Internalization of carbon black and maghemite iron oxide nanoparticle mixtures leads to oxidant production.
The risk of potential human exposure to mixed nanomaterials in consumer, occupational, and medicinal settings is increasing as nanomaterials enter both the workplace and the marketplace. In this study, we investigated the toxicity of mixed engineered carbon black (ECB) and maghemite iron oxide (Fe(2)O(3)) nanoparticles in a cellular system to understand the mechanism of toxicity and potential methods of toxicity mitigation. Lung epithelial cells (A549) were exposed to mixed Fe(2)O(3) and ECB nanoparticles, mixed Fe(2)O(3) and ECB nanoparticles with the addition of L-ascorbic acid, and mixed Fe(2)O(3) and surface-oxidized engineered carbon black (ox-ECB) nanoparticles. The nanoparticles were characterized using transmission electron microscopy, nitrogen adsorption surface area measurement (BET), X-ray diffraction, and surface charge measurement. The carbon black nanoparticles were also characterized with a reductive capacity assay and by X-ray photoelectron spectroscopy (XPS). The cellular uptake of nanoparticles was analyzed via transmission electron microscopy and fluorescence microscopy; the cellular uptake of iron was quantified using inductively coupled plasma mass spectrometry (ICP-MS). Both the MTT assay and the ethidium homodimer and calcein AM live/dead assay were used to measure cellular proliferation and cytotoxicity, respectively. The dichlorofluorescein diacetate (DCFH-DA) assay was used to measure the intracellular generation of reactive oxygen species. Results show that both Fe(2)O(3) and ECB (or Fe(2)O(3) and ox-ECB) were co-internalized in intracellular vesicles. Additionally, after exposure to the mixture of nanoparticles, the amount of acidified lysosomes increased over time. The cellular uptake of Fe(2)O(3) nanoparticles was unaffected by mixing with ECB. Significant oxidant production occurred in cells exposed to mixed Fe(2)O(3) and ECB, but not in cells exposed to mixed Fe(2)O(3) and ox-ECB or in cells exposed to Fe(2)O(3) and ECB with the addition of ascorbic acid. Furthermore, exposure to mixed Fe2O3 and ECB nanoparticles yielded a dose-dependent decrease in the level of cellular proliferation (MTT assay) and a decrease in cellular viability (ethidium homodimer and calcein AM live/dead assay) that were not seen in the Fe(2)O(3) and ox-ECB scenario. The results support the hypothesis that exposure to mixed Fe(2)O(3) and ECB nanoparticles produces oxidants that are mediated by the surface reductive capability of ECB when both particle types are colocalized in acidic cellular compartments. This oxidant production mechanism may lead to oxidative stress, but it can be mitigated by an antioxidant such as ascorbic acid or by surface treatment of the ECB to decrease its surface reductive capacity.


Maskless photolithography via holographic optical projection.
We propose an inexpensive novel rapid prototyping approach to a maskless and fully adaptive photolithographic process. Phase-only computer-generated holograms of lithographic masks displayed on a liquid-crystal-on-silicon spatial light modulator were used in a holographic optical lithography system. Using holographic projection allows diffraction-limited performance within the given parameters of the optical system, adaptive software refocusing, and a continuous, pixel-free pattern. With the demonstrator, we have successfully proven the concept for micrometer-size lithographic features.


Working time of neurosurgical residents in Europe--results of a multinational survey.
The introduction of the European Working Time directive 2003/88/EC has led to a reduction of the working hours with distinct impact on the clinical and surgical activity of neurosurgical residents in training. A survey was performed among European neurosurgical residents between 06/2014 and 03/2015. Multiple logistic regression was used to assess the relationship between responder-specific variables (e.g., age, gender, country, postgraduate year (PGY)) and outcome (e.g., working time). A total of 652 responses were collected, of which n = 532 responses were taken into consideration. In total, 17.5, 22.1, 29.5, 19.5, 5.9, and 5.5 % of European residents indicated to work <40, 40-50, 51-60, 61-70, 71-80, or >80 h/week, respectively. Residents from France and Turkey (OR 4.72, 95 % CI 1.29-17.17, p = 0.019) and Germany (OR 2.06, 95 % CI 1.15-3.67, p = 0.014) were more likely to work >60 h/week than residents from other European countries. In total, 29 % of European residents were satisfied with their current working time, 11.3 % indicated to prefer reduced working time. More than half (55 %) would prefer to work more hours/week if this would improve their clinical education. Residents that rated their operative exposure as insufficient were 2.3 times as likely as others to be willing to work more hours (OR 2.32, 95 % CI 1.47-3.70, p < 0.001). Less than every fifth European resident spends >50 % of his/her working time in the operating room. By contrast, 77.4 % indicate to devote >25 % of their daily working time to administrative work. For every advanced PGY, the likelihood to spend >50 % of the working time in the OR increases by 19 % (OR 1.19, 95 % CI 1.02-1.40, p = 0.024) and the likelihood to spend >50 % of the working time with administrative work decreases by 18 % (OR 0.84, 95 % CI 0.76-0.94, p = 0.002). The results of this survey on >500 European neurosurgical residents clearly prove that less than 40 % conform with the 48-h week as claimed by the WTD2003/88/EC. Still, more than half of them would chose to work even more hours/week if their clinical education were to improve; probably due to subjective impression of insufficient training.


Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment.
The tumour stroma/microenvironment not only provides structural support for tumour development, but more importantly it provides cues to cancer stem cells (CSCs) that regulate their self-renewal and metastatic potential. This is certainly true for pancreatic ductal adenocarcinomas (PDAC), where tumour-associated fibroblasts, pancreatic stellate cells and immune cells create an abundant paracrine niche for CSCs via microenvironment-secreted factors. Thus understanding the role that tumour stroma cells play in PDAC development and CSC biology is of utmost importance. Microarray analyses, tumour microarray immunohistochemical assays, in vitro co-culture experiments, recombinant protein treatment approaches and in vivo intervention studies were performed to understand the role that the immunomodulatory cationic antimicrobial peptide 18/LL-37 (hCAP-18/LL-37) plays in PDAC biology. We found that hCAP-18/LL-37 was strongly expressed in the stroma of advanced primary and secondary PDAC tumours and is secreted by immune cells of the stroma (eg, tumour-associated macrophages) in response to tumour growth factor-β1 and particularly CSC-secreted Nodal/ActivinA. Treatment of pancreatic CSCs with recombinant LL-37 increased pluripotency-associated gene expression, self-renewal, invasion and tumourigenicity via formyl peptide receptor 2 (FPR2)- and P2X purinoceptor 7 receptor (P2X7R)-dependent mechanisms, which could be reversed by inhibiting these receptors. Importantly, in a genetically engineered mouse model of K-Ras-driven pancreatic tumourigenesis, we also showed that tumour formation was inhibited by either reconstituting these mice with bone marrow from cathelicidin-related antimicrobial peptide (ie, murine homologue of hCAP-18/LL-37) knockout mice or by pharmacologically inhibiting FPR2 and P2X7R. Thus, hCAP-18/LL-37 represents a previously unrecognised PDAC microenvironment factor that plays a critical role in pancreatic CSC-mediated tumourigenesis.


Infant EEG activity as a biomarker for autism: a promising approach or a false promise?
The ability to determine an infant's likelihood of developing autism via a relatively simple neurological measure would constitute an important scientific breakthrough. In their recent publication in this journal, Bosl and colleagues claim that a measure of EEG complexity can be used to detect, with very high accuracy, infants at high risk for autism (HRA). On the surface, this appears to be that very scientific breakthrough and as such the paper has received widespread media attention. But a close look at how these high accuracy rates were derived tells a very different story. This stems from a conflation between "high risk" as a population-level property and "high risk" as a property of an individual. We describe the approach of Bosl et al. and examine their results with respect to baseline prevalence rates, the inclusion of which is necessary to distinguish infants with a biological risk of autism from typically developing infants with a sibling with autism. This is an important distinction that should not be overlooked. Please see research article: http://www.biomedcentral.com/1741-7015/9/18 and correspondence article: http://www.biomedcentral.com/1741-7015/9/60.


ATN classification and clinical progression in subjective cognitive decline: The SCIENCe project.
To investigate the relationship between the ATN classification system (amyloid, tau, neurodegeneration) and risk of dementia and cognitive decline in individuals with subjective cognitive decline (SCD). We classified 693 participants with SCD (60 ± 9 years, 41% women, Mini-Mental State Examination score 28 ± 2) from the Amsterdam Dementia Cohort and Subjective Cognitive Impairment Cohort (SCIENCe) project according to the ATN model, as determined by amyloid PET or CSF β-amyloid (A), CSF p-tau (T), and MRI-based medial temporal lobe atrophy (N). All underwent extensive neuropsychological assessment. For 342 participants, follow-up was available (3 ± 2 years). As a control population, we included 124 participants without SCD. Fifty-six (n = 385) participants had normal Alzheimer disease (AD) biomarkers (A-T-N-), 27% (n = 186) had non-AD pathologic change (A-T-N+, A-T+N-, A-T+N+), 18% (n = 122) fell within the Alzheimer continuum (A+T-N-, A+T-N+, A+T+N-, A+T+N+). ATN profiles were unevenly distributed, with A-T+N+, A+T-N+, and A+T+N+ containing very few participants. Cox regression showed that compared to A-T-N-, participants in A+ profiles had a higher risk of dementia with a dose-response pattern for number of biomarkers affected. Linear mixed models showed participants in A+ profiles showed a steeper decline on tests addressing memory, attention, language, and executive functions. In the control group, there was no association between ATN and cognition. Among individuals presenting with SCD at a memory clinic, those with a biomarker profile A-T+N+, A+T-N-, A+T+N-, and A+T+N+ were at increased risk of dementia, and showed steeper cognitive decline compared to A-T-N- individuals. These results suggest a future where biomarker results could be used for individualized risk profiling in cognitively normal individuals presenting at a memory clinic.


