Sex-related influences on the frequency and age of onset of primary dystonia. Epidemiologic Study of Dystonia in Europe (ESDE) Collaborative Group.
We studied 957 cases of primary (idiopathic) dystonia and found a significant excess of female patients for segmental and focal dystonia. A novel observation was a significantly earlier age at onset in males as opposed to females for primary segmental (mean age, 44.6 versus 53.3) and focal dystonia (43.8 versus 47.8). This trend was also apparent in cervical dystonia, blepharospasm, and laryngeal dystonia. For writer's cramp and focal limb dystonia, this trend was reversed with an earlier age at onset in females. These results suggest that focal dystonia should not be treated as an homogenous group, and sex-linked factors may play a role.


The humerus of Eusthenopteron: a puzzling organization presaging the establishment of tetrapod limb bone marrow.
Because of its close relationship to tetrapods, Eusthenopteron is an important taxon for understanding the establishment of the tetrapod body plan. Notably, it is one of the earliest sarcopterygians in which the humerus of the pectoral fin skeleton is preserved. The microanatomical and histological organization of this humerus provides important data for understanding the evolutionary steps that built up the distinctive architecture of tetrapod limb bones. Previous histological studies showed that Eusthenopteron's long-bone organization was established through typical tetrapod ossification modalities. Based on a three-dimensional reconstruction of the inner microstructure of Eusthenopteron's humerus, obtained from propagation phase-contrast X-ray synchrotron microtomography, we are now able to show that, despite ossification mechanisms and growth patterns similar to those of tetrapods, it also retains plesiomorphic characters such as a large medullary cavity, partly resulting from the perichondral ossification around a large cartilaginous bud as in actinopterygians. It also exhibits a distinctive tubular organization of bone-marrow processes. The connection between these processes and epiphyseal structures highlights their close functional relationship, suggesting that either bone marrow played a crucial role in the long-bone elongation processes or that trabecular bone resulting from the erosion of hypertrophied cartilage created a microenvironment for haematopoietic stem cell niches.


Ceramide-induced apoptosis in cortical neurons is mediated by an increase in p38 phosphorylation and not by the decrease in ERK phosphorylation.
Ceramide, the central molecule of the sphingomyelin pathway, serves as a second messenger for cellular functions ranging from proliferation and differentiation to growth arrest and apoptosis. In this study we show that c2-ceramide induces apoptosis in primary cortical neuron cultures and that this effect correlates with differential modulation of mitogen-activated protein kinase (MAPK) cascades. Phosphorylation of extracellular signal-regulated kinases (ERKs) and their upstream activators MAPK kinases (MEKs), as measured by immunoblotting is rapidly decreased by c2-ceramide. However, the MEK inhibitor PD98059 alone does not induce apoptosis and in combination with c2-ceramide it does not modify c2-ceramide-induced apoptosis. Treatment with c2-ceramide increases p38 and c-Jun N-terminal kinase (JNK) phosphorylation before and during caspase-3 activation. The p38 inhibitor SB203580 partially protects cortical neurons against c2-ceramide-induced apoptosis, implicating the p38 pathway in this process. The c2-ceramide treatment also increases levels of c-jun, c-fos and p53 mRNA in primary cortical neuron cultures, but this is independent of p38 activation. Our study further elucidates the time-courses of MAPK cascade modulation, and of c-jun, c-fos and p53 activation during c2-ceramide-induced neuronal apoptosis. It reveals that one of the activated kinases, p38, is necessary for this apoptosis.


Chemokine co-receptor CCR5/CXCR4-dependent modulation of Kv2.1 channel confers acute neuroprotection to HIV-1 glycoprotein gp120 exposure.
Infection with human immunodeficiency virus-1 (HIV-1) within the brain has long been known to be associated with neurodegeneration and neurocognitive disorder (referred as HAND), a condition characterized in its early stages by declining cognitive function and behavioral disturbances. Mechanistically, the HIV-1 coat glycoprotein 120 (gp120) has been suggested to be a critical factor inducing apoptotic cell death in neurons via the activation of p38 mitogen-activated protein kinase (MAPK), upon chronic exposure to the virus. Here we show that acute exposure of neurons to HIV-1 gp120 elicits a homeostatic response, which provides protection against non-apoptotic cell death, involving the major somatodendritic voltage-gated K⁺ (Kv) channel Kv2.1 as the key mediator. The Kv2.1 channel has recently been shown to provide homeostatic control of neuronal excitability under conditions of seizures, ischemia and neuromodulation/neuroinflammation. Following acute exposure to gp120, cultured rat hippocampal neurons show rapid dephosphorylation of the Kv2.1 protein, which ultimately leads to changes in specific sub-cellular localization and voltage-dependent channel activation properties of Kv2.1. Such modifications in Kv2.1 are dependent on the activation of the chemokine co-receptors CCR5 and CXCR4, and subsequent activation of the protein phosphatase calcineurin. This leads to the overall suppression of neuronal excitability and provides neurons with a homeostatic protective mechanism. Specific blockade of calcineurin and Kv2.1 channel activity led to significant enhancement of non-apoptotic neuronal death upon acute gp120 treatment. These observations shed new light on the intrinsic homeostatic mechanisms of neuronal resilience during the acute stages of neuro-HIV infections.


Concurrent validity of kidney transplant questionnaire in US renal transplant recipients.
Valid instrumentation in the assessment of health-related quality of life (HQoL) in renal transplant recipients is critical to identifying particular nuances and determinants of HQoL in this population. Therefore, the validity of disease-specific instruments to measure HQoL in renal transplant recipients, such as the Kidney Transplant Questionnaire (KTQ), needs further investigation. The objective of this study was to assess the concurrent validity of the KTQ in adult US renal transplant recipients using the well established SF-12 Health Survey version 2 (SF-12v2) as the comparison instrument. One hundred and fourteen renal transplant recipients met the following inclusion criteria for this study, ie, were at least 21 years of age, more than two years post-transplant, and receiving immunosuppressant therapy. Subjects were asked to complete a series of HQoL instruments, ie, the KTQ and the SF-12v2 (physical component summary [PCS-12] and mental component summary [MCS-12]). Descriptive statistics were calculated, and correlational analyses were conducted to examine the concurrent validity of the HQoL instruments. Among 100 participants (87.7% response rate), the majority of participants were male (52%), had deceased donor transplants (63%), and received Medicare benefits (84%). PCS-12 was positively correlated with three of five KTQ subscales (P < 0.05), ie, KTQ-physical (r = 0.43), KTQ-fatigue (r = 0.42), and KTQ-uncertainty/fear (r = 0.2). MCS-12 was positively correlated with all KTQ subscales (P < 0.01), ie, KTQ-physical (r = 0.26), KTQ-fatigue (r = 0.48), KTQ-uncertainty/fear (r = 0.33), KTQ-emotional (r = 0.47), and KTQ-appearance (r = 0.28). The findings support the concurrent validity of the KTQ in US renal transplant recipients. Future studies should continue exploring the validity of the KTQ, as well as its practical and research utility in HQoL measurement in the renal transplant population.


Bryophyte diversity and evolution: windows into the early evolution of land plants.
The "bryophytes" comprise three phyla of plants united by a similar haploid-dominant life cycle and unbranched sporophytes bearing one sporangium: the liverworts (Marchantiophyta), mosses (Bryophyta), and hornworts (Anthocerophyta). Combined, these groups include some 20000 species. As descendents of embryophytes that diverged before tracheophytes appeared, bryophytes offer unique windows into the early evolution of land plants. We review insights into the evolution of plant life cycles, in particular the elaboration of the sporophyte generation, the major lineages within bryophyte phyla, and reproductive processes that shape patterns of bryophyte evolution. Recent transcriptomic work suggests extensive overlap in gene expression in bryophyte sporophytes vs. gametophytes, but also novel patterns in the sporophyte, supporting Bower's antithetic hypothesis for origin of alternation of generations. Major lineages of liverworts, mosses, and hornworts have been resolved and general patterns of morphological evolution can now be inferred. The life cycles of bryophytes, arguably more similar to those of early embryophytes than are those in any other living plant group, provide unique insights into gametophyte mating patterns, sexual conflicts, and the efficacy and effects of spore dispersal during early land plant evolution.


Mortality in relation to smoking: 20 years' observations on male British doctors.
In 1951 the British Medical Association forwarded to all British doctors a questionnaire about their smoking habits, and 34440 men replied. With few exceptions, all men who replied in 1951 have been followed for 20 years. The certified causes of all 10 072 deaths and subsequent changes in smoking habits were recorded. The ratio of the death rate among cigarette smokers to that among lifelong non-smokers of comparable age was, for men under 70 years, about 2:1, while for men over 70 years it was about 1-5:1. These ratios suggest that between a half and a third of all cigarette smokers will die because of their smoking, if the excess death rates are actually caused by smoking. To investigate whether this is the case, the relation of many different causes of death to age and tobacco consumption were examined, as were the effects of giving up smoking. Smoking caused death chiefly by heart disease among middle-aged men (and, with a less extreme relative risk, among old men,) lung cancer, chronic obstructive lung disease, and various vascular diseases. The distinctive features of this study were the completeness of follow-up, the accuracy of death certification, and the fact that the study population as a whole reduced its cigarette consumption substantially during the period of observation. As a result lung cancer grew relatively less common as the study progressed, but other cancers did not, thus illustrating in an unusual way the causal nature of the association between smoking and lung cancer.


Accurate sensitivity in optically preamplified direct detection.
We present a novel model for calculating the bit error rate in optical communication systems in the case of on-off keying intensity modulation and optically preamplified direct detection. The model accounts for the intersymbol interference and is based on the Laguerre photon-count probability distribution predicted by photodetection theory. For a non-return-to-zero modulation format an accurate value of the sensitivity for a quantum-limited receiver of 33.9 photons/bit is obtained.


