribute to ineffective insulin release in type 2 diabetes. The conditionally essential amino acid glutamine stimulates GLP-1 secretion in vitro and in vivo. In a randomized, crossover study, we evaluated the effect of oral glutamine, with or without sitagliptin (SIT), on postprandial glycemia and GLP-1 concentration in 15 type 2 diabetes patients (glycated hemoglobin 6.5 ± 0.6%). Participants ingested a low-fat meal (5% fat) after receiving either water (control), 30 g l-glutamine (Gln-30), 15 g L-glutamine (Gln-15), 100 mg SIT, or 100 mg SIT and 15 g L-glutamine (SIT+Gln-15). Studies were conducted 1-2 wk apart. Blood was collected at baseline and postprandially for 180 min for measurement of circulating glucose, insulin, C-peptide, glucagon, and total and active GLP-1. Gln-30 and SIT+Gln-15 reduced the early (t = 0-60 min) postprandial glycemic response compared with control. All Gln treatments enhanced the postprandial insulin response from t = 60-180 min but had no effect on the C-peptide response compared with control. The postprandial glucagon concentration was increased by Gln-30 and Gln-15 compared with control, but the insulin:glucagon ratio was not affected by any treatment. In contrast to Gln-30, which tended to increase the total GLP-1 AUC, SIT tended to decrease the total GLP-1 AUC relative to control (both P = 0.03). Gln-30 and SIT increased the active GLP-1 AUC compared with control (P = 0.008 and P = 0.01, respectively). In summary, Gln-30 decreased the early postprandial glucose response, enhanced late postprandial insulinemia, and augmented postprandial active GLP-1 responses compared with control. These findings suggest that glutamine may be a novel agent for stimulating GLP-1 concentration and limiting postprandial glycemia in type 2 diabetes.


Ethnicity, self-reported health, discrimination and socio-economic status: a study of Sami and non-Sami Norwegian populations.
Investigate the association between ethnicity, social factors and self-reported health conditions of Sami and non-Sami Norwegian populations. Cross-sectional questionnaire. SAMINOR is a population-based study of health and living conditions that was conducted in 24 municipalities in northern Norway during 2003 and 2004. The present study included 12,265 individuals aged between 36 and 79, whose ethnicity was categorized as Sami (33.1%), Kven (7.8%) and Norwegian majority population (59.1%). Sami respondents reported inferior health conditions in comparison to the Norwegian majority population. The most unsatisfactory conditions were reported by Sami females living outside the defined Sami area (with greater integration and assimilation) (p<0.05). Females typically reported less favourable health conditions than did males. Health inequalities varied by age and were more apparent in persons aged in their mid-50s or above. Across ethnic groups, respondents with the highest education and household income were healthier than others. Furthermore, those reporting to have been frequently discriminated against were more likely to report poorer health than those who did not; the odds ratios (95% CI) was found to be 2.88 (1.92-4.32) for women and 1.61 (1.08-2.42) for men. When discrimination was included in the logistical model, the increased risk of poor self-reported health decreased to non-significance for Sami respondents. The estimated risk decreased further when the socio-economic status was taken into account. The findings of this study suggest that self-reported ethnic discrimination combined with low socio-economic status contributes to inequalities in self-reported health when Sami and Norwegian majority population are compared.


Electromagnetic navigation bronchoscopy: A descriptive analysis.
Electromagnetic navigation bronchoscopy (ENB) is an exciting new bronchoscopic technique that promises accurate navigation to peripheral pulmonary target lesions, using technology similar to a car global positioning system (GPS) unit. Potential uses for ENB include biopsy of peripheral lung lesions, pleural dye marking of nodules for surgical wedge resection, placement of fiducial markers for stereotactic radiotherapy, and therapeutic insertion of brachytherapy catheters into malignant tissue. This article will describe the ENB procedure, review the published literature, compare ENB to existing biopsy techniques, and outline the challenges for widespread implementation of this new technology.