Functional characterisation of glyoxalase I from the fungal wheat pathogen Stagonospora nodorum.
During an expressed sequence tag sequencing project, a gene encoding a methylglyoxal lyase (glyoxalase I) was identified, cloned and characterised from the necrotrophic wheat pathogen Stagonospora nodorum. Sequence analysis identified the gene, named Gox1, as having reasonable identity to GLO1 from yeast and hypothetical proteins identified in fungal genome sequencing projects. Expression analysis in vitro revealed Gox1 to be up-regulated in the presence of methylglyoxal and salt but not affected by starvation conditions. Analysis of Gox1 transcription in planta showed its highest expression was in ungerminated spores and during sporulation, suggesting a role for the glycolytic bypass pathway in sporulation. The gene was inactivated by homologous recombination, resulting in a S. nodorum strain with no detectable glyoxalase I activity. The gox1 mutants exhibited no discernable phenotype, with the exception of being more sensitive to the presence of methylglyoxal. Infection assays demonstrated the mutants retained full pathogenicity and sporulation was unaffected. This is the first report describing the characterisation of a glyoxalase I from a pathogen of any description. The gene has been sequenced, functionally characterised and shown not to be required for the infection of wheat by S. nodorum.


Slight increases in the disease activity index and platelet count imply the presence of active intestinal lesions in C-reactive protein-negative Crohn's disease patients.
Although the serum C-reactive protein (CRP) level may, to some extent, predict the disease activity in patients with Crohn's disease (CD), it is not always elevated during periods of disease activity. This study aimed to identify factors predicting the presence of active intestinal lesions in CD patients without an elevated CRP level. CD patients in whom the presence or absence of active intestinal lesions was evaluated using endoscopic and/or radiologic modalities were divided into two groups based on a negative (<3 mg/L) or positive (≥3 mg/L) CRP level. The correlations between the presence of active intestinal lesions and various clinical variables, including the Crohn's Disease Activity Index (CDAI), leukocyte and platelet counts and hemoglobin, serum albumin and CRP levels, were determined in the CRP-negative patients. Of the 128 patients examined, 70 had a negative CRP status, approximately half of whom had active intestinal lesions. The multivariate analysis revealed a CDAI of >100 and platelet count of >33×10(4)/μL to be significant predictive factors for the presence of active lesions in the CRP-negative patients [CDAI >100, odds ratio (OR) =5.55; 95% confidence interval (CI), 1.80-18.74, platelet count >33×10(4)/μL, OR =5.94; 95% CI, 1.34-28.87]. The sensitivity of fulfillment of either criterion for the presence of active intestinal lesions was 83%, while the specificity of fulfillment of both criteria was 94%. A relatively low CDAI and platelet count were identified as predictive markers of the presence of active intestinal lesions in CRP-negative CD patients. These results suggest that symptoms and laboratory data should be evaluated very carefully in such patients.


Association Between Severity of Temporomandibular Disorders and the Frequency of Headache Attacks in Women With Migraine: A Cross-Sectional Study.
The aim of this study was to investigate the magnitude of association of the severity of temporomandibular disorders (TMDs) in women with episodic and chronic migraine. Thirty-one women with episodic migraine (mean age: 33 years), 21 with chronic migraine (mean age: 35 years) and 32 healthy controls (mean age: 31 years) were included. The Fonseca Anamnestic Index was applied to assess severity of TMDs. TMD severity was considered as follows: no TMD (0-19 points), mild TMD (20-49 points), moderate TMD (50-69 points), and severe TMD (70-100 points). To compare the proportion of TMD severity among groups, a χ2 test was performed. Prevalence ratio (PR) was calculated to determine the association of TMD severity and both migraine groups using the control group as the reference. Women with chronic and episodic migraine were more likely to exhibit TMD signs and symptoms of any severity than healthy controls (χ2 = 30.26; P < .001). TMD prevalence was 54% for healthy controls, 78% for episodic migraine, and 100% for chronic migraine. Women with chronic migraine exhibited greater risk of more severe manifestations of TMD than healthy controls (PR: 3.31; P = .008). This association was not identified for episodic migraine (PR: 2.18; P = .101). The presence of TMD signs and symptoms was associated with migraine independently of the frequency; however, the magnitude of the association of more severe TMD was significantly greater in chronic, but not episodic, migraine.


Where is the Target Point to Prevent Cortical Hinge Fracture in Medial Closing-Wedge Distal Femoral Varus Osteotomy?
The purpose of this study was to investigate whether the location of the hinge affects the incidence of hinge fracture during medial closing-wedge distal femoral varus osteotomy (DFVO). Twenty knees from 10 fresh-frozen human cadavers (mean age, 75 ± 17 years) were used to perform uniplanar medial closing-wedge DFVO with a 7-mm wedge. Each specimen was randomly assigned to either group A (supracondylar hinge) or group B (lateral condylar hinge). The incidence of hinge fracture and stability was compared between both groups after uniplanar medial closing-wedge DFVO. In group A, 8 of 10 knees had a lateral cortex fracture during closure of the osteotomy gap, and all fractured knees were unstable. Two knees with an intact lateral cortical hinge showed stability under manual valgus and varus forces. After intentional breakage of the lateral cortical hinge, both knees were found to be unstable under the same force. In group B, 2 of 10 knees had a lateral cortex fracture, and 8 knees had no fractures. All specimens were found to be stable under manual valgus and varus forces. After intentional breakage of the lateral cortical hinge in group B, 2 knees were unstable, while 8 knees remained stable. This study showed a significantly higher incidence of lateral cortical hinge fracture and instability in group A than in group B during closure of the osteotomy gap.


Gender differences in the long-term associations between posttraumatic stress disorder and depression symptoms: findings from the Detroit Neighborhood Health Study.
Posttraumatic stress disorder (PTSD) and depression are known to be highly comorbid. However, previous findings regarding the nature of this comorbidity have been inconclusive. This study prospectively examined whether PTSD and depression are distinct constructs in an epidemiologic sample, as well as assessed the directionality of the PTSD-depression association across time. Nine hundred and forty-two Detroit residents (males: n = 387; females: n = 555) were interviewed by phone at three time points, 1 year apart. At each time point, they were assessed for PTSD (using the PCL-C), depression (PHQ-9), trauma exposure, and stressful life events. First, a confirmatory factor analysis showed PTSD and depression to be two distinct factors at all three waves of assessments (W1, W2, and W3). Second, chi-square analysis detected significant differences between observed and expected rates of comorbidity at each time point, with significantly more no-disorder and comorbid cases, and significantly fewer PTSD only and depression only cases, than would be expected by chance alone. Finally, a cross-lagged analysis revealed a bidirectional association between PTSD and depression symptoms across time for the entire sample, as well as for women separately, wherein PTSD symptoms at an early wave predicted later depression symptoms, and vice versa. For men, however, only the paths from PTSD symptoms to subsequent depression symptoms were significant. Across time, PTSD and depression are distinct, but correlated, constructs among a highly-exposed epidemiologic sample. Women and men differ in both the risk of these conditions, and the nature of the long-term associations between them.


Transient outward potassium channel regulation in healthy and diabetic hearts.
Diabetic patients have a higher incidence of cardiac arrhythmias, including ventricular fibrillation and sudden death, and show important alterations in the electrocardiogram, most of these related to the repolarization. In myocytes isolated from diabetic hearts, the transient outward K+ current (Ito) is the repolarizing current that is mainly affected. Type 1 diabetes alters Ito at 3 levels: the recovery of inactivation, the responsiveness to physiologic regulators, and the functional expression of the channel. Diabetes slows down Ito recovery of inactivation because it triggers the switching from fast-recovering Kv4.x channels to the slow-recovering Kv1.4. Diabetic animals also have decreased responsiveness of Ito towards the sympathetic nervous system; thus, the diabetic heart develops a resistance to its physiologic regulator. Finally, diabetes impairs support of various trophic factors required for the functional expression of the channel and reduces Ito amplitude by decreasing the amount of Kv4.2 and Kv4.3 proteins.


Regulation of Drosophila vasa in vivo through paralogous cullin-RING E3 ligase specificity receptors.
In Drosophila species, molecular asymmetries guiding embryonic development are established maternally. Vasa, a DEAD-box RNA helicase, accumulates in the posterior pole plasm, where it is required for embryonic germ cell specification. Maintenance of Vasa at the posterior pole requires the deubiquitinating enzyme Fat facets, which protects Vasa from degradation. Here, we found that Gustavus (Gus) and Fsn, two ubiquitin Cullin-RING E3 ligase specificity receptors, bind to the same motif on Vasa through their paralogous B30.2/SPRY domains. Both Gus and Fsn accumulate in the pole plasm in a Vasa-dependent manner. Posterior Vasa accumulation is precocious in Fsn mutant oocytes; Fsn overexpression reduces ovarian Vasa levels, and embryos from Fsn-overexpressing females form fewer primordial germ cells (PGCs); thus, Fsn destabilizes Vasa. In contrast, endogenous Gus may promote Vasa activity in the pole plasm, as gus females produce embryos with fewer PGCs, and posterior accumulation of Vas is delayed in gus mutant oocytes that also lack one copy of cullin-5. We propose that Fsn- and Gus-containing E3 ligase complexes contribute to establishing a fine-tuned steady state of Vasa ubiquitination that influences the kinetics of posterior Vasa deployment.


Atrial fibrillation and stroke associated with intravenous bisphosphonate therapy in older patients with cancer.
Recent studies have linked the use of intravenous and orally administered bisphosphonates with subsequent development of atrial fibrillation. Patients with cancer who receive intravenous bisphosphonate therapy may be at particular risk for this adverse event because they receive higher doses of these drugs than do patients treated for other indications. We examined the association of intravenous bisphosphonates with atrial fibrillation, all classifications of supraventricular tachycardia (SVT), and stroke among older patients with cancer. Using Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked data, we identified older (≥ age 65 years) patients with cancer who were treated with intravenous infusions of bisphosphonates between January 1, 1995 and December 31, 2003. We then matched 13,714 bisphosphonate nonusers to 6,857 bisphosphonate users, at a 2:1 ratio, on cancer type, age, sex, presence of bone metastases, and SEER geographic region. Patients were observed until December 31, 2003 or until they lost coverage from Medicare Parts A and B; enrolled in a health maintenance organization; received a diagnosis of atrial fibrillation, any SVT, or stroke; or died. Receipt of intravenous bisphosphonates was modestly associated with an increased risk for atrial fibrillation (hazard ratio [HR] = 1.30; 95% CI, 1.18 to 1.43), all SVT (HR = 1.28; 95% CI, 1.19 to 1.38), and stroke (HR = 1.30; 95% CI, 1.09 to 1.54). The risk for all SVT increased 7% for each increase of five bisphosphonate dose equivalents (HR = 1.07; 95% CI, 1.02 to 1.12). Clinicians who treat patients with cancer who have received intravenous bisphosphonates should be aware of the possible cardiovascular adverse events associated with this treatment.