Epigenetic investigation of variably X chromosome inactivated genes in monozygotic female twins discordant for primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is an autoimmune chronic cholestatic liver disease with a strong genetic susceptibility due to the high concordance in monozygotic (MZ) twins and a striking female predominance. Women with PBC manifest an enhanced X monosomy rate in peripheral lymphocytes and we thus hypothesized an X chromosome epigenetic component to explain PBC female prevalence. While most genes on the female inactive X chromosome are silenced by promoter methylation following X chromosome inactivation (XCI), approximately 10% of X- linked genes exhibit variable escape from XCI in healthy females. This study was designed to test the hypothesis that susceptibility to PBC is modified by one or more X-linked gene with variable XCI status. Peripheral blood mRNA and DNA samples were obtained from a unique cohort of MZ twin sets discordant and concordant for PBC. Transcript levels of the 125 variable XCI status genes was determined by quantitative RT-PCR analysis and two genes (CLIC2 and PIN4) were identified as consistently downregulated in the affected twin of discordant pairs. Both CLIC2 and PIN4 demonstrated partial and variable methylation of CpG sites within 300 bp of the transcription start site that did not predict the XCI status. Promoter methylation of CLIC2 manifested no significant difference between samples and no significant correlation with transcript levels. PIN4 methylation showed a positive trend with transcription in all samples but no differential methylation was observed between discordant twins. A genetic polymorphism affecting the number of CpG sites in the PIN4 promoter did not impact methylation or transcript levels in a heterozygous twin pair and showed a similar frequency in independent series of unrelated PBC cases and controls. Our results suggest that epigenetic factors influencing PBC onset are more complex than methylation differences at X-linked promoters and variably 3 inactivated X-linked genes may be characterized by partial promoter methylation and biallelic transcription.


Neural networks involved in artistic creativity.
Creativity has been proposed to be either the result of solely right hemisphere processes or of interhemispheric interactions. Little information is available, however, concerning the neuronal foundations of creativity. In this study, we introduced a new artistic task, designing a new tool (a pen), which let us quantitatively evaluate creativity by three indices of originality. These scores were analyzed in combination with brain activities measured by functional magnetic resonance imaging (fMRI). The results were compared between subjects who had been formally trained in design (experts) and novice subjects. In the experts, creativity was quantitatively correlated with the degree of dominance of the right prefrontal cortex over that of the left, but not with that of the right or left prefrontal cortex alone. In contrast, in novice subjects, only a negative correlation with creativity was observed in the bilateral inferior parietal cortex. We introduced structure equation modeling to analyze the interactions among these four brain areas and originality indices. The results predicted that training exerts a direct effect on the left parietal cortex. Additionally, as a result of the indirect effects, the activity of the right prefrontal cortex was facilitated, and the left prefrontal and right parietal cortices were suppressed. Our results supported the hypothesis that training increases creativity via reorganized intercortical interactions.


Transfersomes: The Ultra-Deformable Carrier System for Non-Invasive Delivery of Drug.
Vesicular systems have many advantages like prolonging the existence of the drug in the systemic circulation, minimizing the undesirable side-effects and helping the active moieties to reach their target sites using the carriers. However, the main drawback related to transdermal delivery is to cross stratum corneum, which can be overcome by the utilization of novel carrier systems e.g., transfersomes, which are ultra-deformable carrier systems composed of phospholipid (phosphatidylcholine) and edge activators (surfactants). Edge activators are responsible for the flexibility of the bilayer membranes of transfersomes. Different edge activators used in transfersomes include tween, span, bile salts (sodium cholate and sodium deoxycholate) and dipotassium glycyrrhizinate. These activators decrease the interfacial tension, thereby, increasing the deformability of the carrier system. Transfersomes can encapsulate both hydrophilic and hydrophobic drugs into a vesicular structure, which consists of one or more concentric bilayers. Due to the elastic nature of transfersomes, they can easily cross the natural physiological barriers i.e., skin and deliver the drug to its active site. The main benefit of using transfersomes as a carrier is the delivery of macromolecules through the skin by non-invasive route thereby increasing the patient's compliance. The transfersomal formulations can be used in the treatment of ocular diseases, alopecia, vulvovaginal candidiasis, osteoporosis, atopic dermatitis, tumor, leishmaniasis. It is also used in the delivery of growth hormones, anaesthesia, insulin, proteins, and herbal drugs. This review also focuses on the patents and clinical studies for various transfersomal products.


New Natural Hosts of Pepino mosaic virus in Spain.
Pepino mosaic virus (PepMV) was first detected in Spain in 2000 (1). The virus infects tomato (Lycopersicon esculentum Mill.) crops and causes a variety of symptoms including leaf distortion, chlorosis, mosaic, blistering of the leaf surface, green striations on the stem and sepals, and fruit discoloration. PepMV is present along the southern and eastern regions of Spain (provinces of Granada, Almeria, Murcia, Alicante, Valencia, and Barcelona), Balearic, and the Canary Islands. In the summer and autumn of 2001 and 2002, virus-like symptoms were observed in native plants growing in or around tomato fields in Murcia and Almeria provinces. To study the alternate hosts that may serve as virus reservoirs, 62 samples of 42 common weed species, including asymptomatic plants, were collected and analyzed for PepMV using double-antibody sandwich enzyme-linked immunosorbent assay with a commercial antiserum (DSMZ As-0554; Biologische Bundesantstal, Braunschweig, Germany). The following weed hosts tested positive for PepMV: Bassia scoparia (L.) Voss., Calystegia sepium (L.) R.Br., Chenopodium murale L., Convolvulus althaeoides L., Convolvulus arvensis L., Conyza albida Willd. ex Spreng., Coronopus sp., Diplotaxis erucoides (L.) DC, Echium creticum L., E. humile Desf., Heliotropium europaeum L., Moricandia arvensis (L.) DC., Onopordum sp., Piptatherum multiflorum (Cav.) Beauv., Plantago afra L., Rumex sp., Sisymbrium irio L., Sonchus tenerrimus L., and Taraxacum vulgare (Lam.) Schrank. The presence of PepMV in these weed species was confirmed using reverse transcription-polymerase chain reaction with primers specific for PepMV (2). Although the number of samples examined may be insufficient to assess precisely the role of weed reservoirs in outbreaks of PepMV, these findings reveal potential virus sources and contribute to further understanding of PepMV epidemiology in Spain. References: (1) C. Jordá et al. Plant Dis. 85:1292, 2001. (2) P. Martínez-Culebras et al. Eur. J. Plant Pathol. 108:887, 2002.


Chronic antihypertensive treatment improves pulse pressure but not large artery mechanics in a mouse model of congenital vascular stiffness.
Increased arterial stiffness is a common characteristic of humans with Williams-Beuren syndrome and mouse models of elastin insufficiency. Arterial stiffness is associated with multiple negative cardiovascular outcomes, including myocardial infarction, stroke, and sudden death. Therefore, identifying therapeutic interventions that improve arterial stiffness in response to changes in elastin levels is of vital importance. The goal of this study was to determine the effect of chronic pharmacologic therapy with different classes of antihypertensive medications on arterial stiffness in elastin insufficiency. Elastin-insufficient mice 4-6 wk of age and wild-type littermates were subcutaneously implanted with osmotic micropumps delivering a continuous dose of one of the following: vehicle, losartan, nicardipine, or propranolol for 8 wk. At the end of treatment period, arterial blood pressure and large artery compliance and remodeling were assessed. Our results show that losartan and nicardipine treatment lowered blood pressure and pulse pressure in elastin-insufficient mice. Elastin and collagen content of abdominal aortas as well as ascending aorta and carotid artery biomechanics were not affected by any of the drug treatments in either genotype. By reducing pulse pressure and shifting the working pressure range of an artery to a more compliant region of the pressure-diameter curve, antihypertensive medications may mitigate the consequences of arterial stiffness, an effect that is drug class independent. These data emphasize the importance of early recognition and long-term management of hypertension in Williams-Beuren syndrome and elastin insufficiency.


MAN1B-CDG: Novel variants with a distinct phenotype and review of literature.
Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases due to impaired lipid and protein glycosylation. It comprises a characteristic high frequency of intellectual disability (ID) and a wide range of clinical phenotypes. To identify the underlying diagnosis in two families each with two siblings with variable level of ID through trio whole exome sequencing. Both the families were recruited to the Deciphering Developmental Disorders (DDD) study to identify the aetiology for their ID. Further work-up included isoelectric focusing (IEF) of serum transferrin done to add evidence to the molecular diagnosis. These patients were found to have three novel variants in MAN1B1 inherited from their healthy parents. Serum transferrin IEF showed a type 2 pattern. MAN1B1 variants were initially described in association with non-syndromic ID; subsequent literature suggested that variants in MAN1B1 resulted in a CDG-type II syndrome. However, there remains a paucity of literature on detailed clinical phenotyping and it still remains a rare form of CDG. The present patients showed the phenotype previously reported in MAN1B1-CDG: a characteristic facial dysmorphism, hypotonia, truncal obesity and in some, behavioural problems. In unexplained ID, serum transferrin should be included in the first-line screening. With advances in genomic medicine, it is important to diagnose CDG as this has implications for management and recurrence risk counselling.


