Epidemiology and (Patho)Physiology of Folic Acid Supplement Use in Obese Women before and during Pregnancy.
Preconception folic acid supplement use is a well-known method of primary prevention of neural tube defects (NTDs). Obese women are at a higher risk for having a child with a NTD. As different international recommendations on folic acid supplement use for obese women before and during pregnancy exist, this narrative review provides an overview of epidemiology of folate deficiency in obese (pre)pregnant women, elaborates on potential mechanisms underlying folate deficiency, and discusses considerations for the usage of higher doses of folic acid supplements. Women with obesity more often suffer from an absolute folate deficiency, as they are less compliant to periconceptional folic acid supplement use recommendations. In addition, their dietary folate intake is limited due to an unbalanced diet (relative malnutrition). The association of obesity and NTDs also seems to be independent of folate intake, with studies suggesting an increased need of folate (relative deficiency) due to derangements involved in other pathways. The relative folate deficiency, as a result of an increased metabolic need for folate in obese women, can be due to: (1) low-grade chronic inflammation (2) insulin resistance, (3) inositol, and (4) dysbiotic gut microbiome, which plays a role in folate production and uptake. In all these pathways, the folate-dependent one-carbon metabolism is involved. In conclusion, scientific evidence of the involvement of several folate-related pathways implies to increase the recommended folic acid supplementation in obese women. However, the physiological uptake of synthetic folic acid is limited and side-effects of unmetabolized folic acid in mothers and offspring, in particular variations in epigenetic (re)programming with long-term health effects, cannot be excluded. Therefore, we emphasize on the urgent need for further research and preconception personalized counseling on folate status, lifestyle, and medical conditions.


Goal-driven attentional capture by appetitive and aversive smoking-related cues in nicotine-dependent smokers.
Conventionally, involuntary attentional capture by tobacco cues in smokers are seen as an implicit bias, operating independently of current search goals. Prominent attention research, however, has suggested that search goals can induce an involuntary attentional capture. In the current investigation, we tested whether appetitive and aversive smoking images affected attention through such a mechanism and whether there were group differences based on nicotine dependence. We instructed non-smokers (NS), occasional smokers (OS; low dependence), and nicotine-dependent smokers (NDS; moderate-high dependence), to hold search goals for either an aversive or appetitive smoking category, or a category of non-smoking images. These images were presented in a stream of briefly appearing filler images, while task-irrelevant distractors were presented outside the stream. Distractors could be aversive or appetitive smoking images or a category of non-smoking images. Therefore, in some conditions, the distractors matched the current category being searched for, while in others it was incongruent. Task-irrelevant smoking distractors reduced target detection, compared to the non-smoking distractors, only when they were congruent with the specific category being searched for. There was no effect of either aversive or appetitive smoking distractors on performance when participants were searching for the non-smoking targets. Distractor interference did not differ between smokers and non-smokers. The results support a goal-driven mechanism underpinning involuntary attentional capture by smoking cues. These findings can be used to inform models of addiction and attention, and the display of health warnings.


Screening for colorectal cancer and advanced colorectal neoplasia in kidney transplant recipients: cross sectional prevalence and diagnostic accuracy study of faecal immunochemical testing for haemoglobin and colonoscopy.
To investigate whether screening kidney transplant recipients aged over 50 years for colorectal cancer with a faecal immunochemical test for haemoglobin might be justified, by determining the prevalence of advanced colorectal neoplasia and evaluating the diagnostic accuracy of faecal haemoglobin testing compared with colonoscopy in a population of kidney transplant recipients at otherwise average risk. Cross sectional prevalence and diagnostic accuracy study with index test of faecal haemoglobin and reference standard of colonoscopy. Outpatient clinics in metropolitan and regional hospitals in South Australia. 229 kidney transplant recipients aged 50 years and over, who were at least 6 months (mean 9.0 (SD 8.4) years) post-transplant and otherwise at average risk of colorectal cancer, completed the study between June 2008 and October 2011. Faecal immunochemical testing (Enterix Insure) for human haemoglobin, followed by colonoscopy with histological evaluation of retrieved samples. Prevalence of advanced colorectal neoplasia, defined as an adenoma at least 10 mm in diameter, villous features, high grade dysplasia, or colorectal cancer; sensitivity, specificity, and predictive values of faecal haemoglobin testing for advanced neoplasia compared with colonoscopy. Advanced colorectal neoplasia was found in 29 (13%, 95% confidence interval 9% to 18%) participants, including 2% (n=4) with high grade dysplasia and 2% (n=5) with colorectal cancer. Faecal testing for haemoglobin was positive in 12% (n=28); sensitivity, specificity, and positive and negative predictive values for advanced neoplasia were 31.0% (15.3% to 50.8%), 90.5% (85.6% to 94.2%), 32.1% (15.9% to 52.4%), and 90.1% (85.1% to 93.8%). Colonoscopy was well tolerated, with no significant adverse outcomes. To identify one case of advanced neoplasia, 8 (6 to 12) colonoscopies were needed. Kidney transplant recipients aged over 50 years have a high prevalence of advanced colorectal neoplasia. Faecal haemoglobin screening for colorectal neoplasia has similar performance characteristics in transplant recipients to those reported in general population studies, with poor sensitivity but reasonable specificity. Surveillance colonoscopy might be a more appropriate approach in this population. Australian New Zealand Clinical Trials Registry ACTRN12608000154303.


Interpretation of bronchodilator response in patients with obstructive airways disease. The Dutch Chronic Non-Specific Lung Disease (CNSLD) Study Group.
There is no agreement on how a bronchodilator response should be expressed. Ideally, the index used should be able to distinguish asthma from chronic obstructive lung disease and be independent of initial FEV1. Two hundred and seventy four adults (aged 18-60 years) outpatients with obstructive airways disease were studied. Patients were divided into syndrome groups on the basis of a standardised history: asthma (n = 99), asthmatic bronchitis (n = 88), and chronic obstructive lung disease (n = 51); 36 subjects could not be attributed to any subgroup. FEV1 was measured before and 20 minutes after inhalation of 1000 micrograms terbutaline. Different expressions of bronchodilator response (delta FEV1) were compared with respect to their dependence on initial FEV1 and their efficacy in separating subjects with asthma from those with chronic obstructive lung disease. delta FEV1 was expressed as a percentage of initial FEV1 (delta FEV1%init), absolute value (delta FEV1[1]), percentage of predicted FEV1 (delta FEV1%pred), standardised residual (delta SR-FEV1), and percentage of maximal possible increase (delta FEV1%[pred-init]). delta FEV1%init was more dependent on initial FEV1 (p = -0.405) than delta FEV1[1] (r = -0.145), delta FEV1%pred (r = -0.166), and delta SR-FEV1 (r = -0.127). delta FEV1%[pred-init] reached infinity when initial FEV1 approached predicted levels. delta FEV1%pred had a higher likelihood ratio (1.71) for separating patients with asthma from those with chronic obstructive lung disease than other expressions of bronchodilator response. Asthmatic patients had larger mean bronchodilator responses than patients in other subgroups; this difference was largest for delta SR-FEV1 (F = 9.19) and delta FEV1%pred (F = 9.03); it was much smaller for delta FEV1%init (F = 5.89). Despite significant differences in mean response, there was a large overlap of individual responses between diagnostic subgroups. The bronchodilator response was continuously and unimodally distributed for all expressions. delta FEV1%pred appears to be the most useful method of expressing bronchodilator response, both for clinical and for research purposes. Reversibility of airways obstruction in response to a bronchodilator is a continuous variable and not a dichotomous triat. Any cut off level of a "positive" bronchodilator response is therefore arbitrary.


Health related quality of life (HRQOL) in long-term survivors of pediatric low grade gliomas (LGGs).
The purpose of this study was to assess the health-related quality of life (HRQOL) and the impact of treatment on HRQOL in long-term survivors of pediatric low-grade gliomas (LGGs) using an adult instrument. QOL of 121 patients with a diagnosis of LGG from the Mayo Clinic were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30 for cancer in general) and (EORTC QLQ-BN20 specific for brain tumors). Median follow-up was 21.9 years for the participants. Median age at diagnosis was 11.8 years and at assessment was 33 years. Mean (standard deviation) global QOL score for the study was 78 (18) and 76.4 (22.8) in a reference population of healthy adults. Using QLQ-C30, radiation treated patients compared to non-radiation patients reported lower physical functioning (p = 0.002), role functioning (p = 0.004), and more constipation problems (p < 0.001). Patients with tumor recurrence reported lower role functioning (p = 0.016), social functioning (p = 0.040), and more financial problems (p = 0.029) compared to their counterparts. Using QLQ-BN20, patients with deep tumors compared to cortical tumors reported more bladder control problems (p = 0.016). Radiation treated patients also reported more bladder control problems (p < 0.001) compared to their counterparts. In the multivariable analysis, radiation therapy remained an independent predictor of physical and role functioning as well as symptoms related to brain tumors like visual disorders and motor dysfunction. Global QOL of long-term survivors of pediatric LGGs is similar to that of a reference population of healthy adults. The following tumor and treatment related factors were most consistently associated with poorer QOL: CNS tumor location, post-operative radiation, and tumor recurrence. Future studies are necessary to identify strategies to improve QOL in this subgroup of patients.


Integrative workflows for network analysis.
Due to genetic heterogeneity across patients, the identification of effective disease signatures and therapeutic targets is challenging. Addressing this challenge, we have previously developed a network-based approach, which integrates heterogeneous sources of biological information to identify disease specific core-regulatory networks. In particular, our workflow uses a multi-objective optimization function to calculate a ranking score for network components (e.g. feedback/feedforward loops) based on network properties, biomedical and high-throughput expression data. High ranked network components are merged to identify the core-regulatory network(s) that is then subjected to dynamical analysis using stimulus-response and in silico perturbation experiments for the identification of disease gene signatures and therapeutic targets. In a case study, we implemented our workflow to identify bladder and breast cancer specific core-regulatory networks underlying epithelial-mesenchymal transition from the E2F1 molecular interaction map.In this study, we review our workflow and described how it has developed over time to understand the mechanisms underlying disease progression and prediction of signatures for clinical decision making.