Integrated Use of Pyraclostrobin and Epoxiconazole for the Control of Fusarium Head Blight of Wheat in Anhui Province of China.
Fusarium asiaticum and F. graminearum are the primary causal agents of Fusarium head blight (FHB) of wheat in China. Carbendazim (a benzimadazole fungicide, MBC), has been extensively used for the control of FHB, resulting in severe MBC resistance in China. This article presents the baseline sensitivity of F. asiaticum and F. graminearum isolates from Anhui Province of China to fungicides pyraclostrobin (a quinone outside inhibitor) and epoxiconazole (a sterol demethylation inhibitor). In the presence of salicylhydroxamic acid, the 50% effective concentration (EC50) values for pyraclostrobin in inhibiting mycelial growth of the 126 F. asiaticum isolates and 63 F. graminearum isolates were 0.012 to 0.135 μg/ml and 0.010 to 0.105 μg/ml, and the EC50 values for pyraclostrobin in inhibiting conidium germination of the F. asiaticum and F. graminearum populations were 0.047 to 0.291 and 0.042 to 0.255 μg/ml, respectively. The EC50 values for epoxiconazole in inhibiting mycelial growth of the F. asiaticum and F. graminearum populations were 0.12 to 0.95 and 0.16 to 0.93 μg/ml, respectively. All of the baseline sensitivity curves were unimodal. This study also suggested that there was no cross-resistance between MBC and pyraclostrobin or epoxiconazole. In the protective and curative tests, pyraclostrobin and epoxiconazole applied at 200 and 300 μg/ml exhibited over 75% protective and curative control efficacy in all treatments. In field trials, both pyraclostrobin and epoxiconazole at 225 g a.i./ha provided over 80% efficacy in 2010 and 2011 at both sites where MBC resistance occurred, suggesting excellent activity against FHB. Interestingly, integrated use of pyraclostrobin + epoxiconazole applied at 150 + 150 g a.i./ha provided over 85% efficacy at both sites in 2010 and 2011. Pyraclostrobin and epoxiconazole should be good alternatives to MBC for the control of FHB, and integrated use of these two fungicides might achieve greater efficacy.


Subclass mapping: identifying common subtypes in independent disease data sets.
Whole genome expression profiles are widely used to discover molecular subtypes of diseases. A remaining challenge is to identify the correspondence or commonality of subtypes found in multiple, independent data sets generated on various platforms. While model-based supervised learning is often used to make these connections, the models can be biased to the training data set and thus miss inherent, relevant substructure in the test data. Here we describe an unsupervised subclass mapping method (SubMap), which reveals common subtypes between independent data sets. The subtypes within a data set can be determined by unsupervised clustering or given by predetermined phenotypes before applying SubMap. We define a measure of correspondence for subtypes and evaluate its significance building on our previous work on gene set enrichment analysis. The strength of the SubMap method is that it does not impose the structure of one data set upon another, but rather uses a bi-directional approach to highlight the common substructures in both. We show how this method can reveal the correspondence between several cancer-related data sets. Notably, it identifies common subtypes of breast cancer associated with estrogen receptor status, and a subgroup of lymphoma patients who share similar survival patterns, thus improving the accuracy of a clinical outcome predictor.


Trends and disparities in regionalization of pancreatic resection.
The current recommendation is that pancreatic resections be performed at hospitals doing >10 pancreatic resections annually. To evaluate the extent of regionalization of pancreatic resection and the factors predicting resection at high-volume centers (>10 cases/year) in Texas. Using the Texas Hospital Inpatient Discharge Public Use Data File, we evaluated trends in the percentage of patients undergoing pancreatic resection at high-volume centers (>10 cases/year) from 1999 to 2004 and determined the factors that independently predicted resection at high-volume centers. A total of 3,189 pancreatic resections were performed in the state of Texas. The unadjusted in-hospital mortality was higher at low-volume centers (7.4%) compared to high-volume centers (3.0%). Patients resected at high-volume centers increased from 54.5% in 1999 to 63.3% in 2004 (P = 0.0004). This was the result of a decrease in resections performed at centers doing less than five resections/year (35.5% to 26.0%). In a multivariate analysis, patients who were >75 (OR = 0.51), female (OR = 0.86), Hispanic (OR = 0.58), having emergent surgery (OR = 0.39), diagnosed with periampullary cancer (OR = 0.68), and living >75 mi from a high-volume center (OR = 0.93 per 10-mi increase in distance, P < 0.05 for all OR) were less likely to be resected at high-volume centers. The odds of being resected at a high-volume center increased 6% per year. Whereas regionalization of pancreatic resection at high-volume centers in the state of Texas has improved slightly over time, 37% of patients continue to undergo pancreatic resection at low-volume centers, with more than 25% occurring at centers doing less than five per year. There are obvious demographic disparities in the regionalization of care, but additional unmeasured barriers need to be identified.