Omega-3 fatty acids for cardioprotection.
The most compelling evidence for the cardiovascular benefit provided by omega-3 fatty acids comes from 3 large controlled trials of 32,000 participants randomized to receive omega-3 fatty acid supplements containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or to act as controls. These trials showed reductions in cardiovascular events of 19% to 45%. These findings suggest that intake of omega-3 fatty acids, whether from dietary sources or fish oil supplements, should be increased, especially in those with or at risk for coronary artery disease. Patients should consume both DHA and EPA. The target DHA and EPA consumption levels are about 1 g/d for those with known coronary artery disease and at least 500 mg/d for those without disease. Patients with hypertriglyceridemia benefit from treatment with 3 to 4 g/d of DHA and EPA, a dosage that lowers triglyceride levels by 20% to 50%. Although 2 meals of oily fish per week can provide 400 to 500 mg/d of DHA and EPA, secondary prevention patients and those with hypertriglyceridemia must use fish oil supplements if they are to reach 1 g/d and 3 to 4 g/d of DHA and EPA, respectively. Combination therapy with omega-3 fatty acids and a statin is a safe and effective way to improve lipid levels and cardiovascular prognosis beyond the benefits provided by statin therapy alone. Blood DHA and EPA levels could one day be used to identify patients with deficient levels and to individualize therapeutic recommendations.


Value of allogeneic versus autologous stem cell transplantation and chemotherapy in patients with myelodysplastic syndromes and secondary acute myeloid leukemia. Final results of a prospective randomized European Intergroup Trial.
Allogeneic stem cell transplantation is usually considered the only curative treatment option for patients with advanced or transformed myelodysplastic syndromes in complete remission, but post-remission chemotherapy and autologous stem cell transplantation are potential alternatives, especially in patients over 45 years old. We evaluated, after intensive anti-leukemic remission-induction chemotherapy, the impact of the availability of an HLA-identical sibling donor on an intention-to treat basis. Additionally, all patients without a sibling donor in complete remission after the first consolidation course were randomized to either autologous peripheral blood stem cell transplantation or a second consolidation course consisting of high-dose cytarabine. The 4-year survival of the 341 evaluable patients was 28%. After achieving complete remission, the 4-year survival rates of patients under 55 years old with or without a donor were 54% and 41%, respectively, with an adjusted hazard ratio of 0.81 (95% confidence interval [95% CI], 0.49-1.35) for survival and of 0.67 (95% CI, 0.42-1.06) for disease-free survival. In patients with intermediate/high risk cytogenetic abnormalities the hazard ratio in multivariate analysis was 0.58 (99% CI, 0.22-1.50) (P=0.14) for survival and 0.46 (99% CI, 0.22-1.50) for disease-free survival (P=0.03). In contrast, in patients with low risk cytogenetic characteristics the hazard ratio for survival was 1.17 (99% CI, 0.40-3.42) and that for disease-free survival was 1.02 (99% CI, 0.40-2.56). The 4-year survival of the 65 patients randomized to autologous peripheral blood stem cell transplantation or a second consolidation course of high-dose cytarabine was 37% and 27%, respectively. The hazard ratio in multivariate analysis was 1.22 (95% CI, 0.65-2.27) for survival and 1.02 (95% CI, 0.56-1.85) for disease-free survival. Patients with a donor and candidates for allogeneic stem cell transplantation in first complete remission may have a better disease-free survival than those without a donor in case of myelodysplastic syndromes with intermediate/high-risk cytogenetics. Autologous peripheral blood stem cell transplantation does not provide longer survival than intensive chemotherapy.


Aplasia cutis congenita of the scalp, skull and dura associated with Adams-Oliver syndrome.
A 1-day-old boy with the characteristics of Adams-Oliver syndrome was presented. Adams-Oliver syndrome has a wide spectrum of anomalies ranging from aplasia cutis congenita, cutis marmorata telangiectatica congenita and transverse limb defects to lethal anomalies. Our patient had aplasia cutis congenita with scalp, skull and dura defect. He had also a large dura defect with herniation of brain tissue. Besides these he had bilateral clubfoot, cortical fissure and nail hypoplasia in the hands, scrotal hyperpigmentation and generalized cutis marmorata telangiectatica congenita. He was operated on the 3rd day of life. The herniated brain tissue was resected and the dura was repaired with a synthetic dural graft.


IL-10 producing regulatory B cells in mice and humans: state of the art.
IL-10-producing regulatory B cells have been undoubtedly identified in mice and shown to downregulate inflammation, making them potentially important for maintenance of tolerance. Several recent works have also identified IL-10 producing regulatory B cells in humans and have begun to unravel their phenotype and mode of suppression. Cell surface phenotype of human Bregs includes CD38, CD27, CD24 and CD5. Mechanisms of suppression may imply inhibition of CD4+ T proliferation, inhibition of Th1 differentiation, induction of regulatory T cells and suppression of monocytes activation. These recent findings imply that manipulating IL-10 production by human B cells could be a useful therapeutic strategy for modulating immune responses in humans.


3D printing PCL/nHA bone scaffolds: exploring the influence of material synthesis techniques.
It is known that a number of parameters can influence the post-printing properties of bone tissue scaffolds. Previous research has primarily focused on the effect of parameters associated with scaffold design (e.g., scaffold porosity) and specific scaffold printing processes (e.g., printing pressure). To our knowledge, no studies have investigated variations in post-printing properties attributed to the techniques used to synthesize the materials for printing (e.g., melt-blending, powder blending, liquid solvent, and solid solvent). Four material preparation techniques were investigated to determine their influence on scaffold properties. Polycaprolactone/nano-hydroxyapatite 30% (wt.) materials were synthesized through melt-blending, powder blending, liquid solvent, and solid solvent techniques. The material printability and the properties of printed scaffolds, in terms of swelling/degradation, mechanical strength, morphology, and thermal properties, were examined and compared to one another using Kruskal-Wallis nonparametric statistical analysis. Material prepared through the liquid solvent technique was found to have limited printability, while melt-blended material demonstrated the highest degree of uniformity and lowest extent of swelling and degradation. Scaffolds prepared with powder-blended material demonstrated the highest Young's modulus, yield strength, and modulus of resilience; however, they also demonstrated the highest degree of variability. The higher degree of inhomogeneity in the material was further supported by thermal gravimetric analysis. While scaffolds printed from melt-blended, powder-blended, and solid solvent materials demonstrated a high degree of micro-porosity, the liquid solvent material preparation technique resulted in minimal micro-porosity. Study results indicate that specific techniques used to prepare materials influence the printing process and post-printing scaffold properties. Among the four techniques examined, melt-blended materials were found to be the most favorable, specifically when considering the combination of printability, consistent mechanical properties, and efficient preparation. Techniques determined to be favourable based on the properties investigated should undergo further studies related to biological properties and time-dependent properties beyond 21-days.


Fading to increase heterosexual responsiveness in homosexuals.
Heterosexual responsiveness, measured by penile responses and reports of behavior, was strengthened in three homosexuals through a fading procedure. Using two slide projectors, colored slides of nude females were superimposed on colored slides of nude males. As the sexual response was emitted, the nude male was faded out and the nude female faded in. Heterosexual arousal decreased when the fading procedure was reversed or stopped and increased once again when fading was resumed. Homosexual arousal remained high during this experiment but had decreased in two subjects at follow-up. The results suggest that fading was responsible for altering stimulus control of sexual arousal and that aversive techniques may not be necessary in the treatment of sexual deviation.


Deep Transcranial Magnetic Stimulation for the Treatment of Negative Symptoms in Schizophrenia: Beyond an Antidepressant Effect.
Negative symptoms of schizophrenia show limited response to both typical and atypical antipsychotics. Repetitive transcranial magnetic stimulation applied over the prefrontal cortex (PFC) has been proposed as an adjuvant to pharmacological treatment of negative symptoms in schizophrenia, but whether the improvements obtained are specific to negative symptoms or attributable to antidepressant effects is still unclear. The aim of the present study is to determine to which extent the improvements in negative symptoms of schizophrenia obtained after high-frequency stimulation of the bilateral PFC using deep TMS (dTMS) are attributable to antidepressant effects. Repetitive dTMS was administered to the PFC in a cohort of 16 patients with schizophrenia under successful pharmacological control of positive symptoms and predominant negative symptoms. Patients were treated using high-frequency (18 Hz) bilateral stimulation applied over the lateral PFC bilaterally using Brainsway H-2 coil. The effects of dTMS on negative symptoms were measured using the Scale for the Assessment of Negative Symptoms and the Positive and Negative Syndrome Scales. We then compared the improvements in negative symptoms obtained in patients showing depressive symptoms (≥7 points) with those found in patients without depression (>7 points), as determined by the Calgary Scale for Depression. Repetitive dTMS treatment induced significant improvements in negative symptoms as assessed using both Scale for the Assessment of Negative Symptoms and Positive and Negative Syndrome Scales. Comparison of the improvements obtained in patients with or without depression at the beginning of treatment revealed similar improvements in negative symptoms, irrespective of subjacent depression. Our data suggest that the beneficial effects of high frequency dTMS of the PFC cannot be attributed solely to its antidepressant effects.


Interpretable and accurate prediction models for metagenomics data.
Microbiome biomarker discovery for patient diagnosis, prognosis, and risk evaluation is attracting broad interest. Selected groups of microbial features provide signatures that characterize host disease states such as cancer or cardio-metabolic diseases. Yet, the current predictive models stemming from machine learning still behave as black boxes and seldom generalize well. Their interpretation is challenging for physicians and biologists, which makes them difficult to trust and use routinely in the physician-patient decision-making process. Novel methods that provide interpretability and biological insight are needed. Here, we introduce "predomics", an original machine learning approach inspired by microbial ecosystem interactions that is tailored for metagenomics data. It discovers accurate predictive signatures and provides unprecedented interpretability. The decision provided by the predictive model is based on a simple, yet powerful score computed by adding, subtracting, or dividing cumulative abundance of microbiome measurements. Tested on >100 datasets, we demonstrate that predomics models are simple and highly interpretable. Even with such simplicity, they are at least as accurate as state-of-the-art methods. The family of best models, discovered during the learning process, offers the ability to distil biological information and to decipher the predictability signatures of the studied condition. In a proof-of-concept experiment, we successfully predicted body corpulence and metabolic improvement after bariatric surgery using pre-surgery microbiome data. Predomics is a new algorithm that helps in providing reliable and trustworthy diagnostic decisions in the microbiome field. Predomics is in accord with societal and legal requirements that plead for an explainable artificial intelligence approach in the medical field.