A Warning against the Negligent Use of Cannabidiol in Professional and Amateur Athletes.
Cannabidiol (CBD) is a non-psychoactive cannabinoid, widely marketed to athletes for claimed effects such as decreased anxiety, fear memory extinction, anti-inflammatory properties, relief of pain and for post-exercise recovery. The World Anti-Doping Agency (WADA) has excluded CBD from its list of prohibited substances. Nevertheless, caution is currently advised for athletes intending to use the compound-except CBD, all other cannabinoids are still on the prohibited list. CBD products, specifically non-medicinal, so-called full-spectrum cannabis extracts, may contain significant levels of these substances, but also contaminations of tetrahydrocannabinol (THC) (>2.5 mg/day in >30% of products on the German market) potentially leading to positive doping tests. Labelled claims about CBD content and absence of THC are often false and misleading. Contaminations with the psychoactive THC can result in adverse effects on cognition and, in general, the safety profile of CBD with respect to its toxicity is a controversial topic of discussion. For these reasons, we would currently advise against the use of over-the-counter CBD products, especially those from dubious internet sources without quality control.


Quantitative methods for indirect CT lymphography.
In this investigation, we applied quantitative CT methods to characterize contrast enhanced lymph nodes opacified using iodinated contrast media for indirect CT lymphography. Iodinated nanoparticles were injected into the buccal submucosa and SQ into the metatarsus and metacarpus of four normal swine (1.0-4.0 ml/site, 76 mg I/ml). Attenuation (HU), volume (cm3), iodine concentration (mg I/cm3), total iodine uptake (mg I), contrast-to-noise ratio (CNR), and percent injected dose (%ID) were estimated in opacified inguinal, cervical and parotid/mandibular lymph nodes using manual image segmentation techniques on 24 hour post-contrast CT images. Lymph node volumes estimated by multiple slice ROI analysis were compared with estimates obtained by post-excisional weight measurements. HU and iodine concentration increased 5-20 fold in opacified nodes (p < 0.01) and CNR increased more than four-fold (p < 0.001). %ID ranged between 3.5 and 11.9% and did not appear dose related. ROI estimated lymph node volumes approximated volumes calculated from weight measurements. (R2 = 0.94, p < 0.0001). We conclude that interstitially injected iodinated nanoparticles increase attenuation and conspicuity of targeted nodes on CT images. Quantitative methods could play an important clinical role in more accurate metastasis detection.


Synthetic nanocircular RNA for controlling of gene expression.
We designed and synthesized dumbbell-shaped nanocircular RNAs for RNA interference applications, which consist of a stem and two loops(1). RNA dumbbells are specifically recognized and cleaved by the human Dicer enzyme, and are thus transformed into double-stranded RNA in cells, although this RNA is resistant to degradation in serum. The structure was optimized to maximize its RNAi activity. The most potent activity was achieved when the stem length was 23 base pairs. The RNAi activity is prolonged by the shape of the molecule, an endless structure, compared with that of normal siRNA.


Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: a systematic review.
Electronic cigarettes are a recent development in tobacco harm reduction. They are marketed as less harmful alternatives to smoking. Awareness and use of these devices has grown exponentially in recent years, with millions of people currently using them. This systematic review appraises existing laboratory and clinical research on the potential risks from electronic cigarette use, compared with the well-established devastating effects of smoking tobacco cigarettes. Currently available evidence indicates that electronic cigarettes are by far a less harmful alternative to smoking and significant health benefits are expected in smokers who switch from tobacco to electronic cigarettes. Research will help make electronic cigarettes more effective as smoking substitutes and will better define and further reduce residual risks from use to as low as possible, by establishing appropriate quality control and standards.


Mature results of a phase II study of rituximab therapy for nodular lymphocyte-predominant Hodgkin lymphoma.
Universal expression of CD20 by malignant cells in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) led us to evaluate rituximab (R) as a therapeutic option. Patients with previously treated or newly diagnosed NLPHL were treated with R (375 mg/m(2) once per week for 4 weeks) or, after a protocol amendment, with R plus R maintenance (MR; administered once every 6 months for 2 years). Primary and secondary outcome measures were progression-free survival (PFS) and overall response rate (ORR), respectively. A total of 39 patients were enrolled (R, n = 23; R + MR, n = 16). After four once-per-week treatments, ORR was 100% (complete response, 67%; partial response, 33%). At median follow-ups of 9.8 years for R and 5 years for R + MR, median PFS were 3 and 5.6 years (P = .26), respectively; median overall survival (OS) was not reached. Estimated 5-year PFS and OS for patients treated with R versus R + MR were 39.1% (95% CI, 23.5 to 65.1) and 95.7% (95% CI, 87.7 to 100) versus 58.9% (95% CI, 38.0 to 91.2) and 85.7% (95% CI, 69.2 to 100), respectively. Nine of 23 patients experiencing relapse had evidence of transformation to aggressive B-cell lymphoma; six of these patients had infradiaphragmatic involvement at study entry. R is an active agent in NLPHL. Although responses are not durable in most patients, a significant minority experience remissions lasting > 5 years. R + MR results in a nonsignificant increase in PFS compared with R. R may be considered in the relapsed setting for NLPHL. The potential for transformation of NLPHL to aggressive B-cell lymphoma underscores the importance of rebiopsy and long-term follow-up.


GLUT2 in pancreatic islets: crucial target molecule in diabetes induced with multiple low doses of streptozotocin in mice.
In mice, diabetes can be induced by multiple low doses of streptozotocin (MLD-STZ), i.e., 40 mg/kg body wt on each of 5 consecutive days. In this model, diabetes develops only when STZ induces both beta-cell toxicity and T-cell-dependent immune reactions. The target molecule(s) of MLD-STZ-induced beta-cell toxicity are not known, however. In this study, we report that GLUT2 is a target molecule for MLD-STZ toxicity. Ex vivo, a gradual decrement of both GLUT2 protein and mRNA expression was found in pancreatic islets isolated from MLD-STZ-treated C57BL/6 male mice, whereas mRNA expression of beta-actin, glucokinase, and proinsulin remained unaffected. Significant reduction of both GLUT2 protein and mRNA expression was first noted 1 day after the third STZ injection, clearly preceding the onset of hyperglycemia. The extent of reduction increased with the number of STZ injections administered and increased over time, after the last, i.e., fifth, STZ injection. The STZ-induced reduction of GLUT2 protein and mRNA was not due to an essential loss of beta-cells, because ex vivo, not only the total RNA yield and protein content in isolated islets, but also proinsulin mRNA expression, failed to differ significantly in the differently treated groups. Furthermore, islets isolated from MLD-STZ-treated donors responded to the nonglucose secretagogue arginine in a pattern similar to that of solvent-treated donors. Interestingly, the MLD-STZ-induced reduction of both GLUT2 protein and mRNA was prevented by preinjecting mice with 5-thio-D-glucose before each STZ injection. Apparently, GLUT2 is a crucial target molecule of MLD-STZ toxicity, and this toxicity seems to precede the immune reactions against beta-cells.


Novel transthyretin amyloid fibril formation inhibitors: synthesis, biological evaluation, and X-ray structural analysis.
Transthyretin (TTR) is one of thirty non-homologous proteins whose misfolding, dissociation, aggregation, and deposition is linked to human amyloid diseases. Previous studies have identified that TTR amyloidogenesis can be inhibited through stabilization of the native tetramer state by small molecule binding to the thyroid hormone sites of TTR. We have evaluated a new series of beta-aminoxypropionic acids (compounds 5-21), with a single aromatic moiety (aryl or fluorenyl) linked through a flexible oxime tether to a carboxylic acid. These compounds are structurally distinct from the native ligand thyroxine and typical halogenated biaryl NSAID-like inhibitors to avoid off-target hormonal or anti-inflammatory activity. Based on an in vitro fibril formation assay, five of these compounds showed significant inhibition of TTR amyloidogenesis, with two fluorenyl compounds displaying inhibitor efficacy comparable to the well-known TTR inhibitor diflunisal. Fluorenyl 15 is the most potent compound in this series and importantly does not show off-target anti-inflammatory activity. Crystal structures of the TTR:inhibitor complexes, in agreement with molecular docking studies, revealed that the aromatic moiety, linked to the sp(2)-hybridized oxime carbon, specifically directed the ligand in either a forward or reverse binding mode. Compared to the aryl family members, the bulkier fluorenyl analogs achieved more extensive interactions with the binding pockets of TTR and demonstrated better inhibitory activity in the fibril formation assay. Preliminary optimization efforts are described that focused on replacement of the C-terminal acid in both the aryl and fluorenyl series (compounds 22-32). The compounds presented here constitute a new class of TTR inhibitors that may hold promise in treating amyloid diseases associated with TTR misfolding.


Multiple markers contribute to risk of progression from normal to mild cognitive impairment.
To identify a parsimonious set of markers that optimally predicts subsequent clinical progression from normal to mild cognitive impairment (MCI). 250 clinically normal adults (mean age = 73.6 years, SD = 6.0) from the Harvard Aging Brain Study were assessed at baseline on a wide set of markers, including magnetic resonance imaging markers of gray matter thickness and volume, white matter lesions, fractional anisotropy, resting state functional connectivity, positron emission tomography markers of glucose metabolism and β-amyloid (Aβ) burden, and a measure of vascular risk. Participants were also tested annually on a battery of clinical and cognitive tests (median follow-up = 5.0 years, SD = 1.66). We applied least absolute shrinkage and selection operator (LASSO) Cox models to determine the minimum set of non-redundant markers that predicts subsequent clinical progression from normal to MCI, adjusting for age, sex, and education. 23 participants (9.2%) progressed to MCI over the study period (mean years of follow-up to diagnosis = 3.96, SD = 1.89). Progression was predicted by several brain markers, including reduced entorhinal thickness (hazard ratio, HR = 1.73), greater Aβ burden (HR = 1.58), lower default network connectivity (HR = 1.42), and smaller hippocampal volume (HR = 1.30). When cognitive test scores were added to the model, the aforementioned neuroimaging markers remained significant and lower striatum volume as well as lower scores on baseline memory and processing speed tests additionally contributed to progression. Among a large set of brain, vascular and cognitive markers, a subset of markers independently predicted progression from normal to MCI. These markers may enhance risk stratification by identifying clinically normal individuals who are most likely to develop clinical symptoms and would likely benefit most from therapeutic intervention.