Optimizing outcomes for patients with advanced disease in chronic myelogenous leukemia.
The treatment of chronic myelogenous leukemia (CML) has been revolutionized by the development of the small-molecule tyrosine kinase inhibitor imatinib. The primary target for this drug is the oncogenic BCR-ABL kinase. Five-year survival rates for patients in chronic phase CML is now greater than 80%. Patients who have advanced beyond the chronic phase to the accelerated phase or blast crisis, however, have not faired as well. Progression occurs for a variety of reasons, including late diagnosis, slow response to imatinib, and the development of imatinib-resistant clones. Imatinib resistance has, in part, been addressed with the introduction of the new BCR-ABL inhibitors, namely dasatinib and nilotinib. These drugs have shown efficacy in CML patients with wild-type BCR-ABL and some BCR-ABL mutants that are imatinib-resistant. Unfortunately, some BCR-ABL mutations remain resistant to these therapies and will require the development of alternative treatments, and other mechanisms of imatinib resistance besides BCR-ABL mutation exist. In the future, genetic and pharmacologic tests may allow the clinician to predict response to imatinib. More aggressive therapies are being considered for high-risk patients, including increased dosage of the current tyrosine kinase inhibitors, along with combination therapies. Aggressive therapy holds promise, as the data suggest that responses are improved. Unfortunately, toxicities are also increased, and thus a balance must be found to ensure safety and compliance. This is especially important for young CML patients, who hopefully will remain in remission for decades. Polymerase chain reaction analysis has become of primary importance as a means of assessing disease burden, and given the idiosyncrasies of this technique, standards must be established to allow results to be compared across different institutions. Additionally, the nature of advanced disease is being explored. Intriguingly, genetic analysis of transformed blasts from patients in blast crisis has identified numerous members of the Wnt/B-catenin pathway and JunB as being activated. Increased activity of these pathways correlates with poor response and eventual disease progression. In addition to these data, evidence is emerging associating survival of the quiescent blast cell with Wnt activity, leading to the hope that Wnt inhibitors will increase the likelihood of eradicating these cells. Other areas such as microRNA profiling and DNA methylation patterns are likely to provide important information.


Laminar dependence of neuronal correlations in visual cortex.
Neuronal responses are correlated on a range of timescales. Correlations can affect population coding and may play an important role in cortical function. Correlations are known to depend on stimulus drive, behavioral context, and experience, but the mechanisms that determine their properties are poorly understood. Here we make use of the laminar organization of cortex, with its variations in sources of input, local circuit architecture, and neuronal properties, to test whether networks engaged in similar functions but with distinct properties generate different patterns of correlation. We find that slow timescale correlations are prominent in the superficial and deep layers of primary visual cortex (V1) of macaque monkeys, but near zero in the middle layers. Brief timescale correlation (synchrony), on the other hand, was slightly stronger in the middle layers of V1, although evident at most cortical depths. Laminar variations were also apparent in the power of the local field potential, with a complementary pattern for low frequency (<10 Hz) and gamma (30-50 Hz) power. Recordings in area V2 revealed a laminar dependence similar to V1 for synchrony, but slow timescale correlations were not different between the input layers and nearby locations. Our results reveal that cortical circuits in different laminae can generate remarkably different patterns of correlations, despite being tightly interconnected.


In BMI We Trust: Reframing the Body Mass Index as a Measure of Health.
Recent work in medical sociology has provided critical insights into distinguishing between obesity as a condition with severe individual- and population-level health consequences, and obesity as a socially undesirable, stigmatizing construct opposing thinness as the healthy ideal. Less often considered is the role of Body Mass Index (BMI) as the standard by which obesity and healthy weight are measured and defined. Addressing this issue, I begin by distinguishing between BMI as an empirical, objective measure of health, and BMI as an arbitrary, subjective label for categorizing the population. I further consider how BMI is empowered as a measurable quantity through the lens of medicalization and evidence-based medicine, and introduce the "performativity" of BMI as a superior framework for confronting the measure's conceptual limitations. Emphasizing key parallels between BMI and self-rated health as measures with high predictive validity, yet unspecified mechanisms of action, I propose an epistemological shift away from classifying BMI as a biomarker and toward a more flexible view of the measure as a holistic appraisal of health. In closing, I argue that researchers may continue to leverage BMI's ease of collection and interpretation, provided they are attuned to its definitional ambiguity across diverse research methods and contexts.