Nrf2-dependent suppression of azoxymethane/dextran sulfate sodium-induced colon carcinogenesis by the cinnamon-derived dietary factor cinnamaldehyde.
The progressive nature of colorectal cancer and poor prognosis associated with the metastatic phase of the disease create an urgent need for the development of more efficacious strategies targeting colorectal carcinogenesis. Cumulative evidence suggests that the redox-sensitive transcription factor Nrf2 (nuclear factor-E2-related factor 2), a master regulator of the cellular antioxidant defence, represents a promising molecular target for colorectal cancer chemoprevention. Recently, we have identified cinnamon, the ground bark of Cinnamomum aromaticum (cassia cinnamon) and Cinnamomum verum (Ceylon cinnamon), as a rich dietary source of the Nrf2 inducer cinnamaldehyde (CA) eliciting the Nrf2-regulated antioxidant response in human epithelial colon cells, conferring cytoprotection against electrophilic and genotoxic insult. Here, we have explored the molecular mechanism underlying CA-induced Nrf2 activation in colorectal epithelial cells and have examined the chemopreventive potential of CA in a murine colorectal cancer model comparing Nrf2(+/+) with Nrf2(-/-) mice. In HCT116 cells, CA caused a Keap1-C151-dependent increase in Nrf2 protein half-life via blockage of ubiquitination with upregulation of cytoprotective Nrf2 target genes and elevation of cellular glutathione. After optimizing colorectal Nrf2 activation and target gene expression by dietary CA-supplementation regimens, we demonstrated that CA suppresses AOM/DSS-induced inflammatory colon carcinogenesis with modulation of molecular markers of colorectal carcinogenesis. Dietary suppression of colorectal cancer using CA supplementation was achieved in Nrf2(+/+) but not in Nrf2(-/-) mice confirming the Nrf2 dependence of CA-induced chemopreventive effects. Taken together, our data suggest feasibility of colorectal cancer suppression by dietary CA, an FDA-approved food additive derived from the third most consumed spice in the world.


Interaction mechanism of mono-PEGylated proteins in electrostatic interaction chromatography.
The retention and binding mechanisms in electrostatic interaction-based chromatography (ion-exchange chromatography) of PEGylated proteins (covalent attachment of polyethylene glycol chains to protein) were investigated using our previously developed model. Lysozyme and bovine serum albumin were chosen as model proteins. The retention volume of PEGylated proteins shifted to lower elution volumes with increasing PEG molecular weight compared with the non-modified (native) protein retention volume. However, PEGylation did not affect the number of binding sites appreciably. The enzyme activity of PEGylated lysozyme measured with a standard insoluble substrate in suspension decreased considerably, whereas the activity with a soluble small-molecule substrate did not drop significantly. These findings indicate that when a protein is mono-PEGylated, the binding site is not affected and the elution volume reduces due to the steric hindrance between PEGylated protein and ion-exchange ligand.


Biomechanical calculation of human TM joint loading with jaw opening.
A three-dimensional, static mathematical calculation of the stomatognathic system was done to predict total temporomandibular joint (TMJ) loading at different levels of jaw opening. The model assumed that muscle forces acting on the mandible could be simulated by a combination of contractile components (CCs) and elastic components (ECs) and that static equilibrium existed within the body of the mandible. The model also imposed the constraint that any generated joint reaction force would act on the centre of the condyle. The results of the model demonstrated that under all conditions of opening and for all values of the elastic modulus selected, the forces between the TMJ condyle and the articular eminence were compressive in nature. The compressive force magnitude increased from 2.7 to 27.6 N incrementally as the jaw opened from 10 to 40 mm. Overall data in this study indicated that the TMJ tissues undergo low levels of compression at open positions up to 40 mm. Finally, the condition of trismus (increased jaw closing activation with opening) was simulated, the joint reaction force at 20 mm opening increased from 7.7 to 64.9 N with only a 20% activation of the closers.


Evidence that the endometrial microbiota has an effect on implantation success or failure.
Bacterial cells in the human body account for 1-3% of total body weight and are at least equal in number to human cells. Recent research has focused on understanding how the different bacterial communities in the body (eg, gut, respiratory, skin, and vaginal microbiomes) predispose to health and disease. The microbiota of the reproductive tract has been inferred from the vaginal bacterial communities, and the uterus has been classically considered a sterile cavity. However, while the vaginal microbiota has been investigated in depth, there is a paucity of consistent data regarding the existence of an endometrial microbiota and its possible impact in reproductive function. This study sought to test the existence of an endometrial microbiota that differs from that in the vagina, assess its hormonal regulation, and analyze the impact of the endometrial microbial community on reproductive outcome in infertile patients undergoing in vitro fertilization. To identify the existence of an endometrial microbiota, paired samples of endometrial fluid and vaginal aspirates were obtained simultaneously from 13 fertile women in prereceptive and receptive phases within the same menstrual cycle (total samples analyzed n = 52). To investigate the hormonal regulation of the endometrial microbiota during the acquisition of endometrial receptivity, endometrial fluid was collected at prereceptive and receptive phases within the same cycle from 22 fertile women (n = 44). Finally, the reproductive impact of an altered endometrial microbiota in endometrial fluid was assessed by implantation, ongoing pregnancy, and live birth rates in 35 infertile patients undergoing in vitro fertilization (total samples n = 41) with a receptive endometrium diagnosed using the endometrial receptivity array. Genomic DNA was obtained either from endometrial fluid or vaginal aspirate and sequenced by 454 pyrosequencing of the V3-V5 region of the 16S ribosomal RNA (rRNA) gene; the resulting sequences were taxonomically assigned using QIIME. Data analysis was performed using R packages. The χ2 test, Student t test, and analysis of variance were used for statistical analyses. When bacterial communities from paired endometrial fluid and vaginal aspirate samples within the same subjects were interrogated, different bacterial communities were detected between the uterine cavity and the vagina of some subjects. Based on its composition, the microbiota in the endometrial fluid, comprising up to 191 operational taxonomic units, was defined as a Lactobacillus-dominated microbiota (>90% Lactobacillus spp.) or a non-Lactobacillus-dominated microbiota (<90% Lactobacillus spp. with >10% of other bacteria). Although the endometrial microbiota was not hormonally regulated during the acquisition of endometrial receptivity, the presence of a non-Lactobacillus-dominated microbiota in a receptive endometrium was associated with significant decreases in implantation [60.7% vs 23.1% (P = .02)], pregnancy [70.6% vs 33.3% (P = .03)], ongoing pregnancy [58.8% vs 13.3% (P = .02)], and live birth [58.8% vs 6.7% (P = .002)] rates. Our results demonstrate the existence of an endometrial microbiota that is highly stable during the acquisition of endometrial receptivity. However, pathological modification of its profile is associated with poor reproductive outcomes for in vitro fertilization patients. This finding adds a novel microbiological dimension to the reproductive process.


Relapsing CD8+ encephalitis-looking for a solution.
CD8+ encephalitis (CD8+E) is an emerging and incompletely understood HIV-associated neurological syndrome, typically presenting as a steroid-responsive subacute encephalopathy with prominent white matter changes in patients with apparently well-controlled HIV infection. Some cases can be associated with the phenomenon of 'viral escape' (disproportionate replication within the cerebrospinal fluid), but the most important pathophysiology of CD8+E is thought to involve an attack on HIV-infected CD4+ lymphocytes by autoreactive CD8+ cells. We report a case of CD8+E where the initial positive response to steroid treatment was followed by several relapses on withdrawal. This led to the use of mycophenolate mofetil (MMF) as a long-term steroid-sparing agent, which is the first time this approach has been reported in the literature. The patient has now been on treatment with MMF for 10 months and it has been possible to taper the steroids down to a minimal maintenance dose without further relapse.


Multiple insecticide resistance in Anopheles gambiae from Tanzania: a major concern for malaria vector control.
Malaria vector control in Tanzania is based on use of long-lasting insecticide treated nets (LLINs) and indoor residual spraying (IRS), which both rely on the use of chemical insecticides. The effectiveness of these control tools is endangered by the development of insecticide resistance in the major malaria vectors. This study was carried out to monitor the susceptibility status of major malaria vectors to insecticides used for IRS and LLINs in mainland Tanzania. Mosquito larvae were collected in 20 sites of Tanzania mainland in 2015. Phenotypic resistance was determined using standard WHO susceptibility tests. Molecular assay were used to determine distribution of Anopheles gambiae sub-species. A microplate assay approach was used for identifying enzyme levels on single mosquitoes from each sites compared with a susceptible reference strain, An. gambiae sensu stricto (s.s.) Kisumu strain. Anopheles arabiensis was the dominant malaria specie in the country, accounting for 52% of the sibling species identified, while An. gambiae s.s. represented 48%. In Arumeru site, the dominant species was An. arabiensis, which was resistant to both pyrethroids (permethrin and deltamethrin), and pirimiphos-methyl, and had significant elevated levels of GSTs, non-specific esterases, and oxidase enzymes. An. arabiensis was also a dominant species in Kilombero and Kondoa sites, both were resistant to permethrin and deltamethrin with significant activity levels of oxidase enzymes. Resistance to bendiocarb was recorded in Ngara site where specie composition is evenly distributed between An. gambiae s.s. and An.arabiensis. Also bendiocarb resistance was recorded in Mbozi site, where An. gambiae s.s. is the dominant species. Overall, this study confirmed resistance to all four insecticide classes in An. gambiae sensu lato in selected locations in Tanzania. Results are discussed in relation to resistance mechanisms and the optimization of resistance management strategies.