Development of a Comprehensive Battery to Collect Social and Structural Determinants of Health (SSDOH) in Cognitively Normal or Very Mildly Impaired Persons.
Research addressing Alzheimer disease and related dementias must examine nonbiological factors influencing the risk for and expression of Alzheimer disease and related dementias. These factors address the interplay of cognition with lived experiences and social and structural determinants of health (SSDOH). However, coordinated measures of SSDOH are limited. The Knight Alzheimer Disease Research Center (ADRC) at Washington University in St. Louis developed and piloted a comprehensive battery to measure SSDOH. One hundred and twelve participants, very mildly cognitively impaired or unimpaired, enrolled in memory studies completed the electronic SSDOH battery. The Clinical Dementia Rating (CDR) determined the presence or absence of cognitive impairment. Four domains demonstrated above acceptable intraclass correlation scores for test-retest reliability (≥0.70), including adverse childhood events, discrimination, social status, and early education. Twenty very mildly impaired participants completed the electronic pilot study. Our findings indicate that participants with early-stage symptomatic Alzheimer disease are able to participate in electronic SSDOH data collection. In collaboration with the University of Pennsylvania ADRC, we replaced/modified certain assessments to increase intraclass correlation. The resulting battery, Social and Structural Life-courses Influencing Aging and Dementia (SS-DIAD), can serve as a SSDOH collection tool and is currently utilized in cognitively impaired and unimpaired research participants at both ADRCs.


Do patients with schizophrenia exhibit aberrant salience?
It has been suggested that some psychotic symptoms reflect 'aberrant salience', related to dysfunctional reward learning. To test this hypothesis we investigated whether patients with schizophrenia showed impaired learning of task-relevant stimulus-reinforcement associations in the presence of distracting task-irrelevant cues. We tested 20 medicated patients with schizophrenia and 17 controls on a reaction time game, the Salience Attribution Test. In this game, participants made a speeded response to earn money in the presence of conditioned stimuli (CSs). Each CS comprised two visual dimensions, colour and form. Probability of reinforcement varied over one of these dimensions (task-relevant), but not the other (task-irrelevant). Measures of adaptive and aberrant motivational salience were calculated on the basis of latency and subjective reinforcement probability rating differences over the task-relevant and task-irrelevant dimensions respectively. Participants rated reinforcement significantly more likely and responded significantly faster on high-probability-reinforced relative to low-probability-reinforced trials, representing adaptive motivational salience. Patients exhibited reduced adaptive salience relative to controls, but the two groups did not differ in terms of aberrant salience. Patients with delusions exhibited significantly greater aberrant salience than those without delusions, and aberrant salience also correlated with negative symptoms. In the controls, aberrant salience correlated significantly with 'introvertive anhedonia' schizotypy. These data support the hypothesis that aberrant salience is related to the presence of delusions in medicated patients with schizophrenia, but are also suggestive of a link with negative symptoms. The relationship between aberrant salience and psychotic symptoms warrants further investigation in unmedicated patients.


Limb anomalies associated with chorionic villus sampling.
Data on outcome of pregnancy were obtained in 436 (94%) of 463 patients undergoing chorionic villus sampling (CVS) at Humana Hospital-Michael Reese between January 1, 1989 and November 30, 1990. There were 18 elective abortions, 27 fetal and neonatal losses, and 391 surviving infants. Of the 394 fetuses and infants who were adequately evaluated, a total of 13 (3.3%) had major congenital anomalies, including four with transverse limb reduction deformities, three with cleft lip with or without cleft palate, and one each with a nasal encephalocele, large port-wine stain, craniosynostosis, omphalocele with associated defects, ambiguous genitalia, and undescended testes. The limb malformations in the four affected infants were all very similar and were comparable to those described by others in association with CVS. Three of the cases of limb malformations followed transcervical CVS; one followed a transabdominal procedure. The procedures were performed at 9.5, 9.5, 10.5, and 11 weeks' gestation. An adequate sample was obtained with a single attempt in each case. These observations, in conjunction with others in the literature, suggest that there is an increased risk of limb anomalies associated with CVS. A vascular etiology, related to either decreased fetal perfusion or thrombosis of the sampling site with subsequent embolization, is suggested.


Suicidality and sexual orientation among men in Switzerland: findings from 3 probability surveys.
Few population-based surveys in Europe have examined the link between suicidality and sexual orientation. The objective of this study was to assess the prevalences of and risk for suicidality by sexual orientation, especially among adolescent and young adult men. Data came from three probability-based surveys in Switzerland from 2002: 1) Geneva Gay Men's Health Survey (GGMHS) with 571 gay/bisexual men, 2) Swiss Multicenter Adolescent Survey on Health (SMASH) with 7,428 16-20 year olds, and 3) Swiss Recruit Survey (ch-x) with 22,415 new recruits. In GGMHS, suicidal ideation (12 months/lifetime) was reported by 22%/55%, suicide plans 12%/38%, and suicide attempts 4%/19%. While lifetime prevalences and ratios are similar across age groups, men under 25 years reported the highest 12-month prevalences for suicidal ideation (35.4%) and suicide attempts (11.5%) and the lowest attempt ratios (1:1.5 for attempt to plan and 1:3.1 for attempt to ideation). The lifetime prevalence of suicide attempts among homo/bisexual men aged 16-20 years varies from 5.1% in ch-x to 14.1% in SMASH to 22.0% in GGMHS. Compared to their heterosexual counterparts, significantly more homo/bisexual men reported 12-month suicidal ideation, plans, and attempts (OR = 2.09-2.26) and lifetime suicidal ideation (OR = 2.15) and suicide attempts (OR = 4.68-5.36). Prevalences and ratios vary among gay men by age and among young men by both sexual orientation and study population. Lifetime prevalences and ratios of non-fatal suicidal behaviors appear constant across age groups as is the increased risk of suicidality among young homo/bisexual men.


Clinical accuracy of non-contact infrared thermometer from umbilical region in children: A new side.
Measurement from axillary site with digital thermometer has been accepted as the most accurate method. But this method is time consuming. Tympanic and forehead measurements are often used but don't always seem to be more appropriate. Another site, umbilical region, could be an alternative site. This study aims to compare the measurements with axillary digital thermometer and non-contact infrared thermometers at sites from umbilicus and forehead to determine whether umbilical site could be used accurately in children. For each method, 2,048 measurements in total were performed. Using axillary method as gold standard, with a cut-off temperature of 38oC, the sensitivities and specificities, positive and negative predictive values of umbilical and forehead temperatures and area under the ROC curve were determined in non obese children. There was a significant positive correlation between axillary and umbilical temperatures with a correlation coefficient of 0.78. The average difference between the mean of both axillary and umbilical temperatures was -0.47 ± 0.65°C. The Bland-Altman plot showed good accuracy with only 2.5 % of the readings falling outside the 95% level of confidence. Umbilical measurements showed sensitivity of 71.7% and specificity of 95.8%. The area under the ROC curve was 0.93. The easy application may lead noncontact measurements from umbilicus site to be the preferable method for health care providers, but agreement limits mentioned in this study should be considered.


Metacognitive Monitoring and Control of Eyewitness Memory Reports in Autism.
Providing eyewitness testimony involves monitoring one's memory to provide a detailed and accurate account: reporting details likely to be accurate and withholding potentially inaccurate details. Autistic individuals reportedly experience difficulties in both retrieving episodic memories and monitoring their accuracy, which has important implications for eyewitness testimony. Thirty autistic and 33 IQ-matched typically developing (TD) participants viewed a video of a mock bank robbery followed by three phases of questions (with judgments of confidence). In Phase 1, participants freely generated the granularity of their responses (i.e., fine- or coarse-grained). In Phase 2, participants answered the same questions but provided both a fine- and a coarse-grained answer. In Phase 3, participants were instructed to maximize accuracy over informativeness by selecting one of their Phase 2 answers as their final answer. They either received the questions socially (from the experimenter) or answered them online. There were no group differences in accuracy or metacognitive monitoring, with both autistic and TD witnesses demonstrating: (a) a strong preference for reporting fine-grained details at the expense of accuracy; (b) improved though still suboptimal grain size reporting when instructed to maximize accuracy over informativeness; (c) effective accuracy monitoring; and (d) higher overall accuracy when questions were delivered socially. There was, however, a subtle difference in metacognitive control, with autistic witnesses performing more poorly than TD witnesses when questions were delivered socially, but not when they were delivered online. These findings contrast with evidence suggesting that autism is marked by impairments in episodic memory and metacognitive monitoring and control. Autism Res 2020, 13: 2017-2029. © 2020 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Autistic people have been reported to experience subtle difficulties in monitoring and regulating their information reporting, which has important implications for providing eyewitness testimony. We found that autistic witnesses' testimony comprised a similar level of detail and accuracy as non-autistic witnesses' accounts. However, autistic people found it difficult to optimize their testimony when the questions were delivered socially-but not when they answered the questions online. © 2020 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc.