Phase locked neural activity in the human brainstem predicts preference for musical consonance.
When musical notes are combined to make a chord, the closeness of fit of the combined spectrum to a single harmonic series (the 'harmonicity' of the chord) predicts the perceived consonance (how pleasant and stable the chord sounds; McDermott, Lehr, & Oxenham, 2010). The distinction between consonance and dissonance is central to Western musical form. Harmonicity is represented in the temporal firing patterns of populations of brainstem neurons. The current study investigates the role of brainstem temporal coding of harmonicity in the perception of consonance. Individual preference for consonant over dissonant chords was measured using a rating scale for pairs of simultaneous notes. In order to investigate the effects of cochlear interactions, notes were presented in two ways: both notes to both ears or each note to different ears. The electrophysiological frequency following response (FFR), reflecting sustained neural activity in the brainstem synchronised to the stimulus, was also measured. When both notes were presented to both ears the perceptual distinction between consonant and dissonant chords was stronger than when the notes were presented to different ears. In the condition in which both notes were presented to the both ears additional low-frequency components, corresponding to difference tones resulting from nonlinear cochlear processing, were observable in the FFR effectively enhancing the neural harmonicity of consonant chords but not dissonant chords. Suppressing the cochlear envelope component of the FFR also suppressed the additional frequency components. This suggests that, in the case of consonant chords, difference tones generated by interactions between notes in the cochlea enhance the perception of consonance. Furthermore, individuals with a greater distinction between consonant and dissonant chords in the FFR to individual harmonics had a stronger preference for consonant over dissonant chords. Overall, the results provide compelling evidence for the role of neural temporal coding in the perception of consonance, and suggest that the representation of harmonicity in phase locked neural firing drives the perception of consonance.


Patterns of failure and predictors of outcome in cutaneous malignant melanoma of the scalp.
Patients with melanoma of the scalp may have higher failure (recurrence) rates than melanoma of other body sites. We sought to characterize survival and patterns of failure for patients with scalp melanoma. Between 1998 and 2010, 250 nonmetastatic patients underwent wide local excision of a primary scalp melanoma. Kaplan-Meier analyses were performed to evaluate overall survival, scalp control, regional neck control, distant metastases-free survival, and disease-free survival. Five-year overall survival was 86%, 57%, and 45% for stages I, II, and III, respectively, and 5-year scalp control rates were 92%, 75%, and 63%, respectively. Five-year distant metastases-free survival for these stages were 92%, 65%, and 45%, respectively. Of the 74 patients who recurred, the site of first recurrence included distant disease in 47%, although 31% recurred in the scalp alone. This is a retrospective review. Distant metastases-free survival and overall survival for stage II and III patients with scalp melanoma are poor, and stage III patients experience relatively high rates of scalp failure suggesting that these patients may benefit from additional adjuvant systemic and local therapy. Further research is needed to characterize the environmental, microenvironmental, and genetic causes of the increased aggressiveness of scalp melanoma and to identify more effective treatment and surveillance methods.


Blockade of RBP-J-Mediated Notch Signaling Pathway Exacerbates Cardiac Remodeling after Infarction by Increasing Apoptosis in Mice.
Ischemic heart disease (IHD) is the major cause of death in patients with cardiovascular disease. Cardiac remodeling is a common pathological change following myocardial infarction (MI), and cardiomyocyte apoptosis plays a key role in this change. Transcription factor recombination signal-binding protein-J (RBP-J)-mediated Notch signaling pathway has been implicated in several inherited cardiovascular diseases, including aortic valve diseases, but whether the RBP-J-mediated Notch signaling pathway plays a role in cardiomyocyte apoptosis after MI is unclear. We crossed RBP-Jfl/fl mice and Myh6-Cre/Esr1 transgenic mice to delete RBP-J in vivo and to partly inhibit the canonical Notch signaling pathway. MI was induced in mice by permanent ligation of the left anterior descending coronary artery followed by the knockout of RBP-J. Cardiac function and morphology were assessed by echocardiography and histological analysis 4 weeks after infarction. In addition, the expression and regulation of apoptosis-related molecules were examined by real time PCR and western blot. RBP-J knockout decreased the survival rate and deteriorated post-MI remodeling and function in mice, and this effect was associated with increased cardiomyocyte apoptosis. The potential mechanisms might be related to the downregulated expression of bcl-2, upregulated expression of bax, and cleaved-caspase 3 to exacerbate cardiomyocyte apoptosis. These findings show that the RBP-J-mediated Notch signaling pathway in cardiomyocytes limits ventricular remodeling and improves cardiac function after MI. The RBP-J-mediated Notch signaling pathway has a protective role in cardiomyocyte apoptosis following cardiac injury.


The Italian version of the Pain Beliefs and Perceptions Inventory: cross-cultural adaptation, factor analysis, reliability and validity.
To create an Italian version of the Pain Beliefs and Perceptions Inventory (PBAPI-I) and evaluate its psychometric properties. The PBAPI was culturally adapted in accordance with international standards. The psychometric testing included factor analysis, investigating reliability by internal consistency (Cronbach's alpha) and test/retest stability (intraclass correlation coefficient, ICC), and exploring construct validity by comparing the PBAPI-I with a pain numerical rating scale (NRS), the Roland Morris Disability Questionnaire (RMDQ), the Pain Catastrophizing Scale (PCS), the Tampa Scale of Kinesiophobia (TSK), the Hospital Anxiety and Depression Score (HADS) and the Chronic Pain Coping Inventory (Pearson's correlation). One hundred and sixty-seven subjects with chronic low back pain (83 % compliance) completed the tool. Factor analysis revealed a three-factor (Time, Mystery and Self-Blame), 16-item solution (explained variance: 80 %). The questionnaire was internally consistent (α = 0.91-0.96), and its stability was good (ICCs = 0.73-0.82). As expected, the construct validity estimates indicated that the Time and Mystery subscales moderately correlated with the NRS (r = 0.33-0.54), RMDQ (r = 0.34-0.47), PCS (r = 0.37-0.49) and TSK (r = 0.30-0.43), whereas the correlations between the Self-Blame subscale and the same measures were poorer. The correlations with the HADS were moderate and poor (anxiety: r = 0.37-0.05; depression: r = 0.39-0.07). Maladaptive coping strategies were more related to pain beliefs than adaptive strategies. The PBAPI-I has good psychometric properties that replicate those of other versions.


Allocentric spatial memory in humans with hippocampal lesions.
An immersive virtual reality (IVR) system was used to investigate allocentric spatial memory in a patient (PR) who had selective hippocampal damage, and also in patients who had undergone unilateral temporal lobectomies (17 right TL and 19 left TL), their performance compared against normal control groups. A human analogue of the Olton [Olton (1979). Hippocampus, space, and memory. Behavioural Brain Science, 2, 315] spatial maze was developed, consisting of a virtual room, a central virtual circular table and an array of radially arranged up-turned 'shells.' The participant had to search these shells in turn in order to find a blue 'cube' that would then 'move' to another location and so on, until all the shells had been target locations. Within-search errors could be made when the participants returned to a previously visited location during a search, and between-search errors when they revisited previously successful, but now incorrect locations. PR made significantly more between-search errors than his control group, but showed no increase in within-search errors. The right TL group showed a similar pattern of impairment, but the left TL group showed no impairment. This finding implicates the right hippocampal formation in spatial memory functioning in a scenario in which the visual environment was controlled so as to eliminate extraneous visual cues.


Compassion Fatigue among Healthcare, Emergency and Community Service Workers: A Systematic Review.
Compassion fatigue (CF) is stress resulting from exposure to a traumatized individual. CF has been described as the convergence of secondary traumatic stress (STS) and cumulative burnout (BO), a state of physical and mental exhaustion caused by a depleted ability to cope with one's everyday environment. Professionals regularly exposed to the traumatic experiences of the people they service, such as healthcare, emergency and community service workers, are particularly susceptible to developing CF. This can impact standards of patient care, relationships with colleagues, or lead to more serious mental health conditions such as posttraumatic stress disorder (PTSD), anxiety or depression. A systematic review of the effectiveness of interventions to reduce CF in healthcare, emergency and community service workers was conducted. Thirteen relevant studies were identified, the majority of which were conducted on nurses (n = 10). Three included studies focused on community service workers (social workers, disability sector workers), while no studies targeting emergency service workers were identified. Seven studies reported a significant difference post-intervention in BO (n = 4) or STS (n = 3). This review revealed that evidence of the effectiveness of CF interventions in at-risk health and social care professions is relatively recent. Therefore, we recommend more research to determine how best to protect vulnerable workers at work to prevent not only CF, but also the health and economic consequences related to the ensuing, and more disabling, physical and mental health outcomes.


Epidemic hand, foot and mouth disease caused by human enterovirus 71, Singapore.
Singapore experienced a large epidemic of hand, foot and mouth disease (HFMD) in 2000. After reviewing HFMD notifications from doctors and child-care centers, we found that the incidence of HFMD rose in September and declined at the end of October. During this period, 3,790 cases were reported. We performed enteroviral cultures on 311 and 157 specimens from 175 HFMD patients and 107 non-HFMD patients, respectively; human enterovirus 71 (HEV71) was the most frequently isolated virus from both groups. Most of the HFMD patients were </=4 years of age. Three HFMD and two non-HFMD patients died. Specimens from two HFMD and both non-HFMD patients were culture positive for HEV71; a third patient was possibly associated with the virus. Autopsies performed on all three HFMD and one of the non-HFMD case-patients showed encephalitis, interstitial pneumonitis, and myocarditis. A preparedness plan for severe HFMD outbreaks provided for the prompt, coordinated actions needed to control the epidemic.