Mapping the assembly pathway of Bluetongue virus scaffolding protein VP3.
The structure of the Bluetongue virus (BTV) core and its outer layer VP7 has been solved by X-ray crystallography, but the assembly intermediates that lead to the inner scaffolding VP3 layer have not been defined. In this report, we addressed two key questions: (a) the role of VP3 amino terminus in core assembly and its interaction with the transcription complex (TC) components; and (b) the assembly intermediates involved in the construction of the VP3 shell. To do this, deletion mutants in the amino terminal and decamer-decamer interacting region of VP3 (DeltaDD) were generated, expressed in insect cells using baculovirus expression systems, and their ability to assemble into core-like particles (CLPs) and to incorporate the components of TC were investigated. Deletion of the N-terminal 5 (Delta5N) or 10 (Delta10N) amino acids did not affect the ability to assemble into CLPs in the presence of VP7 although the cores assembled using the 10 residue mutant (Delta10N) deletion were very unstable. Removal of five residues also did not effect incorporation of the internal VP1 RNA polymerase and VP4 mRNA capping enzyme proteins of the TC. Removal of the VP3-VP3 interacting domain (DeltaDD) led to failure to assemble into CLPs yet retained interaction with VP1 and VP4. In solution, purified DeltaDD mutant protein readily multimerized into dimers, pentamers, and decamers, suggesting that these oligomers are the authentic assembly intermediates of the subcore. However, unlike wild-type VP3 protein, the dimerization domain-deleted assembly intermediates were found to have lost RNA binding ability. Our study emphasizes the requirement of the N-terminus of VP3 for binding and encapsidation of the TC components, and defines the role of the dimerization domain in subcore assembly and RNA binding.


Association between Bsm1 Polymorphism in Vitamin D Receptor Gene and Diabetic Retinopathy of Type 2 Diabetes in Korean Population.
Type 2 diabetes is one of the most common diseases with devastating complications. However, genetic susceptibility of diabetic complications has not been clarified. The vitamin D endocrine system is related with calcification and lipolysis, insulin secretion, and may be associated with many complicated disease including diabetes and cardiovascular disease. Recent studies reported that single nucleotide polymorphisms of vitamin D receptor (VDR) gene were associated with diabetic complications. In present study, we evaluated the association of BsmI polymorphism of VDR with diabetic complications in Korean diabetes patients. Total of 537 type 2 diabetic subjects from the Endocrinology Clinic of Chungbuk National University Hospital were investigated. Polymerase chain reaction-restriction fragment length polymorphism was used to test the genotype and allele frequency of BsmI (rs1544410; BB, Bb, bb) polymorphisms. Mean age was 62.44±10.64 years and mean disease duration was 13.65±7.39 years. Patients with B allele (BB or Bb) was significantly associated with lower risk of diabetic retinopathy (severe non-proliferative diabetic retinopathy or proliferative retinopathy; 7.4%, 5/68) compared with patients without B allele (bb; 17.3%, 81/469; P=0.035). This association was also significant after adjusting for hemoglobin A1c level, body mass index, age, sex, and diabetes mellitus duration, concurrent dyslipidemia and hypertension (odds ratio, 2.99; 95% confidence interval, 1.08 to 8.29; P=0.035) in logistic regression analysis. Our findings suggest that B allele of Bsm1 polymorphism in VDR gene is associated with lower risk of diabetic retinopathy in type 2 diabetic patients. Bsm1 genotype could be used as a susceptibility marker to predict the risk of diabetes complication.


Coral hybridization or phenotypic variation? Genomic data reveal gene flow between Porites lobata and P. Compressa.
Major gaps remain in our understanding of the ecology, evolution, biodiversity, biogeography, extinction risk, and adaptive potential of reef building corals. One of the central challenges remains that there are few informative genetic markers for studying boundaries between species, and variation within species. Reduced representation sequencing approaches, such as RADseq (Restriction site Associated DNA sequencing) have great potential for resolving such relationships. However, it is necessary to identify loci in order to make inferences for endosymbiotic organisms such as corals. Here, we examined twenty-one coral holobiont ezRAD libraries from Hawai'i, focusing on P. lobata and P. compressa, two species with contrasting morphology and habitat preference that previous studies have not resolved. We used a combination of de novo assembly and reference mapping approaches to identify and compare loci: we used reference mapping to extract and compare nearly complete mitochondrial genomes, ribosomal arrays, and histone genes. We used de novo clustering and phylogenomic methods to compare the complete holobiont data set with coral and symbiont subsets that map to transcriptomic data. In addition, we used reference assemblies to examine genetic structure from SNPs (Single Nucleotide Polymorphisms). All approaches resolved outgroup taxa but failed to resolve P. lobata and P. compressa as distinct, with mito-nuclear discordance and shared mitochondrial haplotypes within the species complex. The holobiont and 'coral transcriptomic' datasets were highly concordant, revealing stronger genetic structure between sites than between coral morphospecies. These results suggest that either branching morphology is a polymorphic trait, or that these species frequently hybridize. This study provides examples of several approaches to acquire, identify, and compare loci across metagenomic samples such as the coral holobiont while providing insights into the nature of coral variability.


E-Leadership and Teleworking in Times of COVID-19 and Beyond: What We Know and Where Do We Go.
Suddenly, COVID-19 has changed the world and the way people work. Companies had to accelerate something they knew was imminent in the future, but not immediate and extremely humongous. This situation poses a huge challenge for companies to survive and thrive in this complex business environment and for employees, who must adapt to this new way of working. An effective e-leadership, which promotes companies' adaptability, is needed. This study investigates the existing knowledge on teleworking and e-leadership; and analyzes the supposed challenges. The literature review shows that companies with effective e-leadership can view teleworking as an opportunity. It is advantageous for not only companies' productivity but also the environment and people who work remotely. However, a traditional or no leadership can result in some risks. Thriving in remote work environments implies that managers must adjust the companies' structure, making them less hierarchical, and developing new abilities to establish a strong and trustworthy relationship with their employees to maintain their competitiveness, while retaining a genuine concern for their employees' well-being. Similarly, successful e-leadership must be able to consolidate and lead effective virtual teams to accomplish organizational goals. This study contributes to the literature and leaders during the pandemic.


Protocol for production of a chewable material for masticatory function tests (Optocal - Brazilian version).
The present article aimed to present a standardized protocol for the production of a chewable test material that has been used in masticatory efficiency and performance studies. This chewable material has advantages in respect to its physical properties when compared to other artificial and natural test foods. It is constituted by mixing condensation silicon (58.3% by weight), common plaster (10.2% by weight), alginate (12.5% by weight), solid vaseline (11.5% by weight), tooth paste (7.5% by weight), and catalyst paste (20.8 mg/g), adding also three drops of mint essence. The mixed material is then inserted into an acrylic mould with perforations of 12 mm in diameter and 5 mm in height to produce rounded tablets with those measures after polymerization. It was named 'Optocal - Brazilian version'. A volume of 3 cm(3) is indicated for a chewing test, which corresponds to 12 tablets using the present methodology. The present protocol can make the production of this chewable material easier, helping in its standardization for studies on masticatory function.


Psychosocial service utilization by patients with bipolar disorders: data from the first 500 participants in the Systematic Treatment Enhancement Program.
Although patients with bipolar disorder have been shown to benefit from psychosocial interventions, the proportion that utilizes these interventions is unknown. We set out to clarify the determinants of psychosocial service utilization in adults with bipolar disorder. We investigated psychosocial service utilization among the first 500 patients admitted to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). In the 3 months prior to enrollment in STEP-BD, a majority of the patients (54%) were engaged in at least one psychosocial service modality in addition to pharmacotherapy. In order of decreasing frequency, these were therapy with a psychologist, self-help group, therapy with a social worker, and therapy with another type of provider. Bipolar patients with personality disorders (80% vs 20%, p = 0.0002), alcohol/drug abuse disorders (76% vs 24%, p = 0.0022), and anxiety disorders (60% vs 40%, p = 0.0043) received more psychosocial services than those without. Poorer global functioning also increased the likelihood of receiving services, whereas being married decreased service utilization. Psychosocial service utilization by outpatients with bipolar disorder is strongly linked to greater severity/complexity of illness. Potential moderators, such as insurance status and availability of care, should be examined in future studies.