Resistance and resilience responses of a range of soil eukaryote and bacterial taxa to fungicide application.
The application of plant protection products has the potential to significantly affect soil microbial community structure and function. However, the extent to which soil microbial communities from different trophic levels exhibit resistance and resilience to such compounds remains poorly understood. The resistance and resilience responses of a range of microbial communities (bacteria, fungi, archaea, pseudomonads, and nematodes) to different concentrations of the strobilurin fungicide, azoxystrobin were studied. A significant concentration-dependent decrease, and subsequent recovery in soil dehydrogenase activity was recorded, but no significant impact on total microbial biomass was observed. Impacts on specific microbial communities were studied using small subunit (SSU) rRNA terminal restriction fragment length polymorphism (T-RFLP) profiling using soil DNA and RNA. The application of azoxystrobin significantly affected fungal and nematode community structure and diversity but had no impact on other communities. Community impacts were more pronounced in the RNA-derived T-RFLP profiles than in the DNA-derived profiles. qPCR confirmed that azoxystrobin application significantly reduced fungal, but not bacterial, SSU rRNA gene copy number. Azoxystrobin application reduced the prevalence of ascomycete fungi, but increased the relative abundance of zygomycetes. Azoxystrobin amendment also reduced the relative abundance of nematodes in the order Enoplia, but stimulated a large increase in the relative abundance of nematodes from the order Araeolaimida.


Coexistence of bacterial sulfide oxidizers, sulfate reducers, and spirochetes in a gutless worm (Oligochaeta) from the Peru margin.
Olavius crassitunicatus is a small symbiont-bearing worm that occurs at high abundance in oxygen-deficient sediments in the East Pacific Ocean. Using comparative 16S rRNA sequence analysis and fluorescence in situ hybridization, we examined the diversity and phylogeny of bacterial symbionts in two geographically distant O. crassitunicatus populations (separated by 385 km) on the Peru margin (water depth, approximately 300 m). Five distinct bacterial phylotypes co-occurred in all specimens from both sites: two members of the gamma-Proteobacteria (Gamma 1 and 2 symbionts), two members of the delta-Proteobacteria (Delta 1 and 2 symbionts), and one spirochete. A sixth phylotype belonging to the delta-Proteobacteria (Delta 3 symbiont) was found in only one of the two host populations. Three of the O. crassitunicatus bacterial phylotypes are closely related to symbionts of other gutless oligochaete species; the Gamma 1 phylotype is closely related to sulfide-oxidizing symbionts of Olavius algarvensis, Olavius loisae, and Inanidrilus leukodermatus, the Delta 1 phylotype is closely related to sulfate-reducing symbionts of O. algarvensis, and the spirochete is closely related to spirochetal symbionts of O. loisae. In contrast, the Gamma 2 phylotype and the Delta 2 and 3 phylotypes belong to novel lineages that are not related to other bacterial symbionts. Such a phylogenetically diverse yet highly specific and stable association in which multiple bacterial phylotypes coexist within a single host has not been described previously for marine invertebrates.


The mammalian interaural time difference detection circuit is differentially controlled by GABAB receptors during development.
Throughout development GABA(B) receptors (GABA(B)Rs) are widely expressed in the mammalian brain. In mature auditory brainstem neurons, GABA(B)Rs are involved in the short-term regulation of the strength and dynamics of excitatory and inhibitory inputs, thus modulating sound analysis. During development, GABA(B)Rs also contribute to long-term changes in input strength. Using a combination of whole-cell patch-clamp recordings in acute brain slices and immunostainings in gerbils, we characterized developmental changes in GABA(B)R-mediated regulation of synaptic inputs to neurons in the medial superior olive (MSO), an auditory brainstem nucleus that analyzes interaural time differences (ITDs). Here, we show that, before hearing onset, GABA(B)R-mediated depression of transmitter release is much stronger for excitation than inhibition, whereas in mature animals GABA(B)Rs mainly control the inhibition. During the same developmental period, GABA(B)R immunoreactivity shifts from the dendritic to the somatic region of the MSO. Furthermore, only before hearing onset (postnatal day 12), stimulation of the fibers originating in the medial and the lateral nucleus of the trapezoid body (MNTB and LNTB) activates GABA(B)Rs on both the inhibitory and the excitatory inputs. After hearing onset, GAD65-positive endings devoid of glycine transporter reactivity suggest GABA release from sources other than the MNTB and LNTB. At this age, pharmacological increase of spontaneous synaptic release activates GABA(B)Rs only on the inhibitory inputs. This indicates not only a profound inhibitory effect of GABA(B)Rs on the major inputs to MSO neurons in neonatal animals but also a direct modulatory role of GABA(B)Rs for ITD analysis in the MSO of adult animals.


Successful reduction of ACTH secretion in a case of intractable Cushing's disease with pituitary Crooke's cell adenoma by combined modality therapy including temozolomide.
Crooke's cell adenoma (CCA) is an aggressive subtype of corticotroph adenoma; however, CCA is associated with a high incidence of low expression of methyl guanine methyl transferase (MGMT), suggesting that temozolomide (TMZ) treatment might be effective for this tumor type. The case of a 56-year-old woman with Cushing's disease caused by a pituitary CCA is presented. At the age of 38 years, the patient presented to our hospital with polyuria and a visual field defect. MRI and laboratory studies showed a 4.5-cm-diameter pituitary tumor with plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels of more than 500 pg/mL and 40 μg/dL, respectively. At 39 years of age, the patient underwent a craniotomy, and her plasma ACTH and cortisol levels decreased to less than 200 pg/mL and 10 μg/dL, respectively; however, these hormone levels increased gradually to 3,940 pg/mL and 70 μg/dL, respectively, by the time the patient was 56 years old. Histopathological re-examination of the previously resected specimen showed that the pituitary tumor was MGMT-negative CCA. TMZ treatment after the second operation decreased the plasma ACTH levels from 600-800 pg/mL to 70-300 pg/mL. No signs of recurrence were observed in the seven years following these treatments with added prophylactic radiation therapy. These clinical findings suggest that TMZ treatment to patients with CCA accompanied with elevated ACTH may be good indication to induce lowering ACTH levels and tumor shrinkage.


Single-Cell Computational Strategies for Lineage Reconstruction in Tissue Systems.
Function at the organ level manifests itself from a heterogeneous collection of cell types. Cellular heterogeneity emerges from developmental processes by which multipotent progenitor cells make fate decisions and transition to specific cell types through intermediate cell states. Although genetic experimental strategies such as lineage tracing have provided insights into cell lineages, recent developments in single-cell technologies have greatly increased our ability to interrogate distinct cell types, as well as transitional cell states in tissue systems. From single-cell data that describe these intermediate cell states, computational tools have been developed to reconstruct cell-state transition trajectories that model cell developmental processes. These algorithms, although powerful, are still in their infancy, and attention must be paid to their strengths and weaknesses when they are used. Here, we review some of these tools, also referred to as pseudotemporal ordering algorithms, and their associated assumptions and caveats. We hope to provide a rational and generalizable workflow for single-cell trajectory analysis that is intuitive for experimental biologists.


Understanding the burden of osteoporosis and use of the World Health Organization FRAX.
Fracture prevention is a critical component of managing osteoporosis, which is not longer defined by T-score alone. The internationally validated World Health Organization Fracture Risk Assessment Tool (FRAX) provides the clinician a state-of-the-art tool for predicting patients at greatest risk for fracture. The FRAX tool takes into account country, bone mineral density of the hip (when available), age, sex, and 8 clinical risk factors to calculate the 10-year probability of a major osteoporotic fracture and the 10-year probability of a hip fracture. From this tool, an absolute fracture risk is generated, aiding clinicians in determining which patients with low bone mass and osteoporosis to treat.


The brief resilience scale: assessing the ability to bounce back.
While resilience has been defined as resistance to illness, adaptation, and thriving, the ability to bounce back or recover from stress is closest to its original meaning. Previous resilience measures assess resources that may promote resilience rather than recovery, resistance, adaptation, or thriving. To test a new brief resilience scale. The brief resilience scale (BRS) was created to assess the ability to bounce back or recover from stress. Its psychometric characteristics were examined in four samples, including two student samples and samples with cardiac and chronic pain patients. The BRS was reliable and measured as a unitary construct. It was predictably related to personal characteristics, social relations, coping, and health in all samples. It was negatively related to anxiety, depression, negative affect, and physical symptoms when other resilience measures and optimism, social support, and Type D personality (high negative affect and high social inhibition) were controlled. There were large differences in BRS scores between cardiac patients with and without Type D and women with and without fibromyalgia. The BRS is a reliable means of assessing resilience as the ability to bounce back or recover from stress and may provide unique and important information about people coping with health-related stressors.


Transcriptome analysis reveals crosstalk of responsive genes to multiple abiotic stresses in cotton (Gossypium hirsutum L.).
Abiotic stress is a major environmental factor that limits cotton growth and yield, moreover, this problem has become more and more serious recently, as multiple stresses often occur simultaneously due to the global climate change and environmental pollution. In this study, we sought to identify genes involved in diverse stresses including abscisic acid (ABA), cold, drought, salinity and alkalinity by comparative microarray analysis. Our result showed that 5790, 3067, 5608, 778 and 6148 transcripts, were differentially expressed in cotton seedlings under treatment of ABA (1 μM ABA), cold (4°C), drought (200 mM mannitol), salinity (200 mM NaCl) and alkalinity (pH=11) respectively. Among the induced or suppressed genes, 126 transcripts were shared by all of the five kinds of abiotic stresses, with 64 up-regulated and 62 down-regulated. These common members are grouped as stress signal transduction, transcription factors (TFs), stress response/defense proteins, metabolism, transport facilitation, as well as cell wall/structure, according to the function annotation. We also noticed that large proportion of significant differentially expressed genes specifically regulated in response to different stress. Nine of the common transcripts of multiple stresses were selected for further validation with quantitative real time RT-PCR (qRT-PCR). Furthermore, several well characterized TF families, for example, WRKY, MYB, NAC, AP2/ERF and zinc finger were shown to be involved in different stresses. As an original report using comparative microarray to analyze transcriptome of cotton under five abiotic stresses, valuable information about functional genes and related pathways of anti-stress, and/or stress tolerance in cotton seedlings was unveiled in our result. Besides this, some important common factors were focused for detailed identification and characterization. According to our analysis, it suggested that there was crosstalk of responsive genes or pathways to multiple abiotic or even biotic stresses, in cotton. These candidate genes will be worthy of functional study under diverse stresses.