Routine off-pump coronary artery bypass grafting is safe and feasible in high-risk patients with left main disease.
Coronary artery bypass graft surgery (CABG) remains the method of choice for patients with left main disease (LMD). The precise role of off-pump coronary artery bypass graft surgery (OPCABG) remains unclear in this setting. We report the safety and feasibility of a routine OPCABG approach to patients with LMD. From 2002 to 2007, 983 patients underwent myocardial revascularization at our institution. We compared 343 OPCABG patients with LMD (group A) to 640 OPCABG patients without LMD (group B). The relationship between the presence of LMD and outcome in OPCABG procedures was statistically assessed. A composite endpoint (30-day mortality, postoperative renal failure, intensive care unit length of stay [>2 days], neurologic complications, use of intra-aortic balloon pump, and conversion to cardiopulmonary bypass) was also used. In addition, completeness of revascularization was compared in both groups. Group A had a lower mortality rate (1.7% versus 2.2%; p=0.81), and no differences were noted in conversion to cardiopulmonary bypass (6.7% versus 5.3%; p=0.39), intra-aortic balloon pump use (0.3% versus 1.4%; p=0.18), and occurrence of composite endpoint (30.9% versus 30.8%; p=0.99). The number of arterial grafts per patient was significantly higher among patients in group A (1.77+/-0.95 versus 1.66+/-0.95; p=0.029) owing to the more frequent use of the right internal mammary artery (49.6% versus 42.3%; p=0.031), whereas the total number of distal anastomoses (3.72+/-0.90 versus 3.62+/-1.01; p=0.28) and complete revascularization (94% versus 95%; p=0.55) were similar. Logistic regression confirmed that LMD is no risk factor for the occurrence of our composite endpoint (odds ratio 1.00; 95% confidence interval: 0.75 to 1.33; p=0.99). A modern OPCABG approach offers low mortality, excellent clinical outcomes, and does not come at the price of less complete revascularization in these high-risk patients.


Induction of lateral lumens through disruption of a monoleucine-based basolateral-sorting motif in betacellulin.
Directed delivery of EGF receptor (EGFR) ligands to the apical or basolateral surface is a crucial regulatory step in the initiation of EGFR signaling in polarized epithelial cells. Herein, we show that the EGFR ligand betacellulin (BTC) is preferentially sorted to the basolateral surface of polarized MDCK cells. By using sequential truncations and site-directed mutagenesis within the BTC cytoplasmic domain, combined with selective cell-surface biotinylation and immunofluorescence, we have uncovered a monoleucine-based basolateral-sorting motif (EExxxL, specifically (156)EEMETL(161)). Disruption of this sorting motif led to equivalent apical and basolateral localization of BTC. Unlike other EGFR ligands, BTC mistrafficking induced formation of lateral lumens in polarized MDCK cells, and this process was significantly attenuated by inhibition of EGFR. Additionally, expression of a cancer-associated somatic BTC mutation (E156K) led to BTC mistrafficking and induced lateral lumens in MDCK cells. Overexpression of BTC, especially mistrafficking forms, increased the growth of MDCK cells. These results uncover a unique role for BTC mistrafficking in promoting epithelial reorganization.


Luminescent lanthanide metal-organic frameworks for chemical sensing and toxic anion detection.
Prototype lanthanide metal-organic frameworks (LnMOFs), Ln(BTC) (Ln = Eu and Tb; BTC = benzene-1,3,5-tricarboxylate), have been considered as luminescent sensors for detecting toxic anions, while their neutral pore structures have limited the entrance and encapsulation of anions to produce highly anion-responsive photoluminescence (PL). To facilitate anions to enter the pore space of Ln(BTC), a one-pot synthesis method was proposed in which BTC was partially replaced with its structural analogue L·BF4 (H3L·BF4 = 2,4,6-tricarboxy-1-methylpyridinium tetrafluoroborate) which consists of an anion affinity site of cationic methylpyridinium. Compared to the original Ln(BTC), the co-doped cationic framework Eu0.05Tb0.95-BTC0.9L0.1 is highly sensitive for detecting different toxic anions by tuning the energy absorption of organic chromophores, the energy transfer efficiency to Ln3+ ions and the energy allocation between different Ln3+ ions in the PL spectra. We demonstrated that the Eu0.05Tb0.95-BTC0.9L0.1 PL sensor has the capability of decoding various toxic anions with a clearly differentiable and unique emission intensity ratio of 5D4 → 7F5 (Tb3+, 545 nm) to 5D0 → 7F2 (Eu3+, 618 nm) transitions (ITb/IEu). Compared to Ln(BTC), the co-doped Eu0.05Tb0.95-BTC0.9L0.1 presents self-calibrating, high distinguishable and stable PL signals for detecting toxic anions.


A longitudinal study of pretend play in autism.
This study describes a longitudinal design (following subjects described in Rutherford & Rogers [2003, Journal of Autism and Developmental Disorder, 33, 289-302]) to test for predictors of pretend play competence in a group of children with autism. We tested the hypothesis that developmental change in pretend play performance can be predicted by earlier measures of either executive function, intersubjectivity, imitation, or general development. Participants at the time of follow-up testing were 28 children with autistic disorder (mean chronological age (CA) 57.6 months), 18 children with other developmental disorders (mean CA 59.0 months), and 27 typically developing children (mean CA 30.1 months). Children with autism were profoundly delayed given both competence (prompted) measures as well as performance (spontaneous) measures. Joint attention at time 1 strongly and uniquely predicted pretend play development.


Nano-composite insert in 1D waveguides for control of elastic power flow.
In this paper, carbon nanotube embedded polymer composite/nano-composites are used to regulate power flow from its source to other parts of the structure. This is done by inserting nano-composite strips in the waveguides which are modelled here as isotropic Euler-Bernoulli beams with axial, transverse and rotational degrees of freedom. The power flow is due to wave propagation resulting from a high frequency broadband impulse load. The underlying concept is that the high stiffness of the insert reduces the wave transmission between different parts of the structures. The simulations are done using a wavelet based spectral finite element (WSFE) technique which is specially tailored for such high frequency wave propagation analysis. Numerical experiments are performed to illustrate the use of inserts in maintaining the power flow in a certain region of the structure below a given threshold value which may be specified depending on various applications. The effects of parameters such as the volume fraction of carbon nanotube (CNT) in the polymer, and the length and position of the inserts are also studied. These studies help in defining the optimal volume fraction of CNT and length of the insert for a specified structural configuration.


Natural selection drives altitudinal divergence at the albumin locus in deer mice, Peromyscus maniculatus.
In populations that are distributed across steep environmental gradients, the potential for local adaptation is largely determined by the spatial scale of fitness variation relative to dispersal distance. Since altitudinal gradients are generally characterized by dramatic ecological transitions over relatively short linear distances, adaptive divergence across such gradients will typically require especially strong selection to counterbalance the homogenizing effect of gene flow. Here we report the results of a study that was designed to test for evidence of adaptive divergence across an altitudinal gradient in a natural population of deer mice, Peromyscus maniculatus. We conducted a multilocus survey of allozyme variation across a steep altitudinal gradient in the southern Rocky Mountains that spanned several distinct biomes, from prairie grassland to alpine tundra. As a control for the effects of altitude, we also surveyed the same loci in mice sampled along a latitudinal transect through the prairie grassland that ran perpendicular to the east-west altitudinal transect. We used a coalescent-based simulation model to identify loci that deviated from neutral expectations, and we then assessed whether locus-specific patterns of variation were nonrandom with respect to altitude. Results indicated that the albumin locus (Alb) reflects a history of diversifying selection across the altitudinal gradient. This conclusion is supported by two main lines of evidence: (1) Alb was characterized by levels of divergence across the altitudinal transect that exceeded neutral expectations in two consecutive years of sampling (in contrast to the spatial pattern of variation across the latitudinal transect), and (2) levels of divergence at the Alb locus exhibited a positive association with altitudinal distance in both years (in contrast to the pattern observed at unlinked loci). We conclude that clinal variation at the Alb locus reflects a balance between gene flow and diversifying selection that results from elevational changes in fitness rankings among alternative genotypes.


A gene mapping bottleneck in the translational route from zebrafish to human.
Among a diversity of animal models of disease, the zebrafish is a promising model organism for enabling novel translational biomedical research. To fully achieve the latter, a key requirement is to match molecular readouts measured in zebrafish with information relevant to health and disease in humans. A fundamental step in this direction is to accurately map gene sequences from zebrafish to humans. Despite significant progress in genome annotation, this remains an intricate and time-consuming challenge. Here we discuss major obstacles that we had to overcome to systematically map genes from zebrafish to human. We identified important disparities, as well as partial agreements, between five public zebrafish-to-human homology resources. There is still a need for standardized, comprehensive genomic mappings between zebrafish and humans. Without this, efforts to use zebrafish as a powerful translational research tool will be stalled.


Cryocrystallography of 3-Isopropylmalate dehydrogenase from Thermus thermophilus and its chimeric enzyme.
The crystal structures of thermostable enzyme, 3-isopropylmalate dehydrogenase of Thermus thermophilus (10T) and a chimeric enzyme between T. thermophilus and Bacillus subtilus with one point mutation (cS82R), were determined at both 100 and 150 K. At the cryogenic condition, the volume of the unit cell decreased by 5% as a result of a contraction in the solvent region. Although the overall structures of both enzymes at low temperature were the same as that of 10T at room temperature, interactions between two domains and between two subunits in a functional dimer of cS82R were significantly altered. The decrease in the average temperature factor of 10T at low temperature and no significant decrease for cS82R suggested that the structure of the engineered enzyme (cS82R) may have many conformational substates even at low temperature, while the native enzyme (10T) at low temperature has a more definite conformation than that at room temperature. The location of water molecules around the enzyme molecule and the calculation of the radii of gyration suggested that cS82R had a weaker hydration than 10T.


Phonological codes are assembled before word fixation: evidence from boundary paradigm in sentence reading.
This experiment employed the boundary paradigm during sentence reading to explore the nature of early phonological coding in reading. Fixation durations were shorter when the parafoveal preview was the correct word than when it was a spelling control pseudoword. In contrast, there was no significant difference between correct word and pseudohomophone previews. These results suggest that the phonological codes are assembled before word fixation and are used for lexical access. Moreover, there was evidence that orthographic codes influence the activation of word meaning. We found that fixation durations were shorter for orthographically similar parafoveal previews, and this orthographic priming effect is limited to pseudohomophones. Thus, it seems that both the orthographic and the phonological similarities of the parafoveal preview to the target play a part in the facilitative effects of the preview.