Bartonella species in fleas from Palestinian territories: prevalence and genetic diversity.
Bartonellosis is an infectious bacterial disease. The prevalence and genetic characteristics of Bartonella spp. in fleas of wild and domestic animals from Palestinian territories are described. Flea samples (n=289) were collected from 121 cats, 135 dogs, 26 hyraxes and seven rats from northern (n=165), central (n=113), and southern Palestinian territories (n=11). The prevalent flea species were: Ctenocephalides felis (n=119/289; 41.2%), Ctenocephalides canis (n=159/289; 55%), and Xenopsylla sp. (n=7/289; 2.4%). Targeting the Intergenic Transcribed Spacer (ITS) locus, DNA of Bartonella was detected in 22% (64/289) of all fleas. Fifty percent of the C. felis and 57% of the Xenopsylla sp. contained Bartonella DNA. DNA sequencing showed the presence of Bartonella clarridgeiae (50%), Bartonella henselae (27%), and Bartonella koehlerae (3%) in C. felis. Xenopsylla sp. collected from Rattus rattus rats were infected with Bartonella tribocorum, Bartonella elizabethae, and Bartonella rochalimae. Phylogenetic sequence analysis using the 16S ribosomal RNA gene obtained four genetic clusters, B. henselae and B. koehlerae as subcluster 1, B. clarridgeiae as cluster 2, while the rat Bartonella species (B. tribocorum and B. elizabethae) were an outgroup cluster. These findings showed the important role of cat and rat fleas as vectors of zoonotic Bartonella species in Palestinian territories. It is hoped that this publication will raise awareness among physicians, veterinarians, and other health workers of the high prevalence of Bartonella spp. in fleas in Palestinian territories and the potential risk of these pathogens to humans and animals in this region.


Stability of 35 biochemical and immunological routine tests after 10 hours storage and transport of human whole blood at 21°C.
Suitable procedures for transport of blood samples from general practitioners to hospital laboratories are requested. Here we explore routine testing on samples stored and transported as whole blood in lithium-heparin or serum tubes. Blood samples were collected from 106 hospitalized patients, and analyzed on Architect c8000 or Advia Centaur XP for 35 analytes at base line, and after storage and transport of whole blood in lithium-heparin or serum tubes at 21 ± 1°C for 10 h. Bias and imprecision (representing variation from analysis and storage) were calculated from values at baseline and after storage, and differences tested by paired t-tests. Results were compared to goals set by the laboratory. We observed no statistically significant bias and results within the goal for imprecision between baseline samples and 10-h samples for albumin, alkaline phosphatase, antitrypsin, bilirubin, creatinine, free triiodothyronine, γ-glutamyl transferase, haptoglobin, immunoglobulin G, lactate dehydrogenase, prostate specific antigen, total carbon dioxide, and urea. Alanine aminotransferase, amylase, C-reactive protein, calcium, cholesterol, creatine kinase, ferritin, free thyroxine, immunoglobulin A, immunoglobulin M, orosomucoid, sodium, transferrin, and triglycerides met goals for imprecision, though they showed a minor, but statistically significant bias in results after storage. Cobalamin, folate, HDL-cholesterol, iron, phosphate, potassium, thyroid stimulating hormone and urate warranted concern, but only folate and phosphate showed deviations of clinical importance. We conclude that whole blood in lithium-heparin or serum tubes stored for 10 h at 21 ± 1°C, may be used for routine analysis without restrictions for all investigated analytes but folate and phosphate.


Apparent cochlear nerve aplasia: to implant or not to implant?
To describe the imaging findings and clinical outcomes of children with apparent cochlear nerve aplasia undergoing cochlear implantation. Retrospective case review. Tertiary care center. Three patients with imaging findings consistent with absent cochlear nerve canal on diagnostic imaging and questionable audiometric responses on testing who underwent promontory stimulation and subsequent cochlear implantation. Magnetic resonance imaging and computed tomography, audiologic assessment, and cochlear implantation. Audiologic performance after cochlear implantation. Three patients were identified to have hearing loss on newborn hearing screening and underwent auditory brainstem response testing revealing absent brainstem responses. ASSR testing was inconclusive when performed. Imaging in all cases identified 1 ear with a small internal auditory canal with 2 nerves present, one of which seems to enter the vestibule in each case and the other is assumed to be the functioning facial nerve. There was a bony plate present over the entrance to the cochlea in 2 of the 3 patients. Over time, 2 of the families reported responses to auditory stimuli with amplification. Promontory stimulation testing showed reproducible responses to electrical stimuli in the ears in question. After cochlear implantation, all 3 patients have shown responses to auditory stimuli. The absence of a visible cochlear nerve or cochlear nerve canal on radiologic imaging does not preclude auditory innervation of the cochlea. Cochlear implantation can be a viable option for patients with apparent cochlear nerve aplasia who have undergone appropriate testing. Electronically evoked auditory brainstem response is critical in the evaluation of this patient group.


Characterization of histopathology and gene-expression profiles of synovitis in early rheumatoid arthritis using targeted biopsy specimens.
The disease category of early rheumatoid arthritis (RA) has been limited with respect to clinical criteria. Pathological manifestations of synovitis in patients whose disease is clinically classified as early RA seem to be heterogeneous, with regular variations. To clarify the relation between the molecular and histopathological features of the synovitis, we analyzed gene-expression profiles in the synovial lining tissues to correlate them with histopathological features. Synovial tissues were obtained from knee joints of 12 patients with early RA by targeted biopsy under arthroscopy. Surgical specimens of long-standing RA (from four patients) were examined as positive controls. Each histopathological parameter characteristic of rheumatoid synovitis in synovial tissues was scored under light microscopy. Total RNAs from synovial lining tissues were obtained from the specimens selected by laser capture microdissection and the mRNAs were amplified by bacteriophage T7 RNA polymerase. Their cDNAs were analyzed in a cDNA microarray with 23,040 cDNAs, and the levels of gene expression in multilayered lining tissues, compared with those of normal-like lining tissues in specimens from the same person, were determined to estimate gene-expression profiles characteristic of the synovial proliferative lesions in each case. Based on cluster analysis of all cases, gene-expression profiles in the lesions in early RA fell into two groups. The groups had different expression levels of genes critical for proliferative inflammation, including those encoding cytokines, adhesion molecules, and extracellular matrices. One group resembled synovitis in long-standing RA and had high scores for some histopathological features - involving accumulations of lymphocytes and plasma cells - but not for other features. Possible differences in the histopathogenesis and prognosis of synovitis between the two groups are discussed in relation to the candidate genes and histopathology.


Cancer Antigen 125 Levels are Significantly Associated With Prognostic Parameters in Uterine Papillary Serous Carcinoma.
Uterine papillary serous carcinoma (UPSC) is a highly aggressive subtype of endometrial carcinoma. Histopathologically, it resembles the pattern of serous papillary carcinoma of the ovary. Cancer antigen 125 (CA-125) is the most widely used biomarker in epithelial ovarian carcinoma. Its use in UPSC evaluation has yet to be determined. The purpose of this study was to investigate the significance of preoperative serum CA-125 as a prognostic factor in patients with UPSC. The study cohort included all women with UPSC operated in our institution between January 2002 and June 2016. All patients underwent complete surgical staging. Preoperative CA-125 was reviewed and correlated with clinical and pathological parameters. Sixty-one women met the study criteria. Median preoperative CA-125 was found to be significantly associated with disease stage. Patients with disease stages I to IV had median preoperative CA-125 levels of 12.15, 19.6, 22.6, and 177.5 U/mL (P < 0.0001) respectively. Levels of CA-125 were significantly associated with positive cytology (P < 0.0001), omental disease (P < 0.0001), pelvic or para-aortic lymph node metastasis (P < 0.0001), and adnexal involvement (P < 0.0001). The optimal cutoff that provided the best sensitivity and specificity for omental and parametrial involvement as well as positive cytology was 57.5 U/mL. For adnexal and lymph node involvement, the optimal cutoff value was 41.8 U/mL. In patients with UPSC, preoperative CA-125 level correlates with known prognostic parameters of endometrial carcinoma and is associated with extrauterine involvement. These data should stimulate the need for further evaluation of the role of CA-125 in predicting recurrence and survival in UPSC.


Dysplasia of the upper aerodigestive tract squamous epithelium.
Dysplasia of the oral, laryngeal and oropharyngeal stratified squamous epithelia is a microscopically defined change that may occur in clinically identifiable lesions including erythroplakia, leukoplakia and erythroleukoplakia, lesions that convey a heightened risk for carcinomatous progression. Dysplastic lesions have been classified microscopically according to degree of cytologic atypia and changes in architectural patterns, usually on a three part or four part gradation scale. Vocal cord epithelial lesions are graded according to either the Ljubljana or the World Health Organization (WHO) system whereas oral dysplasias are generally classified according to WHO criteria. Cytologically atypical cells are considered to represent precancerous changes predicting an increase risk for carcinomatous transformation. Inter- and intra-rater reliability studies among pathologists have disclosed low correlation coefficients for four part grading systems, whereas improved agreement is achieved (kappa correlation values) using the Ljubljana systems. Evidence forwarded by some studies supports the prognostic value of progressively severe dysplastic changes for carcinomatous transformation; however, some studies indicate that the presence of a clinically defined lesion without microscopic evidence of dysplasia also connotes increased risk for carcinomatous transformation. Loss of heterozygosity (LOH) at 3p and 9p microsatellite domains, DNA ploidy analysis and nuclear image analyses may have predictive value as molecular and histomorphological biomarkers.


Microbial contamination of pig carcasses at a slaughterhouse in Vientiane capital, Lao PDR.
A cross-sectional study was conducted to determine microbial contamination of pig carcasses at a slaughterhouse in Vientiane, capital of Lao People Democratic Republic (Lao PDR). Between November 2004 and April 2005, 62 pig carcasses were randomly selected. From each carcass, pooled swabs (from "1" prior to and "2" after evisceration) and 25 g of tissue of mesenteric lymph nodes (MLN) were collected. The swab samples were examined for Aerobic Plate Count (APC) and Enterobacteriaceae Counts (EBC) and cultured for Salmonella. The lymph nodes were cultured for Salmonella only. Swabs1 and 2 had mean APC of 4.70 and 4.85 log10CFU/cm2, respectively. These two means were significantly (p = 0.0001) different. The means of EBC were 2.81 log10CFU/cm2 for Swab 1, and 2.98 log10CFU/cm2 for Swab 2. The difference were also statistical significant (p = 0.0001). The frequency of Salmonella isolation from Swab 1 was 46.8%, for Swab 2 was 66.1%, and from mesenteric lymphnodes was 53.2%. Eight different Salmonella serotypes were identified. The most frequent (29.1%) serotype was S. Rissen, followed by S. Anatum (26.2%), S. Derby (18.4%), and S. Elisabethville (8.7%). The other serotypes identified were S. Amsterdam (7.8%), S. Typhimurium (4.9%), S. Agona (2.9%), and S. Enteritidis (1.9%). Results of this study showed the levels of contamination with aerobic bacteria and Enterobacteriaceae were higher than recommended standards, and the carcasses were contaminated with Salmonella.