A comparison of narrative exposure therapy, supportive counseling, and psychoeducation for treating posttraumatic stress disorder in an african refugee settlement.
Little is known about the usefulness of psychotherapeutic approaches for traumatized refugees who continue to live in dangerous conditions. Narrative exposure therapy (NET) is a short-term approach based on cognitive-behavioral therapy and testimony therapy. The efficacy of narrative exposure therapy was evaluated in a randomized controlled trial. Sudanese refugees living in a Ugandan refugee settlement (N = 43) who were diagnosed as suffering from posttraumatic stress disorder (PTSD) either received 4 sessions of NET, 4 sessions of supportive counseling (SC), or psychoeducation (PE) completed in 1 session. One year after treatment, only 29% of the NET participants but 79% of the SC group and 80% of the PE group still fulfilled PTSD criteria. These results indicate that NET is a promising approach for the treatment of PTSD for refugees living in unsafe conditions.


Alertness can be improved by an interaction between orienting attention and alerting attention in schizophrenia.
Attention is impaired in schizophrenia. Early attention components include orienting and alerting, as well as executive control networks. Previous studies have shown mainly executive control deficits, while few of them found orienting and alerting abnormalities. Here we explore the different attentive networks, their modulation and interactions in patients with schizophrenia. Twenty-one schizophrenic patients (DSMIV), compared to 21 controls, performed a modified version of the Attention Network Task, in which an orienting paradigm (with valid, invalid and no cues) was combined with a flanker task (congruent/incongruent) and an alerting signal (tone/no tone), to assess orienting, executive control and alerting networks independently. Patients showed an abnormal alerting effect and slower overall reaction time compared to controls. Moreover, there was an interaction between orienting and alerting: patients are helped more than controls by the alerting signal in a valid orientation to solve the incongruent condition. These results suggest that patients with schizophrenia have altered alerting abilities. However, the orienting and alerting cues interact to improve their attention performance in the resolution of conflict, creating possibilities for cognitive remediation strategies.


Novel cloud and SOA-based framework for e-health monitoring using wireless biosensors.
Various and independent studies are showing that an exponential increase of chronic diseases (CDs) is exhausting governmental and private healthcare systems to an extent that some countries allocate half of their budget to healthcare systems. To benefit from the IT development, e-health monitoring and prevention approaches revealed to be among top promising solutions. In fact, well-implemented monitoring and prevention schemes have reported a decent reduction of CDs risk and have narrowed their effects, on both patients' health conditions and on government budget spent on healthcare. In this paper, we propose a framework to collect patients' data in real time, perform appropriate nonintrusive monitoring, and propose medical and/or life style engagements, whenever needed and appropriate. The framework, which relies on service-oriented architecture (SOA) and the Cloud, allows a seamless integration of different technologies, applications, and services. It also integrates mobile technologies to smoothly collect and communicate vital data from a patient's wearable biosensors while considering the mobile devices' limited capabilities and power drainage in addition to intermittent network disconnections. Then, data are stored in the Cloud and made available via SOA to allow easy access by physicians, paramedics, or any other authorized entity. A case study has been developed to evaluate the usability of the framework, and the preliminary results that have been analyzed are showing very promising results.


Enhanced thermophilic fermentative hydrogen production from cassava stillage by chemical pretreatments.
Acid and alkaline pretreatments for enhanced hydrogen production from cassava stillage were investigated in the present study. The result showed that acid pretreatment was suitable for enhancement of soluble carbohydrate while alkaline pretreatment stimulated more soluble total organic carbon production from cassava stillage. Acid pretreatment thereby has higher capacity to promote hydrogen production compared with alkaline pretreatment. Effects of pretreatment temperature, time and acid concentration on hydrogen production were also revealed by response surface methodology. The results showed that the increase of all factors increased the soluble carbohydrate production, whereas hydrogen production was inhibited when the factors exceeded their optimal values. The optimal conditions for hydrogen production were pretreatment temperature 89.5 °C, concentration 1.4% and time 69 min for the highest hydrogen production of 434 mL, 67% higher than raw cassava stillage.


How topoisomerase IV can efficiently unknot and decatenate negatively supercoiled DNA molecules without causing their torsional relaxation.
Freshly replicated DNA molecules initially form multiply interlinked right-handed catenanes. In bacteria, these catenated molecules become supercoiled by DNA gyrase before they undergo a complete decatenation by topoisomerase IV (Topo IV). Topo IV is also involved in the unknotting of supercoiled DNA molecules. Using Metropolis Monte Carlo simulations, we investigate the shapes of supercoiled DNA molecules that are either knotted or catenated. We are especially interested in understanding how Topo IV can unknot right-handed knots and decatenate right-handed catenanes without acting on right-handed plectonemes in negatively supercoiled DNA molecules. To this end, we investigate how the topological consequences of intersegmental passages depend on the geometry of the DNA-DNA juxtapositions at which these passages occur. We observe that there are interesting differences between the geometries of DNA-DNA juxtapositions in the interwound portions and in the knotted or catenated portions of the studied molecules. In particular, in negatively supercoiled, multiply interlinked, right-handed catenanes, we detect specific regions where DNA segments belonging to two freshly replicated sister DNA molecules form left-handed crossings. We propose that, due to its geometrical preference to act on left-handed crossings, Topo IV can specifically unknot supercoiled DNA, as well as decatenate postreplicative catenanes, without causing their torsional relaxation.


N-acetylcysteine treatment blocks the development of ethanol-induced behavioural sensitization and related ΔFosB alterations.
Ethanol addiction is a serious public health problem that still needs more effective pharmacological treatment. A key factor in the development and maintenance of this disease is the advent of neuroadaptations in the mesocorticolimbic brain pathway upon chronic ethanol abuse. In general, these neuroadaptations are maladaptive and affect numerous neurotransmitter systems and intracellular molecules. One of these molecules is ΔFosB, a transcription factor that is altered after chronic drug use. Behavioural sensitization is a useful model for the study of the neuroadaptations related to addiction. Recent works have shown a role for the imbalance of glutamatergic neurotransmission in the symptoms found in addicted people. In this sense, the treatment with N-acetylcysteine, a l-cysteine prodrug that acts by restoring extrasynaptic concentrations of glutamate through the activation of cystine-glutamate antiporter, has shown promising results in the treatment of addiction. Thus, an animal model of behavioural sensitization was used to evaluate the effects of N-acetylcysteine treatment in the behavioural and molecular alterations induced by chronic ethanol administration. Swiss mice were subject to 13 days of daily ethanol administration to induce behavioural sensitization. Two hours before each ethanol administration and locomotor activity evaluation, the animals received intraperitoneally N-acetylcysteine injections. Immediately after the last test session, their brains were removed for ΔFosB and cystine-glutamate antiporter quantification. It was found that N-acetylcysteine treatment blocked ethanol-induced behavioural sensitization, the increase of ΔFosB content in the prefrontal cortex, and its reduction in the nucleus accumbens. The results suggest a possible use of N-acetylcysteine in ethanol-related disorders.


Sagittula stellata gen. nov., sp. nov., a lignin-transforming bacterium from a coastal environment.
A numerically important member of marine enrichment cultures prepared with lignin-rich, pulp mill effluent was isolated. This bacterium was gram negative and rod shaped, did not form spores, and was strictly aerobic. The surfaces of its cells were covered by blebs or vesicles and polysaccharide fibrils. Each cell also had a holdfast structure at one pole. The cells formed rosettes and aggregates. During growth in the presence of lignocellulose or cellulose particles, cells attached to the surfaces of the particles. The bacterium utilized a variety of monosaccharides, disaccharides, amino acids, and volatile fatty acids for growth. It hydrolyzed cellulose, and synthetic lignin preparations were partially solubilized and mineralized. As determined by 16S rRNA analysis, the isolate was a member of the alpha subclass of the phylum Proteobacteria and was related to the genus Roseobacter. A signature secondary structure of the 16S rRNA is proposed. The guanine-plus-cytosine content of the genomic DNA was 65.0 mol%. On the basis of the results of 16S rRNA sequence and phenotypic characterizations, the isolate was sufficiently different to consider it a member of a new genus. Thus, a novel genus and species, Sagittula stellata, are proposed; the type strain is E-37 (= ATCC 700073).


Role of tissue inhibitor of metalloproteinases-1 in the development of autoimmune lymphoproliferation.
Inherited defects decreasing function of the Fas death receptor cause autoimmune lymphoproliferative syndrome and its variant Dianzani's autoimmune lymphoproliferative disease. Analysis of the lymphocyte transcriptome from a patient with this latter condition detected striking over-expression of osteopontin and tissue inhibitor of metalloproteinases-1. Since previous work on osteopontin had detected increased serum levels in these patients, associated with variations of its gene, the aim of this work was to extend the analysis to tissue inhibitor of metalloproteinases-1. Tissue inhibitor of metalloproteinases-1 levels were evaluated in sera and culture supernatants from patients and controls by enzyme-linked immunosorbent assay. Activation- and Fas-induced cell death were induced, in vitro, using anti-CD3 and anti-Fas antibodies, respectively. Tissue inhibitor of metalloproteinases-1 levels were higher in sera from 32 patients (11 with autoimmune lymphoproliferative syndrome and 21 with Dianzani's autoimmune lymphoproliferative disease) than in 50 healthy controls (P<0.0001), unassociated with variations of the tissue inhibitor of metalloproteinases-1 gene. Both groups of patients also had increased serum levels of osteopontin. In vitro experiments showed that osteopontin increased tissue inhibitor of metalloproteinases-1 secretion by peripheral blood monocytes. Moreover, tissue inhibitor of metalloproteinases-1 significantly inhibited both Fas- and activation-induced cell death of lymphocytes. These data suggest that high osteopontin levels may support high tissue inhibitor of metalloproteinases-1 levels in autoimmune lymphoproliferative syndrome and Dianzani's autoimmune lymphoproliferative disease, and hence worsen the apoptotic defect in these diseases.