Phenylobacterium parvum sp. nov., isolated from lake water.
A Gram-stain-negative, rod-shaped and aerobic bacterium, designated HYN0004T, was isolated from lake water. The strain grew at 15-35 °C and pH 7.0-9.0 on R2A. The isoprenoid quinone was Q10 and major polar lipids were phosphatidylglycerol and one unidentified glycolipid. The genome was 2.83 Mb with a DNA G+C content of 69.9 mol%. 16S rRNA gene sequence analyses revealed that HYN0004T represented a member of the genus Phenylobacterium and shared sequence similarities with Phenylobacterium conjunctum (97.8 %), Phenylobacterium koreense (97.5 %), Phenylobacterium aquaticum (97.2 %), and Phenylobacteriumheamatophilum (97.0 %). In addition to the low sequence similarities, the phylogenetic tree shapes indicated that HYN0004Trepresents an independent species of this genus. The genomic and phenotypic properties, including small genome size, inability to carry out numerous enzymatic reactions and high ratio of C18 : 1ω6c and/or C18 : 1ω7c in fatty acids, verified the differentiation between HYN0004T and related species. Thus, we propose a novel species of the genus Phenylobacterium, named as Phenylobacterium parvum sp. nov. The type strain is HYN0004T (=KACC 19185T=NBRC 112736T).


Cytologic findings of tracheobronchial aspirates from 66 thoroughbred racehorses.
Tracheobronchial aspirates obtained from 66 healthy Thoroughbred racehorses in training at the same track were examined. Twenty-seven percent of the horses had greater than 20% neutrophils in the aspirate. Eosinophils, mast cells, giant cells, and Curschmann's spirals of mucus were observed in 94, 83, 65, and 42% of the horses, respectively. Hemosiderophages were observed in 86% of the horses, half of which had previous confirmation of exercise-induced pulmonary hemorrhage. Although fungal elements were seen in 70% of the horses, bacteria were detected in only 3% of the horses. The authors conclude that inflammatory airway disease is widespread in the racing Thoroughbred population.


A comparative review of nurse turnover rates and costs across countries.
To compare nurse turnover rates and costs from four studies in four countries (US, Canada, Australia, New Zealand) that have used the same costing methodology; the original Nursing Turnover Cost Calculation Methodology. Measuring and comparing the costs and rates of turnover is difficult because of differences in definitions and methodologies. Comparative review. Searches were carried out within CINAHL, Business Source Complete and Medline for studies that used the original Nursing Turnover Cost Calculation Methodology and reported on both costs and rates of nurse turnover, published from 2014 and prior. A comparative review of turnover data was conducted using four studies that employed the original Nursing Turnover Cost Calculation Methodology. Costing data items were converted to percentages, while total turnover costs were converted to US 2014 dollars and adjusted according to inflation rates, to permit cross-country comparisons. Despite using the same methodology, Australia reported significantly higher turnover costs ($48,790) due to higher termination (~50% of indirect costs) and temporary replacement costs (~90% of direct costs). Costs were almost 50% lower in the US ($20,561), Canada ($26,652) and New Zealand ($23,711). Turnover rates also varied significantly across countries with the highest rate reported in New Zealand (44·3%) followed by the US (26·8%), Canada (19·9%) and Australia (15·1%). A significant proportion of turnover costs are attributed to temporary replacement, highlighting the importance of nurse retention. The authors suggest a minimum dataset is also required to eliminate potential variability across countries, states, hospitals and departments.


HIV-1 reverse transcriptase shows no specificity for the binding of primer tRNA(Lys3).
The transcription initiation primer for HIV-1 is a specific cellular tRNA species, tRNA(Lys3). We used several methods to assess the binding of tRNA by recombinant HIV-1 p51/p66 reverse transcriptase (RT), gel retardation analysis, intrinsic RT protein fluorescence quenching, and nitrocellulose filter binding assays. The binding of tRNA to RT was saturable, implying a distinct site or sites on the enzyme for tRNA interaction. However, this binding was non-selective, with all tRNA isoacceptors and total unfractionated tRNA binding with similar affinity as primer tRNA(Lys3). In contrast, no significant binding of tRNA by RT was noted. Our results show that HIV-1 RT has no specificity for the binding of primer tRNA(Lys3), and imply that factors other than RT sequences may be important for the selective incorporation of primer tRNA into the virion particle.


Effect of including environmental data in investigations of gene-disease associations in the presence of qualitative interactions.
Complex diseases are likely to be caused by the interplay of genetic and environmental factors. Despite this, gene-disease associations are frequently investigated using models that focus solely on a marginal gene effect, ignoring environmental factors entirely. Failing to take into account a gene-environment interaction can weaken the apparent gene-disease association, leading to loss in statistical power and, potentially, inability to identify genuine risk factors. If a gene-environment interaction exists, therefore, a joint analysis allowing the effect of the gene to differ between groups defined by the environmental exposure can have greater statistical power than a marginal gene-disease model. However, environmental data are subject to measurement error. Substantial losses in statistical power for detecting gene-environment interactions can arise from measurement error in the environmental exposure. It is unclear, however, what effect measurement error may have on the power of the joint analysis. We consider the potential benefits, in terms of statistical power, of collecting concurrent environmental data within large cohorts in order to enhance gene detection. We further consider whether these benefits remain in the presence of misclassification in both the gene and the environmental exposure. We find that when an effect of the gene is apparent only in the presence of the environmental exposure, the joint analysis has greater power than a marginal gene-disease analysis. This comparative increase in power remains in the presence of likely levels of misclassification of either the gene or environmental exposure.


Poor adherence to sleep and physical activity guidelines among children with epilepsy.
To assess physical activity and sleep rates in a cohort of children with epilepsy (CWE) and determine if there is a relationship between physical activity and sleep time. Children aged 8-14 years with a diagnosis of epilepsy and at least one seizure in the past 12 months were monitored via a wrist-worn activity tracker for 16 weeks, to objectively measure daily physical activity, as assessed by step counts, and sleep time. Adherence to physical activity (≥12,000 steps/day) and sleep recommendations (≥9 h for children aged 8-12 years, or ≥8 h for children aged 13-15 years) was determined. To predict daily activity or nightly sleep, a series of multivariable models incorporating age, sex, day-type (all combinations of weekday or weekend and summer holiday or school), participant (as a random effect), daily physical activity (for models predicting sleep), nightly sleep (for models predicting physical activity), and autoregressive terms of previous sleep or physical activity were constructed, and the best-performing models were selected with Akaike information criterion analysis. Twenty-two children with mild to moderate epilepsy were recruited (54.5% female, median (IQR) age 11 (10, 13) years) and monitored for 16 weeks. They met the recommended level of physical activity only in 38.0% (21.7%, 59.4%), and sleep in 49.1% (30.0%, 68.5%) of days. They met both physical activity and sleep guidelines on the same day in only 17.8% (95% CI 7.1%, 38.0%). There was no association between meeting the recommended levels of daily physical activity and sleep time (p = 0.86, ρ = 0.03). In the best-performing model, age, sex, day type, and participant explained 28.9% of the variance in daily physical activity, with no additional insight provided by measures of sleep time. Age, sex, day type, participant, and daily physical activity explained 17.3% of the variance in nightly sleep time, with a statistically discernable but small association between physical activity and sleep time (1.79 ± 0.53, p = 0.001). Our cohort of children with mild to moderate epilepsy showed poor adherence to sleep and physical activity guidelines. There was no clinically relevant association between daily physical activity and sleep among these children who were similarly active to healthy peers. Future studies should assess the effect of increased sleep hygiene and physical activity on overall well-being and seizure control in CWE.


Haplotype mapping of the bronchiolitis susceptibility locus near IL8.
Susceptibility to viral bronchiolitis, the commonest cause of infant admissions to hospital in the industrialised world, is associated with polymorphism at the IL8 locus. Here we map the genomic boundaries of the disease association by case-control analysis and TDT in 580 affected UK infants. Markers for association mapping were chosen after determining patterns of linkage disequilibrium across the surrounding region of chromosome 4q, a 550-kb segment containing nine genes, extending from AFP to PPBP. The region has three major clusters of high linkage disequilibrium and is notable for its low haplotypic diversity. We exclude adjacent chemokine genes as the cause of the association, and identify a disease-associated haplotype that spans a 250-kb region from AFM to IL8. In between these two genes there is only one structural feature of interest, a novel gene RASSF6, which is predicted to encode a Ras effector protein.


New records of sharks (Elasmobranchii) from the Andaman and Nicobar Archipelago in India with notes on current checklists.
The diversity of sharks occurring off the Andaman and Nicobar Archipelago in India has received increased attention in recent years. Yet, available checklists are out of date, often with inaccurate information and a number of commercially important species have not been documented through research and fish landing surveys. Here we report on shark species examined during fish landing surveys conducted from January 2017 to April 2018. Records of twelve previously unreported species from the archipelago are presented and include the bignose shark (Carcharhinus altimus), pigeye shark (Carcharhinus amboinensis), bull shark (Carcharhinus leucas), snaggletooth shark (Hemipristis elongata), slender weasel shark (Paragaleus randalli), Arabian smoothhound shark (Mustelus mosis), Indonesian houndshark (Hemitriakis indroyonoi), sand tiger shark (Carcharias taurus), Indonesian bambooshark (Chiloscyllium hasseltii), tawny nurse shark (Nebrius ferrugineus), dwarf gulper shark (Centrophorus atromarginatus), and the Indonesian shortsnout spurdog (Squalus hemipinnis). These records increase the reported shark species for the archipelago from 47 to 59 and for India from 114 to 116. Additionally, a size extension in the total length of C. hasseltii by 27 cm and of P. randalli by 8 cm is reported. Owing to the bio-geographical location of these islands, species diversity around the archipelago is unique and appears to overlap with that of southeast Asia. With increasing reports of over-exploitation and the operation of a targeted shark fishery by distant water fleets in these waters, the limited information on shark diversity from this region is of concern. Systematic and long-term monitoring of catches, combined with accurate species identification, is crucial to provide information on management measures.