Higher order optical vortices and formation of speckles.
We have experimentally generated higher order optical vortices and scattered them through a ground glass plate that results in speckle formation. Intensity autocorrelation measurements of speckles show that their size decreases with an increase in the order of the vortex. It implies an increase in the angular diameter of the vortices with their order. The characterization of vortices in terms of their annular bright ring also helps us to understand these observations. The results may find applications in stellar intensity interferometry and thermal ghost imaging.


Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis--an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks.
There are several guidelines addressing the issues around the use of NSAIDs. However, none has specifically addressed the upper versus lower gastrointestinal (GI) risk of COX-2 selective and non-selective compounds nor the interaction at both the GI and cardiovascular (CV) level of either class of drugs with low-dose aspirin. This Consensus paper aims to develop statements and guidance devoted to these specific issues through a review of current evidence by a multidisciplinary group of experts. A modified Delphi consensus process was adopted to determine the level of agreement with each statement and to determine the level of agreement with the strength of evidence to be assigned to the statement. For patients with both low GI and CV risks, any non-selective NSAID (ns-NSAID) alone may be acceptable. For those with low GI and high CV risk, naproxen may be preferred because of its potential lower CV risk compared with other ns-NSAIDs or COX-2 selective inhibitors, but celecoxib at the lowest approved dose (200 mg once daily) may be acceptable. In patients with high GI risk, if CV risk is low, a COX-2 selective inhibitor alone or ns-NSAID with a proton pump inhibitor appears to offer similar protection from upper GI events. However, only celecoxib will reduce mucosal harm throughout the entire GI tract. When both GI and CV risks are high, the optimal strategy is to avoid NSAID therapy, if at all possible. Time is now ripe for offering patients with osteoarthritis the safest and most cost-effective therapeutic option, thus preventing serious adverse events which could have important quality of life and resource use implications. Please see related article: http://dx.doi.org/10.1186/s12916-015-0291-x.


Establishing a community of practice for dementia champions (innovative practice).
This discussion paper considers the currently evolving roles of dementia champions and describes an initiative designed to support their activities. The aim of this initiative was to establish a county-wide group that has a shared group identity and sufficient critical mass that is able to identify and implement dementia training and development needs for the health and social care workforce. The approach used to achieve this aim was a Dementia Champion Community of Practice Project, which involved dementia leads in various NHS Trusts. Whilst this approach might be effective at practitioner level, the Dementia Champion Community of Practice Project experience suggests that if such initiatives are to be sustainable they need to be strategically placed within networks that can bring together service providers, educators and commissioners.


FDG volumetric parameters and survival outcomes after definitive chemoradiotherapy in patients with recurrent head and neck squamous cell carcinoma.
The purpose of this study was to establish the predictive value of (18)F-FDG parameters for overall survival in biopsy-proven recurrent head and neck squamous cell cancer (HNSCC) patients after definitive chemoradiotherapy. We conducted a retrospective study including 34 patients with HNSCC who had biopsy-proven recurrence between April 2004 and March 2012 and underwent FDG PET/CT at our institution at the time of recurrence. Maximum standardized uptake value (SUVmax), peak SUV (SUVpeak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured. The primary outcome measure was overall survival. ROC analysis, univariate and multivariate Cox regression models, and Kaplan-Meir survival curves were performed. In univariate analyses, human papillomavirus (HPV) status (p = 0.04), primary site recurrence of MTV (p = 0.03), metastasis of MTV (p = 0.02), metastasis of TLG (p = 0.02), total MTV (p = 0.002), and total TLG (p = 0.04) were significantly associated with overall survival outcome. Total MTV remained as significant independent prognostic factor when adjusted for all other covariates except for primary site recurrence SUVmax and SUVpeak and lymph node SUVmax and SUVpeak. There was a significant difference in time to survival between patients with total MTV above and below the 50th percentile (Mantel-Cox log-rank test, p = 0.05 and Gehan-Breslow-Wilcoxon test, p = 0.03) and the optimum threshold of 16.8 mL (Mantel-Cox log-rank test, p = 0.01 and Gehan-Breslow-Wilcoxon test, p = 0.01; hazard ratio [HR], 0.25). FDG PET/CT-based total MTV and clinical HPV status may be significant prognostic markers for overall survival of patients with recurrent HNSCC after definitive chemoradiotherapy.


Optimal SARS-CoV-2 vaccine allocation using real-time seroprevalence estimates in Rhode Island and Massachusetts.
As three SARS-CoV-2 vaccines come to market in Europe and North America in the winter of 2020-2021, distribution networks will be in a race against a major epidemiological wave of SARS-CoV-2 that began in autumn 2020. Rapid and optimized vaccine allocation is critical during this time. With 95% efficacy reported for two of the vaccines, near-term public health needs require that distribution is prioritized to the elderly, health-care workers, teachers, essential workers, and individuals with co-morbidities putting them at risk of severe clinical progression. Here, we evaluate various age-based vaccine distributions using a validated mathematical model based on current epidemic trends in Rhode Island and Massachusetts. We allow for varying waning efficacy of vaccine-induced immunity, as this has not yet been measured. We account for the fact that known COVID-positive cases may not be included in the first round of vaccination. And, we account for current age-specific immune patterns in both states. We find that allocating a substantial proportion ( > 75%) of vaccine supply to individuals over the age of 70 is optimal in terms of reducing total cumulative deaths through mid-2021. As we do not explicitly model other high mortality groups, this result on vaccine allocation applies to all groups at high risk of mortality if infected. Our analysis confirms that for an easily transmissible respiratory virus, allocating a large majority of vaccinations to groups with the highest mortality risk is optimal. Our analysis assumes that health systems during winter 2020-2021 have equal staffing and capacity to previous phases of the SARS-CoV-2 epidemic; we do not consider the effects of understaffed hospitals or unvaccinated medical staff. Vaccinating only seronegative individuals avoids redundancy in vaccine use on individuals that may already be immune, and will result in 1% to 2% reductions in cumulative hospitalizations and deaths by mid-2021. Assuming high vaccination coverage ( > 28%) and no major relaxations in distancing, masking, gathering size, or hygiene guidelines between now and spring 2021, our model predicts that a combination of vaccination and population immunity will lead to low or near-zero transmission levels by the second quarter of 2021.


Minimum distance between pattern transformation manifolds: algorithm and applications.
Transformation invariance is an important property in pattern recognition, where different observations of the same object typically receive the same label. This paper focuses on a transformation-invariant distance measure that represents the minimum distance between the transformation manifolds spanned by patterns of interest. Since these manifolds are typically nonlinear, the computation of the manifold distance (MD) becomes a nonconvex optimization problem. We propose representing a pattern of interest as a linear combination of a few geometric functions extracted from a structured and redundant basis. Transforming the pattern results in the transformation of its constituent parts. We show that, when the transformation is restricted to a synthesis of translations, rotations, and isotropic scalings, such a pattern representation results in a closed-form expression of the manifold equation with respect to the transformation parameters. The MD computation can then be formulated as a minimization problem whose objective function is expressed as the difference of convex functions (DC). This interesting property permits optimally solving the optimization problem with DC programming solvers that are globally convergent. We present experimental evidence which shows that our method is able to find the globally optimal solution, outperforming existing methods that yield suboptimal solutions.


Proximal femoral structure and the prediction of hip fracture in men: a large prospective study using QCT.
The structure of the femoral neck contributes to hip strength, but the relationship of specific structural features of the hip to hip fracture risk is unclear. The objective of this study is to determine the contribution of structural features and volumetric density of both trabecular and cortical bone in the proximal femur to the prediction of hip fracture in older men. Baseline QCT scans of the hip were obtained in 3347 men >or=65 yr of age enrolled in the Osteoporotic Fractures in Men Study (MrOS). All men were followed prospectively for an average of 5.5 yr. Areal BMD (aBMD) by DXA was also assessed. We determined the associations between QCT-derived measures of femoral neck structure, volumetric bone density, and hip fracture risk. Forty-two men sustained incident hip fractures during follow-up: an overall rate of 2.3/1000 person-years. Multivariable analyses showed that, among the QCT-derived measures, lower percent cortical volume (hazard ratio [HR] per SD decrease: 3.2; 95% CI: 2.2-4.6), smaller minimal cross-sectional area (HR: 1.6; 95% CI: 1.2-2.1), and lower trabecular BMD (HR: 1.7; 95% CI: 1.2-2.4) were independently related to increased hip fracture risk. Femoral neck areal BMD was also strongly related to hip fracture risk (HR: 4.1; 95% CI: 2.7-6.4). In multivariable models, percent cortical volume and minimum cross-sectional area remained significant predictors of hip fracture risk after adjustment for areal BMD, but overall prediction was not improved by adding QCT parameters to DXA. Specific structural features of the proximal femur were related to an increased risk of hip fracture. Whereas overall hip fracture prediction was not improved relative to aBMD, by adding QCT parameters, these results yield useful information concerning the causation of hip fracture, the evaluation of hip fracture risk, and potential targets for therapeutic intervention.