CT- and MRI-based seed localization in postimplant evaluation after prostate brachytherapy.
To compare the uncertainties in CT- and MRI-based seed reconstruction in postimplant evaluation after prostate seed brachytherapy in terms of interobserver variability and quantify the impact of seed detection variability on a selection of dosimetric parameters for three postplan techniques: (1) CT, (2) MRI-T1 weighted fused with MRI-T2 weighted, and (3) CT fused with MRI-T2 weighted. Seven physicists reconstructed the seed positions on postimplant CT and MRI-T1 images of three patients. For each patient and imaging modality, the interobserver variability was calculated with respect to a reference seed set. The effect of this variability on dosimetry was calculated for CT and CT + MRI-T2 (CT-based seed reconstruction), as well as for MRI-T1 + MRI-T2 (MRI-T1-based seed reconstruction), using fixed CT and MRI-T2 prostate contours. Averaged over three patients, the interobserver variability in CT-based seed reconstruction was 1.1 mm (1 SDref, i.e., standard deviation with respect to the reference value). The D90 (dose delivered to 90% of the target) variability was 1.5% and 1.3% (1 SDref) for CT and CT + MRI-T2, respectively. The mean interobserver variability in MRI-based seed reconstruction was 3.0 mm (1 SDref), and the impact of this variability on D90 was 6.6% for MRI-T1 + MRI-T2. Seed reconstruction on MRI-T1-weighted images was less accurate than on CT. This difference in uncertainties should be weighted against uncertainties due to contouring and image fusion when comparing the overall reliability of postplan techniques.


Comparisons of optical properties of the coastal ocean derived from satellite ocean color and in situ measurements.
Satellite-derived optical properties are compared to in situ mooring and ship-based measurements at a coastal site. Comparisons include remote sensing reflectance (R(rs)), chlorophyll concentration (Chl) using two different Chl algorithms, and spectral absorption [a(pg)(lambda)] and backscattering coefficients [b(b)(555)] using three different bio-optical algorithms. For mooring/shipboard comparisons, we observed mean relative errors of 70.5%/-3.8% (SeaWiFS OC4v4), -21.4%/-49.3% (SeaWiFS Stumpf), 109.5%/13.4% (MODIS OC3m) and 0.5%/-48.9% (MODIS Stumpf) for Chl. For satellite-derived and mooring comparisons of a(pg)(412), we found mean relative errors of -69.4% (-67.1%), -52.6% (- 48.9%), and -62.7% (-65.4%) for the Arnone, GSM, and QAA algorithms for SeaWiFS (MODIS), respectively. Mean relative errors of 21.3%, 19.9%, and 16.5% were found between SeaWiFS-derived (Arnone, GSM, and QAA algorithms, respectively) and moored b(b)(555) measurements. Discrepancies in Rrs at blue wavelengths are attributed to the satellite atmospheric correction and sea surface variations of the moored radiometers. High spatial and temporal variability of bio-optical properties coupled with differences in measurement techniques (pixel versus point) contribute to inconsistencies between remotely sensed and in situ biooptical properties.


Role of heme iron coordination and protein structure in the dynamics and geminate rebinding of nitric oxide to the H93G myoglobin mutant: implications for nitric oxide sensors.
The influence of the heme iron coordination on nitric oxide binding dynamics was investigated for the myoglobin mutant H93G (H93G-Mb) by picosecond absorption and resonance Raman time-resolved spectroscopies. In the H93G-Mb, the glycine replacing the proximal histidine does not interact with the heme iron so that exogenous substituents like imidazole may coordinate to the iron at the proximal position. Nitrosylation of H93G-Mb leads to either 6- or 5-coordinate species depending on the imidazole concentration. At high concentrations, (imidazole)-(NO)-6-coordinate heme is formed, and the photoinduced rebinding kinetics reveal two exponential picosecond phases ( approximately 10 and approximately 100 ps) similar to those of wild type myoglobin. At low concentrations, imidazole is displaced by the trans effect leading to a (NO)-5-coordinate heme, becoming 4-coordinate immediately after photolysis as revealed from the transient Raman spectrum. In this case, NO rebinding kinetics remain bi-exponential with no change in time constant of the fast component whose amplitude increases with respect to the 6-coordinate species. Bi-exponential NO geminate rebinding in 5-coordinate H93G-Mb is in contrast with the single-exponential process reported for nitrosylated soluble guanylate cyclase (Negrerie, M., Bouzhir, L., Martin, J. L., and Liebl, U. (2001) J. Biol. Chem. 276, 46815-46821). Thus, our data show that the iron coordination state or the heme iron out-of-plane motion are not at the origin of the bi-exponential kinetics, which depends upon the protein structure, and that the 4-coordinate state favors the fast phase of NO geminate rebinding. Consequently, the heme coordination state together with the energy barriers provided by the protein structure control the dynamics and affinity for NO-binding enzymes.