Prenatal Exposure to DEHP Affects Spermatogenesis and Sperm DNA Methylation in a Strain-Dependent Manner.
Di-(2-ethylhexyl)phtalate (DEHP) is a plasticizer with endocrine disrupting properties found ubiquitously in the environment and altering reproduction in rodents. Here we investigated the impact of prenatal exposure to DEHP on spermatogenesis and DNA sperm methylation in two distinct, selected, and sequenced mice strains. FVB/N and C57BL/6J mice were orally exposed to 300 mg/kg/day of DEHP from gestation day 9 to 19. Prenatal DEHP exposure significantly decreased spermatogenesis in C57BL/6J (fold-change = 0.6, p-value = 8.7*10-4), but not in FVB/N (fold-change = 1, p-value = 0.9). The number of differentially methylated regions (DMRs) by DEHP-exposure across the entire genome showed increased hyper- and decreased hypo-methylation in C57BL/6J compared to FVB/N. At the promoter level, three important subsets of genes were massively affected. Promoters of vomeronasal and olfactory receptors coding genes globally followed the same trend, more pronounced in the C57BL/6J strain, of being hyper-methylated in DEHP related conditions. In contrast, a large set of micro-RNAs were hypo-methylated, with a trend more pronounced in the FVB/N strain. We additionally analyze both the presence of functional genetic variations within genes that were associated with the detected DMRs and that could be involved in spermatogenesis, and DMRs related with the DEHP exposure that affected both strains in an opposite manner. The major finding in this study indicates that prenatal exposure to DEHP can decrease spermatogenesis in a strain-dependent manner and affects sperm DNA methylation in promoters of large sets of genes putatively involved in both sperm chemotaxis and post-transcriptional regulatory mechanisms.


Pneumococcal antibody responses in elite swimmers.
The ability of elite swimmers to mount an antibody response to the pneumococcal vaccine, Pneumovax 23, was assessed at the end of an intensive 12-week training programme. Antibody titres to six pneumococcal polysaccharide types were measured in 20 elite swimmers (10 male, 10 female) aged 17-23 years and 19 sedentary age- and sex-matched students (eight male, 11 female) aged 18-23 years. Blood samples were tested 14 days apart to assess the magnitude of the antibody response and changes in serum immunoglobulin isotypes and IgG subclasses. There were no significant differences in any of the pneumococcal antibody responses to the Pneumovax between swimmers and controls, and no gender effect, either before or after vaccination. The clinically adequate response to the vaccine was greatest for the pneumococcal serotype 4, which was 97% for the total study population. There were no significant correlations between the magnitude of any of the pneumococcal antibody responses and (i) changes in the scores for the swimmers' international performance; (ii) infection rates in either swimmers or controls; (iii) any psychological variables, assessed by the Profile of Mood States (POMS) questionnaire for either swimmers or controls. Swimmers had significantly lower concentrations of serum IgG2 (P = 0.04) and IgG3 (P = 0.002) before pneumococcal vaccination. The swimmers had an increase in all immunoglobulin isotypes and IgG subclasses post-vaccination, suggesting a polyclonal response to the vaccine that was not observed in control subjects. The magnitude of the subclass responses after vaccination was significantly greater in swimmers compared with controls for IgG1 (P = 0.04), IgG3 (P = 0.04) and IgG4 (P = 0.01). The data indicated that elite swimmers undertaking an intensive training programme were capable of mounting an antibody response to pneumococcal antigens equivalent to that of age- and sex-matched sedentary control subjects, despite the swimmers having lower prevaccination levels of serum immunoglobulins.


Do Malnutrition, Sarcopenia and Frailty Overlap in Nursing-Home Residents?
To study the prevalence and overlap between malnutrition, sarcopenia and frailty in a selected group of nursing home (NH) residents. Cross-sectional descriptive study. Nursing homes (NH). 92 residents taking part in an exercise and oral nutritional supplementation study; >75 years old, able to rise from a seated position, body mass index ≤30 kg/m2 and not receiving protein-rich oral nutritional supplements. The MNA-SF and Global Leadership Initiative on Malnutrition (GLIM) criteria were used for screening and diagnosis of malnutrition (moderate or severe), respectively. Sarcopenia risk was assessed by the SARC-F Questionnaire (0-10p; ≥4=increased risk), and for diagnosis the European Working Group of Sarcopenia in Older People (EWGSOP2) criteria was used. To screen for frailty the FRAIL Questionnaire (0-5p; 1-2p indicating pre-frailty, and >3p indicating frailty), was employed. Average age was 86 years; 62% were women. MNA-SF showed that 30 (33%) people were at risk or malnourished. The GLIM criteria verified malnutrition in 16 (17%) subjects. One third (n=33) was at risk for sarcopenia by SARC-F. Twenty-seven (29%) subjects displayed confirmed sarcopenic according to EWGSOP2. Around 50% (n=47) was assessed as pre-frail or frail. Six people (7%) suffered from all three conditions. Another five (5%) of the residents were simultaneously malnourished and sarcopenic, but not frail, while frailty coexisted with sarcopenia in 10% (n=9) of non-malnourished residents. Twenty-nine (32%) residents were neither malnourished, sarcopenic nor frail. In a group of selected NH residents a majority was either (pre)frail (51%), sarcopenic (29%) or malnourished (17%). There were considerable overlaps between the three conditions.


Hepatic circadian clock oscillators and nuclear receptors integrate microbiome-derived signals.
The liver is a key organ of metabolic homeostasis with functions that oscillate in response to food intake. Although liver and gut microbiome crosstalk has been reported, microbiome-mediated effects on peripheral circadian clocks and their output genes are less well known. Here, we report that germ-free (GF) mice display altered daily oscillation of clock gene expression with a concomitant change in the expression of clock output regulators. Mice exposed to microbes typically exhibit characterized activities of nuclear receptors, some of which (PPARα, LXRβ) regulate specific liver gene expression networks, but these activities are profoundly changed in GF mice. These alterations in microbiome-sensitive gene expression patterns are associated with daily alterations in lipid, glucose, and xenobiotic metabolism, protein turnover, and redox balance, as revealed by hepatic metabolome analyses. Moreover, at the systemic level, daily changes in the abundance of biomarkers such as HDL cholesterol, free fatty acids, FGF21, bilirubin, and lactate depend on the microbiome. Altogether, our results indicate that the microbiome is required for integration of liver clock oscillations that tune output activators and their effectors, thereby regulating metabolic gene expression for optimal liver function.


The optimal ratio of fat-to-carbohydrate in the diet.
A major issue in human nutrition is the optimal relation of carbohydrate-to-fat in the diet. According to some investigators, a high proportion of fat energy to total energy favors the development of several chronic diseases. Among these are obesity, coronary heart disease, diabetes, and cancer. The theory that a high proportion of fat relative to other nutrients promotes the development of obesity is founded on research with experimental animals and in human population surveys. This theory has been difficult to prove in prospective feeding studies in humans; therefore it remains a contentious issue. Regarding coronary heart disease, little evidence supports a claim that a high proportion of dietary fat predisposes to disease. On the other hand, strong evidence bolsters the claim that certain fatty acids raise the risk for coronary heart disease. These include saturated fatty acids and trans fatty acids, both of which raise serum cholesterol levels. In contrast, neither monounsaturated nor polyunsaturated fatty acids raise serum cholesterol levels and seemingly pose little risk for coronary disease. The relationship between dietary fat and type 2 diabetes is tied largely to the issue of obesity, because obesity is a major cause of diabetes. Although animal studies and epidemiological studies have implicated dietary fat as a factor in cancer, recent prospective epidemiological data in humans have cast doubt on the possibility of a strong relationship. In summary, clear evidence points to the need to reduce intakes of saturated and trans fatty acids in the diet. Beyond this change, a balanced ratio of unsaturated fatty acids to carbohydrate leading to fat intake of approximately 30% of total energy seems appropriate for the American public.


Concentrated bovine colostrum protein supplementation reduces the incidence of self-reported symptoms of upper respiratory tract infection in adult males.
Anecdotal reports suggest that bovine colostrum may prevent upper respiratory tract infection (URTI). There is scant evidence to support such claims, although salivary IgA protects against URTI, and it was recently shown that bovine colostrum increases salivary IgA. The present invesigation examined whether concentrated bovine colostrum protein (CBC) affected the incidence or duration of self-reported symptoms of URTI in adult males. We examined logbooks containing self-reported symptoms of illness from previous studies which examined physiological effects of CBC. In these double-blind, placebo controlled studies, subjects had been randomly allocated to consume 60g. day(-1) of CBC (n = 93) or whey protein (WP) (n = 81) for eight weeks. Symptoms were coded using established criteria to identify those related to URTI. Since the incubation period for an URTI is up to five days, symptoms reported during the first week of supplementation (PRE-EXP) were analysed separately to preclude those arising from infection prior to study commencement. During PRE-EXP, there was no difference in the proportion of subjects taking the different supplements who reported symptoms of URTI (CBC, 11%,WP, 5%; 95% Confidence Interval (95% CI) -14% to 2%; P = 0.16). During the subsequent seven weeks (i. e. the experimental period), a significantly lesser proportion of subjects taking CBC reported symptoms of URTI compared with those taking WP (CBC, 32%,WP, 48%, P = 0.03; 95 % CI -30 % to -2 %), but symptom duration did not differ (CBC, 6.8 +/- 4.2 days,WP, 6.0 +/- 4.4 days; P = 0.27). This study provides preliminary evidence that CBC may enhance resistance to the development of symptoms of URTI.


Malnutrition associated with a formula of barley water, corn syrup, and whole milk.
Five infants, age 1 to 7 months, were given a formula of barley water, whole milk, and corn syrup (Karo) or honey. Three patients had subnormal growth, two fit the criteria for failure to thrive, and two demonstrated a microcytic hypochromic anemia. The delayed growth and anemia were corrected by institution of a standard infant formula and nutrient supplementation. The barley water formula provides less than the recommended daily allowance of iron and vitamins A and C. The illnesses of these infants and the deficiencies of the diet illustrate the importance of obtaining a careful dietary history for all infants not receiving standard diets.


Intracellular trafficking of HLA-E and its regulation.
Interest in MHC-E-restricted CD8+ T cell responses has been aroused by the discovery of their efficacy in controlling simian immunodeficiency virus (SIV) infection in a vaccine model. The development of vaccines and immunotherapies utilizing human MHC-E (HLA-E)-restricted CD8+ T cell response requires an understanding of the pathway(s) of HLA-E transport and antigen presentation, which have not been clearly defined previously. We show here that, unlike classical HLA class I, which rapidly exits the endoplasmic reticulum (ER) after synthesis, HLA-E is largely retained because of a limited supply of high-affinity peptides, with further fine-tuning by its cytoplasmic tail. Once at the cell surface, HLA-E is unstable and is rapidly internalized. The cytoplasmic tail plays a crucial role in facilitating HLA-E internalization, which results in its enrichment in late and recycling endosomes. Our data reveal distinctive transport patterns and delicate regulatory mechanisms of HLA-E, which help to explain its unusual immunological functions.