Adjustable subwavelength localization in a hybrid plasmonic waveguide.
The hybrid plasmonic waveguide consists of a high-permittivity dielectric nanofiber embedded in a low-permittivity dielectric near a metal surface. This architecture is considered as one of the most perspective candidates for long-range subwavelength guiding. We present qualitative analysis and numerical results which reveal advantages of the special waveguide design when dielectric constant of the cylinder is greater than the absolute value of the dielectric constant of the metal. In this case the arbitrary subwavelength mode size can be achieved by controlling the gap width. Our qualitative analysis is based on consideration of sandwich-like conductor-gap-dielectric system. The numerical solution is obtained by expansion of the hybrid plasmonic mode over single cylinder modes and the surface plasmon-polariton modes of the metal screen and matching the boundary conditions.


Markov models from the square root approximation of the Fokker-Planck equation: calculating the grid-dependent flux.
Molecular dynamics (MD) are extremely complex, yet understanding the slow components of their dynamics is essential to understanding their macroscopic properties. To achieve this, one models the MD as a stochastic process and analyses the dominant eigenfunctions of the associated Fokker-Planck operator, or of closely related transfer operators. So far, the calculation of the discretized operators requires extensive MD simulations. The square-root approximation of the Fokker-Planck equation is a method to calculate transition rates as a ratio of the Boltzmann densities of neighboring grid cells times a flux, and can in principle be calculated without a simulation. In a previous work we still used MD simulations to determine the flux. Here, we propose several methods to calculate the exact or approximate flux for various grid types, and thus estimate the rate matrix without a simulation. Using model potentials we test computational efficiency of the methods, and the accuracy with which they reproduce the dominant eigenfunctions and eigenvalues. For these model potentials, rate matrices with up to [Formula: see text] states can be obtained within seconds on a single high-performance compute server if regular grids are used.


Glyphosate induces benign monoclonal gammopathy and promotes multiple myeloma progression in mice.
Glyphosate is the most widely used herbicide in the USA and worldwide. There has been considerable debate about its carcinogenicity. Epidemiological studies suggest that multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) have a positive and statistically significant association with glyphosate exposure. As a B cell genome mutator, activation-induced cytidine deaminase (AID) is a key pathogenic player in both MM and B cell NHL. Vk*MYC is a mouse line with sporadic MYC activation in germinal center B cells and considered as the best available MM animal model. We treated Vk*MYC mice and wild-type mice with drinking water containing 1000 mg/L of glyphosate and examined animals after 72 weeks. Vk*MYC mice under glyphosate exposure developed progressive hematological abnormalities and plasma cell neoplasms such as splenomegaly, anemia, and high serum IgG. Moreover, glyphosate caused multiple organ dysfunction, including lytic bone lesions and renal damage in Vk*MYC mice. Glyphosate-treated wild-type mice developed benign monoclonal gammopathy with increased serum IgG, anemia, and plasma cell presence in the spleen and bone marrow. Finally, glyphosate upregulated AID in the spleen and bone marrow of both wild-type and Vk*MYC mice. These data support glyphosate as an environmental risk factor for MM and potentially NHL and implicate a mechanism underlying the B cell-specificity of glyphosate-induced carcinogenesis observed epidemiologically.


White button mushrooms increase microbial diversity and accelerate the resolution of Citrobacter rodentium infection in mice.
The effect of feeding C57BL/6 mice white button (WB) mushrooms or control (CTRL) diets for 6 wk was determined on the bacterial microflora, urinary metabolome, and resistance to a gastrointestinal (GI) pathogen. Feeding mice a diet containing 1 g WB mushrooms/100 g diet resulted in changes in the microflora that were evident at 2 wk and stabilized after 4 wk of WB feeding. Compared with CTRL-fed mice, WB feeding (1 g/100 g diet) increased the diversity of the microflora and reduced potentially pathogenic (e.g., Clostridia) bacteria in the GI tract. Bacteria from the Bacteroidetes phylum increased and the Firmicutes phylum decreased in mushroom-fed mice compared with CTRL. The changes in the microflora were also reflected in the urinary metabolome that showed a metabolic shift in the WB-fed compared with the CTRL-fed mice. The WB feeding and changes in the microbiome were associated with fewer inflammatory cells and decreased colitis severity in the GI mucosa following Citrobacter rodentium infection compared with CTRL. Paradoxically, the clearance of C. rodentium infection did not differ even though Ifn-γ and Il-17 were higher in the colons of the WB-fed mice compared with CTRL. Adding modest amounts of WB mushrooms (1 g/100 g diet) to the diet changed the composition of the normal flora and the urinary metabolome of mice and these changes resulted in better control of inflammation and resolution of infection with C. rodentium.


An ultrasound model to calculate the brain blood outflow through collateral vessels: a pilot study.
The quantification of the flow returning from the head through the cervical veins and the collaterals of the internal jugular vein (IJV), is becoming of prominent interest in clinical practice. We developed a novel model to calculate the cerebral venous return, normalized to the arterial inflow, in the different segments of the IJV. We assessed, by established Echo Colour Doppler (ECD) methodology, the head inflow (HBinF) defined as the sum of common carotids and vertebral arteries, as well as the cerebral flow (CBF) defined as the sum of internal carotid and vertebral arteries. We also assessed the head outflow (HBoutF) defined as the sum of the measurements at the junction of the IJV and the vertebral veins. In addition, we also calculated the collateral flow index (CFI) by estimating the flow which re-enters directly into the superior vena cava as the amount of blood extrapolated by the difference between the HBinF and the HBoutF. We preliminarily tested the model by comparing ten healthy controls (HC) with ten patients affected by chronic cerebral spinal venous insufficiency (CCSVI), a condition characterized by some blockages in the IJV which are bypassed by collateral circulation. In HC the HBinF was 956+-105ml/min, whereas the HBoutF was > 90% of the HBinF, leading to a final CFI value of 1%. The last result shows that a very small amount of blood is drained by the collaterals. In upright we confirmed a reduction of the outflow through the IJV which increased CFI to 9%. When we applied the model to CCSVI, the HBinF was not significantly different from controls. In supine, the flow of CCSVI patients in the IJV junction was significantly lower (p < 0.001) while the correspondent CFI value significantly increased (61%, p < 0.0002). Our preliminary application of the novel model in the clinical setting suggests the pivotal role of the collateral network in draining the blood into the superior vena cava under CCSVI condition.


A New Piece of the Puzzle to Understand Cervical Sagittal Alignment: Utilizing a Novel Angle δ to Describe the Relationship among T1 Vertebral Body Slope, Cervical Lordosis, and Cervical Sagittal Alignment.
Cervical alignment has become increasingly important in the planning of spine surgery. A relationship between the slope of T1 (T1S), the cervical lordosis (CL), and the overall cervical sagittal vertical axis (cSVA) has previously been demonstrated, but the exact nature of this relationship is poorly understood. In this study, we derive theoretical and empirical equations to better understand how T1S and CL affect cSVA. The first equation was developed on a theoretical basis using inherent trigonometric relationships of the cervical spine. By treating the cervical spine as the arc of a circumference, and by taking into account the cervical height (CH), the geometric relationship between theT1S, CL, and cSVA was described via a trigonometric identity utilizing a novel angle δ subtended by the CH and cSVA (δ = T1S-CL/2). The second equation was developed on an empiric basis by performing a multiple linear regression on data obtained from a retrospective review of a large multicenter deformity database. The theoretical equation determined that the value of cSVA could be expressed as: $cSVA\ = \ CH*{\rm{tan}}( {\pi /180*( {T1S - CL/2} )} )$. The empirical equation determined that value of cSVA could be expressed as: $cSVA=({1.1*T1} )\ - ( {0.43*CL} ) + 6.69$. In both, the sagittal alignment of the head over the shoulders is directly proportional to the T1S and inversely proportional to CL/2. These 2 equations may allow surgeons to better understand how the CL compensates for the T1S, to accurately predict the postoperative cSVA, and to customize cervical interbody grafts by taking into consideration each individual patient's specific cervical spine parameters.


High Serum Folate Concentrations Are Associated with Decreased Risk of Mortality among Japanese Adults.
Folate and vitamin B-12 are essential nutrients for normal cell growth and replication, but the association of serum folate and vitamin B-12 concentrations with mortality risk remains uncertain. This study was performed to investigate the associations of serum folate and vitamin B-12 concentrations with mortality risk and test whether the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism modifies these associations. A total of 3050 Japanese community residents aged ≥40 y were prospectively followed-up for mortality between 2002 and 2012. Cox proportional hazards models and restricted cubic splines were used to estimate HRs and 95% CIs of mortality. During a median follow-up period of 10.2 y, 336 participants died. Higher serum folate concentrations were associated with lower risks of all-cause mortality [multivariable-adjusted HR: 0.73; 95% CI: 0.56, 0.96 for the second tertile (8.8-12.2 nmol/L; median 10.4 nmol/L) and HR: 0.61; 95% CI: 0.46, 0.80 for the third tertile (≥12.5 nmol/L; median 15.6 nmol/L) serum folate concentrations compared with the first tertile (≤8.6 nmol/L; median 7.0 nmol/L)]. This association remained significant in all sensitivity analyses. Spline analyses showed a steady decline in all-cause mortality risk with increasing serum folate concentrations up to 20-25 nmol/L. This association persisted regardless of the MTHFR C677T genotypes. For serum vitamin B-12, the multivariable-adjusted HR of 1.32 (95% CI: 0.97, 1.79) of all-cause mortality was marginally significantly greater in the first tertile compared with the second tertile. This association was attenuated and nonsignificant after the exclusion of participants with a history of cardiovascular disease or cancer, or participants aged ≥85 y at baseline, or deaths in the first 3 y of follow-up. Serum folate concentrations were inversely associated with the risk of all-cause mortality in Japanese adults. Serum vitamin B-12 concentrations were not consistently associated with all-cause mortality risk after accounting for reverse-causation bias.


Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials.
A prospective, pooled analysis of six randomised phase 3 trials was done to investigate disease-free survival regarding non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer; non-inferiority was not shown. Here, we report the final overall survival results. In this prospective, pooled analysis of six randomised phase 3 trials, we included patients with stage III colon cancer aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-1 recruited between June 20, 2007, and Dec 31, 2015, across 12 countries in the CALGB/SWOG 80702, IDEA France, SCOT, ACHIEVE, TOSCA, and HORG trials, who started any treatment (modified intention-to-treat). Patients in all trials were randomly assigned to 3 months or 6 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) every 2 weeks or capecitabine and oxaliplatin (CAPOX) in different doses and methods every 3 weeks, at the treating physician's discretion. The primary endpoint was disease-free survival (time to relapse, secondary colorectal primary tumour, or death due to all causes), and overall survival (time to death due to all causes) was the prespecified secondary endpoint. The non-inferiority margin for overall survival was set as a hazard ratio (HR) of 1·11. Pre-planned subgroup analyses included regimen and risk group. Non-inferiority was declared if the one-sided false discovery rate adjusted (FDRadj) p value was less than 0·025. With median follow-up of 72·3 months (IQR 72·2-72·5), 2584 deaths among 12 835 patients were observed. 5064 (39·5%) patients received CAPOX and 7771 (60·5%) received FOLFOX. 5-year overall survival was 82·4% (95% CI 81·4-83·3) with 3 months of therapy and 82·8% (81·8-83·8) with 6 months of therapy (HR 1·02 [95% CI 0·95-1·11]; non-inferiority FDRadj p=0·058). For patients treated with CAPOX, 5-year overall survival was 82·1% (80·5-83·6) versus 81·2% (79·2-82·9; HR 0·96 [0·85-1·08]); non-inferiority FDRadj p=0·033), and for patients treated with FOLFOX 5-year overall survival was 82·6% (81·3-83·8) and 83·8% (82·6-85·0; HR 1·07 [0·97-1·18]; non-inferiority FDRadj p=0·34). Updated disease-free survival results confirmed previous findings (HR 1·08 [95% CI 1·02-1·15]; non-inferiority FDRadj p=0·25). Data on adverse events were not further recorded. Non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer was not confirmed in terms of overall survival, but the absolute 0·4% difference in 5-year overall survival should be placed in clinical context. Overall survival results support the use of 3 months of adjuvant CAPOX for most patients with stage III colon cancer. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies, and cost associated with a shorter treatment duration. US National Cancer Institute.


Therapeutic algorithm to treat common iliac artery aneurysms by endovascular means.
Use of endovascular means is gaining ever greater acceptance in the treatment of aorto-iliac aneurysms. Especially, the treatment of patients with common iliac aneurysms (CIAs) may be very challenging due to the complexity of the underlying disease with often involvement of the hypogastric artery. Additionally, the variety of endovascular therapeutic options such as the use of iliac branch devices, parallel grafts, the bell-bottom technique or coil embolization of the hypogastric artery and overstenting of the origin represents significant limitation regarding the presentation of a clear and robust endovascular therapeutic algorithm. Aim of the present article was the demonstration of the institutional experience with the endovascular management of CIAs in order to provide a clinical recommendation and algorithm.


Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction.
FGFR2 is a membrane-spanning tyrosine kinase that serves as a high affinity receptor for several members of the fibroblast growth factor (FGF) family. To explore functions of FGF/FGFR2 signals in development, we have mutated FGFR2 by deleting the entire immunoglobin-like domain III of the receptor. We showed that murine FGFR2 is essential for chorioallantoic fusion and placenta trophoblast cell proliferation. Fgfr2(DeltaIgIII/DeltaIgIII) embryos displayed two distinct defects that resulted in failures in formation of a functional placenta. About one third of the mutants failed to form the chorioallantoic fusion junction and the remaining mutants did not have the labyrinthine portion of the placenta. Consequently, all mutants died at 10-11 days of gestation. Interestingly, Fgfr2(DeltaIgIII/DeltaIgIII) embryos do not form limb buds. Consistent with this defect, the expression of Fgf8, an apical ectodermal factor, is absent in the mutant presumptive limb ectoderm, and the expression of Fgf10, a mesenchymally expressed limb bud initiator, is down regulated in the underlying mesoderm. These findings provide direct genetic evidence that FGF/FGFR2 signals are absolutely required for vertebrate limb induction and that an FGFR2 signal is essential for the reciprocal regulation loop between FGF8 and FGF10 during limb induction.


Validating estimates of prevalence of non-communicable diseases based on household surveys: the symptomatic diagnosis study.
Easy-to-collect epidemiological information is critical for the more accurate estimation of the prevalence and burden of different non-communicable diseases around the world. Current measurement is restricted by limitations in existing measurement systems in the developing world and the lack of biometry tests for non-communicable diseases. Diagnosis based on self-reported signs and symptoms ("Symptomatic Diagnosis," or SD) analyzed with computer-based algorithms may be a promising method for collecting timely and reliable information on non-communicable disease prevalence. The objective of this study was to develop and assess the performance of a symptom-based questionnaire to estimate prevalence of non-communicable diseases in low-resource areas. As part of the Population Health Metrics Research Consortium study, we collected 1,379 questionnaires in Mexico from individuals who suffered from a non-communicable disease that had been diagnosed with gold standard diagnostic criteria or individuals who did not suffer from any of the 10 target conditions. To make the diagnosis of non-communicable diseases, we selected the Tariff method, a technique developed for verbal autopsy cause of death calculation. We assessed the performance of this instrument and analytical techniques at the individual and population levels. The questionnaire revealed that the information on health care experience retrieved achieved 66.1% (95% uncertainty interval [UI], 65.6-66.5%) chance corrected concordance with true diagnosis of non-communicable diseases using health care experience and 0.826 (95% UI, 0.818-0.834) accuracy in its ability to calculate fractions of different causes. SD is also capable of outperforming the current estimation techniques for conditions estimated by questionnaire-based methods. SD is a viable method for producing estimates of the prevalence of non-communicable diseases in areas with low health information infrastructure. This technology can provide higher-resolution prevalence data, more flexible data collection, and potentially individual diagnoses for certain conditions.


Arabidopsis jasmonate signaling pathway.
Jasmonates control defense gene expression, growth, and fertility throughout the plant kingdom and have been studied extensively in Arabidopsis thaliana. The prohormone jasmonic acid (JA) is conjugated to amino acids such as isoleucine to form the active hormone jasmonoyl-isoleucine (JA-Ile). A series of breakthroughs has identified the SCF [SCF consists of four subunits: a cullin, SKP1 (S-phase kinase-associated protein 1), a RING finger protein (RBX1/HRT1/ROC1), and an F-box protein] CORONATINE INSENSITIVE1 (COI1) E3 ubiquitin ligase complex and the JASMONATE ZIM-DOMAIN (JAZ) proteins as central components in the perception of and transcriptional response to JA-Ile. JAZ proteins (most probably as dimers) bind transcription factors such as MYC2 before JA-Ile production. JA-Ile binds to COI1 to facilitate the formation of COI1-JAZ complexes, leading to ubiquitination and subsequent degradation of JAZ proteins. The degradation of JAZ proteins liberates transcription factors that function in the presence of the RNA polymerase II coregulatory complex Mediator to permit the expression of a number of jasmonate-regulated genes. Recent developments include the identification of COI1 as a receptor for jasmonates. Upstream of the signaling events, microRNA319 (miR319) negatively regulates the production of JA and JA-derived signals.


Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes.
Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI -0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95% CI -0.38 to -0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: -0.03 SD; 95% CI -0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.


Dissecting the Mechanisms of Doxorubicin and Oxidative Stress-Induced Cytotoxicity: The Involvement of Actin Cytoskeleton and ROCK1.
We have recently reported that ROCK1 deficiency in mouse embryonic fibroblasts (MEF) has superior anti-apoptotic and pro-survival effects than antioxidants against doxorubicin, a chemotherapeutic drug. Although oxidative stress is the most widely accepted mechanism, our studies suggest that ROCK1-dependent actin cytoskeleton remodeling plays a more important role in mediating doxorubicin cytotoxicity on MEFs. To further explore the contributions of ROCK1-dependent actin cytoskeleton remodeling in response to stress, this study investigates the mechanistic differences between the cytotoxic effects of doxorubicin versus hydrogen peroxide (H2O2), with a focus on cytoskeleton alterations, apoptosis and necrosis induction. We found that both types of stress induce caspase activation but with different temporal patterns and magnitudes in MEFs: H2O2 induces the maximal levels (2 to 4-fold) of activation of caspases 3, 8, and 9 within 4 h, while doxorubicin induces much higher maximal levels (15 to 25-fold) of caspases activation at later time points (16-24 h). In addition, necrosis induced by H2O2 reaches maximal levels within 4 h while doxorubicin-induced necrosis largely occurs at 16-24 h secondary to apoptosis. Moreover, both types of stress induce actin cytoskeleton remodeling but with different characteristics: H2O2 induces disruption of stress fibers associated with cytosolic translocation of phosphorylated myosin light chain (p-MLC) from stress fibers, while doxorubicin induces cortical F-actin formation associated with cortical translocation of p-MLC from central stress fibers. Furthermore, N-acetylcysteine (an antioxidant) is a potent suppressor for H2O2-induced cytotoxic effects including caspase activation, necrosis, and cell detachment, but shows a much reduced inhibition on doxorubicin-induced changes. On the other hand, ROCK1 deficiency is a more potent suppressor for the cytotoxic effects induced by doxorubicin than by H2O2. These results support the notion that doxorubicin induces caspase activation, necrosis, and actin cytoskeleton alterations largely through ROCK1-dependent and oxidative stress-independent pathways.