The latitudinal distribution of clouds on Titan.
Clouds have been observed recently on Titan, through the thick haze, using near-infrared spectroscopy and images near the south pole and in temperate regions near 40 degrees S. Recent telescope and Cassini orbiter observations are now providing an insight into cloud climatology. To study clouds, we have developed a general circulation model of Titan that includes cloud microphysics. We identify and explain the formation of several types of ethane and methane clouds, including south polar clouds and sporadic clouds in temperate regions and especially at 40 degrees in the summer hemisphere. The locations, frequencies, and composition of these cloud types are essentially explained by the large-scale circulation.


Dynamic Facial Expressions Prime the Processing of Emotional Prosody.
Evidence suggests that emotion is represented supramodally in the human brain. Emotional facial expressions, which often precede vocally expressed emotion in real life, can modulate event-related potentials (N100 and P200) during emotional prosody processing. To investigate these cross-modal emotional interactions, two lines of research have been put forward: cross-modal integration and cross-modal priming. In cross-modal integration studies, visual and auditory channels are temporally aligned, while in priming studies they are presented consecutively. Here we used cross-modal emotional priming to study the interaction of dynamic visual and auditory emotional information. Specifically, we presented dynamic facial expressions (angry, happy, neutral) as primes and emotionally-intoned pseudo-speech sentences (angry, happy) as targets. We were interested in how prime-target congruency would affect early auditory event-related potentials, i.e., N100 and P200, in order to shed more light on how dynamic facial information is used in cross-modal emotional prediction. Results showed enhanced N100 amplitudes for incongruently primed compared to congruently and neutrally primed emotional prosody, while the latter two conditions did not significantly differ. However, N100 peak latency was significantly delayed in the neutral condition compared to the other two conditions. Source reconstruction revealed that the right parahippocampal gyrus was activated in incongruent compared to congruent trials in the N100 time window. No significant ERP effects were observed in the P200 range. Our results indicate that dynamic facial expressions influence vocal emotion processing at an early point in time, and that an emotional mismatch between a facial expression and its ensuing vocal emotional signal induces additional processing costs in the brain, potentially because the cross-modal emotional prediction mechanism is violated in case of emotional prime-target incongruency.


Hepatitis Delta Virus Alters the Autophagy Process To Promote Its Genome Replication.
A substantial number of viruses have been demonstrated to subvert autophagy to promote their own replication. Recent publications have reported the proviral effect of autophagy induction on hepatitis B virus (HBV) replication. Hepatitis delta virus (HDV) is a defective virus and an occasional obligate satellite of HBV. However, no previous work has studied the relationship between autophagy and HDV. In this article, we analyze the impact of HBV and HDV replication on autophagy as well as the involvement of the autophagy machinery in the HDV life cycle when produced alone and in combination with HBV. We prove that HBxAg and HBsAg can induce early steps of autophagy but ultimately block flux. It is worth noting that the two isoforms of the HDV protein, the small HDAg (S-HDAg) and large HDAg (L-HDAg) isoforms, can also efficiently promote autophagosome accumulation and disturb autophagic flux. Using CRISPR-Cas9 technology to generate specific knockouts, we demonstrate that the autophagy machinery, specifically the proteins implicated in the elongation step (ATG7, ATG5, and LC3), is important for the release of HBV without affecting the level of intracellular HBV genomes. Surprisingly, the knockout of ATG5 and ATG7 decreased the intracellular HDV RNA level in both Huh7 and HepG2.2.15 cells without an additional effect on HDV secretion. Therefore, we conclude that HBV and HDV have evolved to utilize the autophagy machinery so as to assist at different steps of their life cycle.IMPORTANCE Hepatitis delta virus is a defective RNA virus that requires hepatitis B virus envelope proteins (HBsAg) to fulfill its life cycle. Thus, HDV can only infect individuals at the same time as HBV (coinfection) or superinfect individuals who are already chronic carriers of HBV. The presence of HDV in the liver accelerates the progression of infection to fibrosis and to hepatic cancer. Since current treatments against HBV are ineffective against HDV, it is of paramount importance to study the interaction between HBV, HDV, and host factors. This will help unravel new targets whereby a therapy that is capable of simultaneously impeding both viruses could be developed. In this research paper, we evidence that the autophagy machinery promotes the replication of HBV and HDV at different steps of their life cycle. Notwithstanding their contribution to HBV release, autophagy proteins seem to assist HDV intracellular replication but not its secretion.