Targeted disruption of the estrogen receptor-alpha gene in female mice: characterization of ovarian responses and phenotype in the adult.
Targeted disruption of the mouse estrogen receptor-alpha gene (estrogen receptor-alpha knockout; ERKO) results in a highly novel ovarian phenotype in the adult. The ERKO mouse model was used to characterize ER alpha-dependent processes in the ovary. Visualization of the ovaries of 10-, 20-, and 50-day-old wild-type (WT) and ERKO mice showed that the ERKO phenotype developed between 20 and 50 days of age. Developmental progression through the primordial, primary, and antral follicle stages appeared normal, but functional maturation of preovulatory follicles was arrested resulting in atresia or in anovulatory follicles, which in many cases formed large, hemorrhagic cysts. Corpora lutea were absent, which also indicates that the normal biochemical and mechanical processes that accomplish ovulation were compromised. Northern and ribonuclease protection analyses indicated that ERKO ovary FSH receptor (FSHR) messenger RNA (mRNA) expression was approximately 4-fold greater than in WT controls. Ovarian LH receptor (LHR) mRNA expression was also higher in the ERKO animals. Cellular localization studies by in situ hybridization analysis of ERKO ovaries showed a high level of LHR mRNA expression in the granulosa and thecal layers of virtually all the antral follicles. Ribonuclease protection analyses showed that ovarian progesterone receptor and androgen receptor mRNA expression were similar in the two groups. These results indicated that ER alpha action was not a prerequisite for LHR mRNA expression by thecal or granulosa cells or for ovarian expression of progesterone receptor mRNA. Ovarian estrogen receptor beta (ER beta) was detected immunohistochemically, was sharply compartmentalized to the granulosa cells, and was expressed approximately equally in the ERKO animals and the WT controls. In contrast, ER alpha staining was present in the thecal cells but not the granulosa cells of the WT animals. The summary findings indicate that in the adult the major cause of the ERKO phenotype is high circulating LH interacting with functional LHR of the theca and granulosa cells. These features result in a failure of the normal maturational events leading to successful ovulation and luteinization and presumably involve both hypothalamic-pituitary and intraovarian mechanisms dependent upon ER alpha action. The presence of ER beta in the granulosa cells did not rescue the phenotype of the ovary.


Distinct Motivational Effects of Contingent and Noncontingent Rewards.
When rewards are available, people expend more energy, increasing their motivational vigor. In theory, incentives might drive behavior for two distinct reasons: First, they increase expected reward; second, they increase the difference in subjective value between successful and unsuccessful performance, which increases contingency-the degree to which action determines outcome. Previous studies of motivational vigor have never compared these directly. Here, we indexed motivational vigor by measuring the speed of eye movements toward a target after participants heard a cue indicating how outcomes would be determined. Eye movements were faster when the cue indicated that monetary rewards would be contingent on performance than when the cue indicated that rewards would be random. But even when the cue indicated that a reward was guaranteed regardless of speed, movement was still faster than when no reward was available. Motivation by contingent and certain rewards was uncorrelated across individuals, which suggests that there are two separable, independent components of motivation. Contingent motivation generated autonomic arousal, and unlike noncontingent motivation, was effective with penalties as well as rewards.


Dietary determinants of changes in waist circumference adjusted for body mass index - a proxy measure of visceral adiposity.
Given the recognized health effects of visceral fat, the understanding of how diet can modulate changes in the phenotype "waist circumference for a given body mass index (WC(BMI))", a proxy measure of visceral adiposity, is deemed necessary. Hence, the objective of the present study was to assess the association between dietary factors and prospective changes in visceral adiposity as measured by changes in the phenotype WC(BMI). We analyzed data from 48,631 men and women from 5 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Anthropometric measurements were obtained at baseline and after a median follow-up time of 5.5 years. WC(BMI) was defined as the residuals of waist circumference regressed on body mass index, and annual change in WC(BMI) (DeltaWC(BMI), cm/y) was defined as the difference between residuals at follow-up and baseline, divided by follow-up time. The association between energy, energy density (ED), macronutrients, alcohol, glycemic index (GI), glycemic load (GL), fibre and DeltaWC(BMI) was modelled using centre-specific adjusted linear regression, and random-effects meta-analyses to obtain pooled estimates. Men and women with higher ED and GI diets showed significant increases in their WC(BMI), compared to those with lower ED and GI [1 kcal/g greater ED predicted a DeltaWC(BMI) of 0.09 cm (95% CI 0.05 to 0.13) in men and 0.15 cm (95% CI 0.09 to 0.21) in women; 10 units greater GI predicted a DeltaWC(BMI) of 0.07 cm (95% CI 0.03 to 0.12) in men and 0.06 cm (95% CI 0.03 to 0.10) in women]. Among women, lower fibre intake, higher GL, and higher alcohol consumption also predicted a higher DeltaWC(BMI). Results of this study suggest that a diet with low GI and ED may prevent visceral adiposity, defined as the prospective changes in WC(BMI). Additional effects may be obtained among women of low alcohol, low GL, and high fibre intake.


Peptides mediating DNA transport on microtubules and their impact on non-viral gene transfer efficiency.
Synthetic vectors such as cationic polymers and cationic lipids remain attractive tools for non-viral gene transfer which is a complex process whose effectiveness relies on the ability to deliver a plasmid DNA (pDNA) into the nucleus of non-dividing cells. Once in the cytosol, the transport of pDNAs towards the nuclear envelope is strongly impaired by their very low cytosolic mobility due to their large size. To promote their movement towards the cell nucleus, few strategies have been implemented to exploit dynein, the microtubule's (MT's) motor protein, for propagation of cytosolic pDNA along the MTs towards the cell nucleus. In the first part of this review, an overview on MTs, dynein, dynein/virus interaction feature is presented followed by a summary of the results obtained by exploitation of LC8 and TCTEL1 dynein light chain association sequence (DLC-AS) for non-viral transfection. The second part dedicated to the adenoviral protein E3-14.7K, reports the transfection efficiency of polyplexes and lipoplexes containing the E3-14.7K-derived P79-98 peptide linked to pDNA. Here, several lines of evidence are given showing that dynein can be targeted to improve cytosolic pDNA mobility and accumulate pDNA near nuclear envelope in order to facilitate its transport through the nuclear pores. The linkage of various DLC-AS to pDNA carriers led to modest transfection improvements and their direct interaction with MTs was not demonstrated. In contrast, pDNA linked to the P79-98 peptide interacting with TCTEL1 via a cytosolic protein (fourteen seven K-interacting protein-1 (FIP-1)), interaction with MTs is evidenced in cellulo and transfection efficiency is improved.


Improving efficacy of hyperthermia in oncology by exploiting biological mechanisms.
It has long been established that hyperthermia increases the therapeutic benefit of radiation and chemotherapy in cancer treatment. During the last few years there have been substantial technical improvements in the sources used to apply and measure heat, which greatly increases enthusiasm for the clinical use of hyperthermia. These advances are converging with a better understanding of the physiological and molecular effects of hyperthermia. Therefore, we are now at a juncture where the parameters that will influence the efficacy of hyperthermia in cancer treatment can be optimised in a more systematic and rational manner. In addition, the novel insights in hyperthermia's many biological effects on tumour cells will ultimately result in new treatment regimes. For example, the molecular effects of hyperthermia on the essential cellular process of DNA repair suggest novel combination therapies, with DNA damage response targeting drugs that should now be clinically explored. Here, we provide an overview of recent studies on the various macroscopic and microscopic biological effects of hyperthermia. We indicate the significance of these effects on current treatments and suggest how they will help design novel future treatments.


Functional characterisation of the type 1 von Willebrand disease candidate VWF gene variants: p.M771I, p.L881R and p.P1413L.
Abnormalities in the biosynthetic pathway or increased clearance of plasma von Willebrand factor (VWF) are likely to contribute to decreased plasma VWF levels in inherited type 1 von Willebrand disease (VWD). Recent studies demonstrated that 65% of type 1 VWD patients have candidate VWF mutations, the majority of which are missense variants. The purpose of this study was to explore the effects of three VWF missense mutations (p.M771I, p.L881R and p.P1413L) located in different functional domains of VWF, reported as candidate mutations in type 1 VWD patients in the course of the MCMDM-1VWD study. The focus of these studies was on the intracellular biosynthetic processing and localisation of VWF in a heterologous cell system. Molecular dynamic simulation for p.M771I and p.P1413L was also performed to analyse the conformational effects of the changes. As determined by immunofluorescence antibody staining and confocal microscopy of HEK293 cells, the intracellular localisation of recombinant VWF with the p.M771I variation was impaired. Transient transfection studies and phorbol myristate acetate stimulation in COS-7 cells revealed significant intracellular retention. In addition, major loss of VWF multimers was observed for only the p.M771I mutation. Molecular dynamic simulations on p.M771I mutant VWF revealed distinct structural rearrangements including a large deviation in the E' domain, and significant loss of β-sheet secondary structure. The pathogenic effects of candidate VWF gene mutations were explored in this study. In vitro expression studies in heterologous cell systems revealed impaired secretion of VWF and a dominant negative effect on the processing of the wild-type protein for only the p.M771I mutation and none of the mutations affected the regulated secretion.


Is supratotal resection achievable in low-grade gliomas? Feasibility, putative factors, safety, and functional outcome.
Surgery for low-grade gliomas (LGGs) aims to achieve maximal tumor removal and maintenance of patients' functional integrity. Because extent of resection is one of the factors affecting the natural history of LGGs, surgery could be extended further than total resection toward a supratotal resection, beyond tumor borders detectable on FLAIR imaging. Supratotal resection is highly debated, mainly due to a lack of evidence of its feasibility and safety. The authors explored the intraoperative feasibility of supratotal resection and its short- and long-term impact on functional integrity in a large cohort of patients. The role of some putative factors in the achievement of supratotal resection was also studied. Four hundred forty-nine patients with a presumptive radiological diagnosis of LGG consecutively admitted to the neurosurgical oncology service at the University of Milan over a 5-year period were enrolled. In all patients, a policy was adopted to perform surgery according to functional boundaries, aimed at achieving a supratotal resection whenever possible, without any patient or tumor a priori selection. Feasibility, general safety, and tumor or patient putative factors possibly affecting the achievement of a supratotal resection were analyzed. Postsurgical patient functional performance was evaluated in five cognitive domains (memory, language, praxis, executive functions, and fluid intelligence) using a detailed neuropsychological evaluation and quality of life (QOL) examination. Total resection was feasible in 40.8% of patients, and supratotal resection in 32.3%. The achievement of a supratotal versus total resection was independent of age, sex, education, tumor volume, deep extension, location, handedness, appearance of tumor border, vicinity to eloquent sites, surgical mapping time, or surgical tools applied. Supratotal resection was associated with a long clinical history and histological grade II, suggesting that reshaping of brain networks occurred. Although a consistent amount of apparently MRI-normal brain was removed with this approach, the procedure was safe and did not carry additional risk to the patient, as demonstrated by detailed neuropsychological evaluation and QOL examination. This approach also improved seizure control. Supratotal resection is feasible and safe in routine clinical practice. These results show that a long clinical history may be the main factor associated with its achievement.