Flipping of the coordinated triazine moiety in Cu(I)-L2 and the small electronic factor, κel, for direct outer-sphere cross reactions: syntheses, crystal structures and redox behaviour of copper(II)/(I)-L2 complexes (L = 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine).
Six-coordinate [Cu(pdt)2(H2O)2](2+) and four-coordinate [Cu(pdt)2](+) complexes were synthesized and the cross redox reactions were studied in acetonitrile (pdt = 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine). Single crystal analyses revealed that [Cu(pdt)2(H2O)2](BF4)2 was of pseudo-D2h symmetry with two axial water molecules and two symmetrically coordinated equatorial pdt ligands, while the coordination structure of [Cu(pdt)2]BF4 was a squashed tetrahedron (dihedral angle = 54.87°) with an asymmetric coordination by two pdt ligands: one pdt ligand was coordinated to Cu(i) through pyridine-N and triazine-N2 while another pdt ligand was coordinated through pyridine-N and triazine-N4, and a stacking interaction between the phenyl ring on one pdt ligand and the triazine ring on another pdt ligand caused the squashed structure and non-equivalent Cu-N bond lengths. The cyclic voltammograms for [Cu(pdt)2(H2O)2](2+) and [Cu(pdt)2](+) in acetonitrile were identical to each other and quasi-reversible. The reduction of [Cu(pdt)2(H2O)2](2+) by decamethylferrocene and the oxidation of [Cu(pdt)2](+) by [Co(2,2'-bipyridine)3](3+) in acetonitrile revealed that both cross reactions were sluggish through a gated process (the structural change took place prior to the electron transfer) accompanied by slow direct electron transfer processes. It was found that the triazine ring of the coordinated pdt ligand rotates around the C-C bond between the triazine and pyridine rings with the kinetic parameters k = 51 ± 5 s(-1) (297.8 K), ΔH(‡) = 6.2 ± 1.1 kJ mol(-1) and ΔS(‡) = -192 ± 4 J mol(-1) K(-1). The electron self-exchange process was directly measured using the line-broadening method: kex = (9.9 ± 0.5) × 10(4) kg mol(-1) s(-1) (297.8 K) with ΔH(‡) = 44 ± 7 kJ mol(-1) and ΔS(‡) = 0.2 ± 2.6 J mol(-1) K(-1). By comparing this rate constant with the self-exchange rate constants estimated from the cross reactions using the Marcus cross relation, the non-adiabaticity (electronic) factors, κel, for the direct electron transfer processes between [Cu(pdt)2](+/2+) and non-copper metal (Fe(2+) and Co(3+)) complexes were estimated as ca. 10(-7), indicating that the electronic coupling between the d orbitals of copper and of non-copper metals is very small.


Cytokine profiles of AIDS patients are similar to those of mice with disseminated Cryptococcus neoformans infection.
Cryptococcosis is an hematogenously disseminated meningoencephalitis during which the relationship between the disease severity and the immune response remains unclear. We thus analyzed, by enzyme-linked immunosorbent assay, proinflammatory (tumor necrosis factor alpha [TNF-alpha] and interleukin-6 [IL-6]) and anti-inflammatory (IL-10) cytokine levels in plasma at the time of diagnosis in 51 AIDS patients with culture-proven cryptococcosis. We used a murine model to determine the correlation between cytokine levels and fungal burden in blood and tissues and the kinetics of the immune response and of the formation of cerebral lesions. In AIDS patients, plasma TNF-alpha and IL-10, but not IL-6, levels were significantly higher in the case of fungemia or disseminated infection than in their absence, whereas the presence of meningitis had no influence on these levels. In mice, none of these cytokines were detected within the first day after inoculation. Later on, TNF-alpha and IL-10, but not IL-6, levels in plasma correlated significantly with the fungal burden in the blood and spleen but not the brain. In the brain, cytokine levels were low compared to those in other compartments, and tissue lesions and a degree of infection similar to those observed in humans were seen, further suggesting the relevance of this experimental model. Thus, AIDS patients with cryptococcosis produce an immune response that reflects the dissemination but not the meningeal involvement. This murine model of disseminated cryptococcosis can be used to investigate the pathophysiology of cryptococcosis and new therapeutic approaches.


The Concise Guide to PHARMACOLOGY 2013/14: overview.
The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties from the IUPHAR database. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. This compilation of the major pharmacological targets is divided into seven areas of focus: G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors & Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates.


Apoptotic cell responses in the splenic marginal zone: a paradigm for immunologic reactions to apoptotic antigens with implications for autoimmunity.
Apoptotic cells drive innate regulatory responses that result in tolerogenic immunity. This is a critical aspect of cell physiology as apoptotic cells expose potentially dangerous nuclear antigens on the surface in apoptotic blebs, and failure in their recognition, phagocytosis, or destruction can cause dramatic autoimmunity in experimental models and is linked to development and progression of systemic pathology in human. The marginal zone is a specialized splenic environment that serves as a transitional site from circulation to peripheral lymphoid structures. The marginal zone serves a key role in trapping of particulates and initiation of innate responses against systemic microbial pathogens. However in recent years, it has become clear the marginal zone is also important for initiation of immune tolerance to apoptotic cells, driving a coordinated response involving multiple phagocyte and lymphocyte subsets. Recent reports linking defects in splenic macrophage function to systemic lupus erythematosus in a manner analogous to marginal zone macrophages in lupus-prone mice provide an impetus to better understand the mechanistic basis of the apoptotic cell response in the marginal zone and its general applicability to apoptotic cell-driven tolerance at other tissue sites. In this review, we discuss immune responses to apoptotic cells in the spleen in general and the marginal zone in particular, the relationship of these responses to autoimmune disease, and comparisons to apoptotic cell immunity in humans.


Bovine steroid 21-hydroxylase: regulation of biosynthesis.
A recombinant cDNA clone, PBC21-1, specific for bovine steroid 21-hydroxylase cytochrome P-450 (P-450C21) was identified in a bovine adrenocortical cDNA library, and this identity was confirmed by nucleotide sequencing which revealed significant amino acid homology (77%) with human P-450C21 cDNA. The pBC21-1 insert is 1.7 kilobases in length and includes a 1128 base pair region that encodes the C-terminal 376 amino acids of bovine P-450C21 as well as 535 base pairs of 3'-untranslated sequence. A novel feature of this insert is a 20 base pair intervening sequence near the 5' end, apparently the result of an aberrant splicing event. Northern blot analysis reveals that bovine P-450C21 is encoded by two transcripts, 2.3 and 2.0 kilobases in length which are detected in adrenal cortical RNA. Bovine liver, heart, kidney, and corpus luteum do not contain detectable P-450C21 transcripts. Regulation of P-450C21 gene expression by adrenocorticotropin was investigated with pBC21-1 and bovine adrenocortical cells in primary, monolayer culture. Treatment with ACTH or analogues of cAMP increases the steady-state levels of P-450C21 RNA in such cell cultures. In vitro transcription run-on assays suggest that this increase is, at least in part, due to the enhanced transcriptional activity of the P-450C21 gene.


Effects of ethanol on excitatory and inhibitory synaptic transmission in rat cortical neurons.
The gamma-aminobutyric acid-A (GABA(A)) receptor and glutamate receptors are among the most important target sites for the behavioral effects of ethanol. However, data in the literature concerning the ethanol modulation of the GABA(A) and glutamate receptors have been controversial. The activity of the neuronal nicotinic acetylcholine (ACh) receptors (nAChRs) has recently been reported to be potently augmented by ethanol. The activation of nAChRs is also known to cause the release of various neurotransmitters including GABA and glutamate. Thus, ethanol potentiation of nAChRs is expected to stimulate the GABAergic and glutamatergic systems. Whole-cell patch clamp experiments were performed using rat cortical neurons in primary culture to record spontaneous miniature inhibitory postsynaptic currents (mIPSCs) and spontaneous miniature excitatory postsynaptic currents (mEPSCs). Two types of neurons were distinguished: bipolar neurons possessed alpha4beta2 nAChRs generating a steady current in response to 30 nM ACh, and multipolar neurons that did not generate a current by ACh application. Acetylcholine greatly increased the frequency of mEPSCs and mIPSCs in bipolar neurons but not in multipolar neurons. The amplitude of neither type of neuron was affected by ACh. Ethanol at 10 to 100 mM suppressed the amplitude of mEPSCs while augmenting the amplitude of mIPSCs in both bipolar and multipolar neurons, indicating the direct action on the respective receptors. In bipolar neurons, ACh plus 100 mM ethanol greatly increased the frequency of mIPSCs beyond the levels achieved by ACh alone, while no such increases were observed in multipolar neurons. It is concluded that ethanol stimulation of nAChRs modulates the activity of both glutamate and GABA receptors in rat cortical bipolar neurons.


Measurement issues across different cultures.
The purposes of this methodologic paper are to (1) describe theoretical background in conducting research across different cultures; (2) address measurement issues related to instrument administration; and (3) provide strategies to deal with measurement issues. A thorough review of the literature was conducted. A theoretical background is provided, and examples of administering instrument in studies are described. When applying an instrument to different cultures, both equivalence and bias need to be established. Three levels of equivalence, i.e., construct equivalence, measurement unit equivalence, and full score comparability, need to be explained to maintain the same concept being measured. In this paper, sources of bias in construct, method, and item are discussed. Issues related to instrument administration in a cross-cultural study are described. Researchers need to acknowledge various group differences in concept and/or language that include a specific set of symbols and norms. There is a need to question the philosophical and conceptual appropriateness of an assessment measure that has been conceptualized and operationalized in a different culture. Additionally, testing different response formats such as narrowing response range can be considered to reduce bias.


TRPV3 mutants causing Olmsted Syndrome induce impaired cell adhesion and nonfunctional lysosomes.
TRPV3 is a non-selective cationic channel and is important for several physiological functions. It can be activated by physiological temperature and selective endogenous and exogenous compounds. TRPV3 is one of the key ion channel involved in Ca2+-signaling in keratinocyte and thus involved in skin-related functions. Recently, naturally occurring mutations in TRPV3, namely G573A, G573S, G573C and W692G have been detected which are linked with the development of pathophysiological conditions such as Olmsted Syndrome (OS) and other skin disorders. Our qualitative and quantitative data suggests that these naturally occurring TRPV3 mutants are mainly restricted in the ER. Expression of OS-mutants cause impaired vesicular trafficking resulting reduced surface localization of these mutants and other membrane proteins too. OS-mutants also cause reduced cell adhesion, altered distribution and less number of lysosomes. Our data confirms that TRPV3 is a lysosomal protein suggesting that Olmsted Syndrome is a lysosomal disorder. These findings may have a broad implication in the context of keratinocyte functions, skin-degeneration and in skin-cancer.