Genome-wide association study in accessions of the mini-core collection of mungbean (Vigna radiata) from the World Vegetable Gene Bank (Taiwan).
Mungbean (Vigna radiata (L.) R. Wilczek, or green gram) is important tropical and sub-tropical legume and a rich source of dietary protein and micronutrients. In this study we employ GWAS to examine the genetic basis of variation in several important traits in mungbean, using the mini-core collection established by the World Vegetable Center, which includes 296 accessions that represent the major market classes. This collection has been grown in a common field plot in southern European part of Russia in 2018. We used 5041 SNPs in 293 accessions that passed strict filtering for genetic diversity, linkage disequilibrium, population structure and GWAS analysis. Polymorphisms were distributed among all chromosomes, but with variable density. Linkage disequilibrium decayed in approximately 105 kb. Four distinct subgroups were identified within 293 accessions with 70% of accessions attributed to one of the four populations. By performing GWAS on the mini-core collection we have found several loci significantly associated with two important agronomical traits. Four SNPs associated with possibility of maturation in Kuban territory of Southern Russia in 2018 were identified within a region of strong linkage which contains genes encoding zinc finger A20 and an AN1 domain stress-associated protein. The core collection of mungbean established by the World Vegetable Center is a valuable resource for mungbean breeding. The collection has been grown in southern European part of Russia in 2018 under incidental stresses caused by abnormally hot weather and different photoperiod. We have found several loci significantly associated with color of hypocotyl and possibility of maturation under these stressful conditions. SNPs associated with possibility of maturation localize to a region on chromosome 2 with strong linkage, in which genes encoding zinc finger A20 and AN1 domain stress associated protein (SAP) are located. Phenotyping of WorldVeg collection for maturation traits in temperate climatic locations is important as phenology remains a critical breeding target for mungbean. As demand rises for mungbean, production in temperate regions with shorter growing seasons becomes crucial to keep up with needs. Uncovering SNPs for phenology traits will speed breeding efforts.


Neuroendocrine and viral correlates of premature immunosenescence.
Aging continuously remodels the immune system, a process known as immunosenescence. Here, we review evidence of premature immunosenescence in younger individuals under conditions of chronic psychological stress, chronic inflammation, or exposure to certain persistent viral infections. Chronic stress may accelerate various features of immunosenescence by activating key allostatic systems, notably the hypothalamic-pituitary-adrenal axis and increased cortisol levels. Chronic stress is associated with thymic involution, blunted T cell proliferation, increased serum proinflammatory markers, and shorter telomere lengths. Human cytomegalovirus (CMV) infection has been implicated in accelerating immunosenescence by shrinking the T cell receptor repertoire and causing clonal expansion of senescent CD8(+) CD28(-) T cells with a proinflammatory profile. These factors increase inflammation associated with aging, or "inflammaging," particularly as it relates to etiology of several age-related diseases and increased mortality. Patients with rheumatoid arthritis have been shown to have several signatures of premature immunosenescence, including expansion of senescent T cells associated with cognitive impairment. We end by speculating that bipolar disorder can be considered as a model of accelerated aging because it has been associated with shortened telomeres, higher CMV IgG titers, and expansion of senescent and regulatory T cells.


New diagnostic method for liver fibrosis and cirrhosis.
Liver fibrosis, i.e. excessive accumulation of extracellular matrix proteins, occurs in most types of chronic liver diseases. The prognosis and management of chronic liver diseases depend on the degree of liver fibrosis. Therefore, the assessment of liver fibrosis provides useful information not only for diagnosis but also for treatment planning. Although liver biopsy is still the gold standard for assessing hepatic fibrosis, it has some technical limitations and risks. Furthermore, the dynamic process of liver fibrosis resulting from progression and regression cannot be quantified by liver biopsy. Therefore, alternative, simple, reliable and noninvasive tests are needed to assess the stage of fibrosis. Several noninvasive direct and indirect serum markers able to predict the presence of significant fibrosis or cirrhosis in patients with chronic liver disease with considerable accuracy have been reported. However, since most of these markers require complicated calculations, clinical application is difficult. Transient elastography (FibroScan) is a new method for the evaluation of liver stiffness. The technique is based on changes in tissue elasticity induced by hepatic fibrosis. Liver stiffness measured by transient elastography is a noninvasive, reproducible and reliable method to assess hepatic fibrosis as well as to diagnose liver cirrhosis. Based on accumulating clinical data, clinical applications of elastography will increase in the near future.


A new large-bodied oviraptorosaurian theropod dinosaur from the latest Cretaceous of western North America.
The oviraptorosaurian theropod dinosaur clade Caenagnathidae has long been enigmatic due to the incomplete nature of nearly all described fossils. Here we describe Anzu wyliei gen. et sp. nov., a new taxon of large-bodied caenagnathid based primarily on three well-preserved partial skeletons. The specimens were recovered from the uppermost Cretaceous (upper Maastrichtian) Hell Creek Formation of North and South Dakota, and are therefore among the stratigraphically youngest known oviraptorosaurian remains. Collectively, the fossils include elements from most regions of the skeleton, providing a wealth of information on the osteology and evolutionary relationships of Caenagnathidae. Phylogenetic analysis reaffirms caenagnathid monophyly, and indicates that Anzu is most closely related to Caenagnathus collinsi, a taxon that is definitively known only from a mandible from the Campanian Dinosaur Park Formation of Alberta. The problematic oviraptorosaurs Microvenator and Gigantoraptor are recovered as basal caenagnathids, as has previously been suggested. Anzu and other caenagnathids may have favored well-watered floodplain settings over channel margins, and were probably ecological generalists that fed upon vegetation, small animals, and perhaps eggs.


Smoking-related attitudes and perceptions among young adults in Malta and the UK.
Although youth smoking in Europe has been highlighted as a significant public health concern, there is little data available to guide development of population-specific smoking prevention measures. In this study, we examined smoking-prevalence and smoking-related attitudes and perceptions among 118 young adults in Malta (a country for which there is little existing data), with comparison data from a sample of young adults in the UK (N = 112). To ensure that samples were demographically similar (e.g. in terms of age, level of education, and social status) we obtained data from university students. Only students of Maltese nationality (in Malta), or British nationality (in the UK) were invited to participate. Participants completed measures of smoking behavior, perceived risks of smoking, subjective norms, temptation to smoke, and attitudes towards smoking cessation. Almost half (46%) of the Maltese students were current smokers, compared to 25% of the British students. British students were more aware of the risks of smoking than their Maltese counterparts, perceived greater social pressure not to smoke and held more positive attitudes towards smoking cessation; Maltese students reported greater temptation to smoke and were around others who smoke more often than the British students. Attitudes and perceptions were associated with smoking behavior in both samples although the relative importance of psychological determinants of smoking varied between the two samples. Our data indicate higher smoking prevalence and more pro-smoking attitudes/ perceptions among students in Malta, consistent with data for other Southern European countries. Findings also indicate that the influence of smoking-related attitudes and perceptions varies between populations and the influence of social norms in particular may be moderated by nationality.


Coherent-array imaging using phased subarrays. Part I: basic principles.
The front-end hardware complexity of a coherent array imaging system scales with the number of active array elements that are simultaneously used for transmission or reception of signals. Different imaging methods use different numbers of active channels and data collection strategies. Conventional full phased array (FPA) imaging produces the best image quality using all elements for both transmission and reception, and it has high front-end hardware complexity. In contrast, classical synthetic aperture (CSA) imaging only transmits on and receives from a single element at a time, minimizing the hardware complexity but achieving poor image quality. We propose a new coherent array imaging method--phased subarray (PSA) imaging--that performs partial transmit and receive beam-forming using a subset of adjacent elements at each firing step. This method reduces the number of active channels to the number of subarray elements; these channels are multiplexed across the full array and a reduced number of beams are acquired from each subarray. The low-resolution subarray images are laterally upsampled, interpolated, weighted, and coherently summed to form the final high-resolution PSA image. The PSA imaging reduces the complexity of the front-end hardware while achieving image quality approaching that of FPA imaging.


Targeting TRAIL death receptor 4 with trivalent DR4 Atrimer complexes.
TRAIL is a trimeric protein that potently induces apoptosis in cancer cells by binding to the trimeric death receptors (DR4 or DR5). Death receptors are attractive therapeutic targets through both the recombinant TRAIL ligand as well as receptor agonist monoclonal antibodies. Although efficacy of the ligand is hampered by its short half-life, agonistic antibodies have a much longer half-life and have shown some clinical efficacy as antitumor agents. However, the efficacy of these antibodies may be limited by their bivalent nature that does not optimally mimic the trimeric ligand. To overcome limitations of currently used death receptor-targeting agents, we engineered trimeric proteins called Atrimer complexes that selectively bind DR4 and potently induce apoptosis in a variety of cancer cells. Atrimer complexes are based on human tetranectin, a trimeric plasma protein of approximately 60 kDa. Loop regions within the tetranectin C-type lectin domains (CTLD) were randomized to create a large phage display library that was used to select DR4-binding complexes. A panel of unique and potent agonist DR4 Atrimer complexes with subnanomolar affinity to DR4 and no detectable binding to DR5 or the decoy receptors was identified. Mechanism of action studies with a selected Atrimer complex, 1G(2), showed that Atrimer complexes induce caspase-dependent and DR4-specific apoptosis in cancer cells while sparing normal human fibroblasts and, importantly, hepatocytes. This proof-of-principle study supports the use of alternative proteins engineered to overcome limitations of therapeutically desirable molecules such as TRAIL.