Effect of disease-related pain on the health-related quality of life of children and adolescents with cystic fibrosis.
The authors' objective was to describe the effect of recurrent pain symptoms on the health-related quality of life (HRQOL) of children and adolescents with cystic fibrosis (CF). Frequent pain, independent of disease severity, was hypothesized to be associated with broad decrements in physical, psychological, and social functioning. Forty-six children and adolescents (mean age 12.9 years; 52% female) completed the Cystic Fibrosis Questionnaire-Revised (CFQ-R) to assess their HRQOL and a retrospective pain interview to assess pain location, frequency, intensity, duration, and bother during a routine clinic visit. Forced expiratory volume in 1 second as percent of predicted (FEV1%) was recorded from medical charts to assess the children's disease severity. As hypothesized, pain symptoms were related to children's physical, emotional, and role functioning, CF-related symptoms, and overall perception of their health. Children with frequent pain had significantly reduced physical functioning, vitality, role limitations, and overall perceptions of their health, and increased eating disturbances, treatment burden, respiratory, and digestive symptoms compared with children with no pain or less frequent pain. After controlling for the effects of disease severity, pain frequency continued to predict children's HRQOL in each of these areas. Children with frequent CF-related pain experienced broad decrements in their HRQOL. These findings are similar to those found in other populations of children experiencing disease-related pain, suggesting a pervasive impact of pain on overall health and well-being. Future research is needed to evaluate treatments to reduce pain symptoms and improve HRQOL in children with cystic fibrosis.


New Approaches to Continuing Medical Education: a QStream (spaced education) Program for Research Translation in Ovarian Cancer.
Continuing medical education (CME) is challenging and often has limited impact on clinician behavior or patient outcomes. This study examined the impact of an online Qstream education program on senior clinicians to determine its utility for increasing clinician knowledge about the latest guidelines regarding genetic assessment and consideration of genetic testing for women with particular types of ovarian, fallopian tube and primary peritoneal cancer. Participants were recruited into a pilot study that involved responding to case-based scenarios at spaced and repeated intervals. At the completion of the program, semi-structured interviews were conducted to ascertain the impact on their knowledge and referral behavior. Findings from interviews were subject to thematic analysis that involved the identification of categories and themes. Twenty-one participants commenced the program, seventeen completed and twelve participated in semi-structured interviews. Thematic analysis yielded several themes including knowledge change, curriculum and format and changes in referral patterns. A majority of participants (n = 10) agreed the program had helped update their knowledge about referring women, and eight agreed they would now change their referral patterns. The use of QStream as an approach to CME has significant advantages when working with busy clinicians. QStream has a well accepted format and most participants indicated it is very appropriate for disseminating updates to clinical guidelines and protocols. It is important to supplement CME programs with other implementation techniques, such as audit and feedback as multifaceted approaches are more likely to result in behavior change.


Complications associated with surgical repair of syndromic scoliosis.
There are a number of syndromes that have historically been associated with scoliosis e.g.: Marfan, Down, and Neurofibromatosis. These syndromes have been grouped together as one etiology of scoliosis, known as syndromic scoliosis. While multiple studies indicate that these patients are at high risk for perioperative complications, there is a paucity of literature regarding the collective complication rates and surgical needs of this population. PubMed and Embase databases were searched for literature encompassing the surgical complications associated with the surgical management of patients undergoing correction of scoliosis in the syndromic scoliosis population. Following exclusion criteria, 24 articles were analyzed for data regarding these complications. The collective complication rates and findings of these articles were categorized based on specific syndrome. The rates and types of complications for each syndrome and the special needs of patients with each syndrome are discussed. Several complication trends of note were observed, including but not limited to the universally nearly high rate of wound infections (>5% in each group), high rate of pulmonary complications in patients with Rett syndrome (29.2%), high rate (>10%) of dural tears in Marfan and Ehlers-Danlos syndrome patients, high rate (>20%) of implant failure in Down and Prader-Willi syndrome patients, and high rate (>25%) of pseudarthrosis in Down and Ehlers-Danlos patients. Though these syndromes have been classically grouped together under the umbrella term "syndromic," there may be specific needs for patients with each of these ailments. Given the high rate of complications, further research is necessary to understand the unique needs for each of these patient groups in the preoperative, intraoperative, and postoperative settings.


Traditional massage of newborns in Nepal: implications for trials of improved practice.
Mustard oil massage of newborns is an integral component of traditional care practices in many communities. Recent evidence suggests that this practice may have detrimental effects, particularly for preterm infants or for those whose skin barrier function is otherwise sub-optimal. Other natural oils such as sunflower, sesame or safflower seed oil may have a beneficial impact on newborn health and survival. Little is known, however, about cultural and other factors related to the acceptance and uptake of alternative, more beneficial oils for massage of the newborn. A questionnaire concerning the usage and reasons for application of mustard and other oils to newborn skin was administered to the caretakers of 8580 newborns in Sarlahi district of rural Nepal. Four focus group discussions among representative groups were conducted to describe the perceived benefits of oil massage and the factors involved in the decision to apply oil. The potential for the introduction of alternative natural oils was explored. Approximately 99 per cent of newborns were massaged at least once with mustard oil in the 2 weeks after birth, and 80 per cent were massaged at least twice daily. Promotion of strength, maintenance of health, and provision of warmth were the most commonly cited reasons for application of mustard oil. Focus group discussion participants noted that smell, oiliness, mode of pre-massage preparation, and perceived absorptive potential on the skin are important contextual factors involved in the practice. Caretakers are willing to consider adaptation of established traditions for the promotion of positive health outcomes if essential contextual criteria are met. An understanding of cultural, social, and economic factors that shape the context of traditional healthcare practices is essential to the design and implementation of intervention trials examining the relative efficacy of application of oils in reducing neonatal mortality and morbidity.


Palladium-catalysed inter- and intramolecular formation of C-O bonds from allenes.
The Pd-catalysed formation of a C-O bond from allenes mainly occurs via the inter- or intramolecular reaction with a hydroxyl group belonging to an alcohol, a phenol or an acid. A carbonyl or a carbonate entity can also be involved. In most cases, the formation of the C-O bond is one step of a domino reaction leading also to a C-C or C-N bond, or to another C-O bond. Thus, a wide range of products, in particular highly functionalized heterocycles, have been synthesised. Catalytic cycles have been proposed but the mechanisms often remain speculative.


Multiparametric analyses reveal the pH-dependence of silicon biomineralization in diatoms.
Diatoms, the major contributors of the global biogenic silica cycle in modern oceans, account for about 40% of global marine primary productivity. They are an important component of the biological pump in the ocean, and their assemblage can be used as useful climate proxies; it is therefore critical to better understand the changes induced by environmental pH on their physiology, silicification capability and morphology. Here, we show that external pH influences cell growth of the ubiquitous diatom Thalassiosira weissflogii, and modifies intracellular silicic acid and biogenic silica contents per cell. Measurements at the single-cell level reveal that extracellular pH modifications lead to intracellular acidosis. To further understand how variations of the acid-base balance affect silicon metabolism and theca formation, we developed novel imaging techniques to measure the dynamics of valve formation. We demonstrate that the kinetics of valve morphogenesis, at least in the early stages, depends on pH. Analytical modeling results suggest that acidic conditions alter the dynamics of the expansion of the vesicles within which silica polymerization occurs, and probably its internal pH. Morphological analysis of valve patterns reveals that acidification also reduces the dimension of the nanometric pores present on the valves, and concurrently overall valve porosity. Variations in the valve silica network seem to be more correlated to the dynamics and the regulation of the morphogenesis process than the silicon incorporation rate. These multiparametric analyses from single-cell to cell-population levels demonstrate that several higher-level processes are sensitive to the acid-base balance in diatoms, and its regulation is a key factor for the control of pattern formation and silicon metabolism.


TorsinA controls TAN line assembly and the retrograde flow of dorsal perinuclear actin cables during rearward nuclear movement.
The nucleus is positioned toward the rear of most migratory cells. In fibroblasts and myoblasts polarizing for migration, retrograde actin flow moves the nucleus rearward, resulting in the orientation of the centrosome in the direction of migration. In this study, we report that the nuclear envelope-localized AAA+ (ATPase associated with various cellular activities) torsinA (TA) and its activator, the inner nuclear membrane protein lamina-associated polypeptide 1 (LAP1), are required for rearward nuclear movement during centrosome orientation in migrating fibroblasts. Both TA and LAP1 contributed to the assembly of transmembrane actin-associated nuclear (TAN) lines, which couple the nucleus to dorsal perinuclear actin cables undergoing retrograde flow. In addition, TA localized to TAN lines and was necessary for the proper mobility of EGFP-mini-nesprin-2G, a functional TAN line reporter construct, within the nuclear envelope. Furthermore, TA and LAP1 were indispensable for the retrograde flow of dorsal perinuclear actin cables, supporting the recently proposed function for the nucleus in spatially organizing actin flow and cytoplasmic polarity. Collectively, these results identify TA as a key regulator of actin-dependent rearward nuclear movement during centrosome orientation.


A Novel Real-Time Reference Key Frame Scan Matching Method.
Unmanned aerial vehicles represent an effective technology for indoor search and rescue operations. Typically, most indoor missions' environments would be unknown, unstructured, and/or dynamic. Navigation of UAVs in such environments is addressed by simultaneous localization and mapping approach using either local or global approaches. Both approaches suffer from accumulated errors and high processing time due to the iterative nature of the scan matching method. Moreover, point-to-point scan matching is prone to outlier association processes. This paper proposes a low-cost novel method for 2D real-time scan matching based on a reference key frame (RKF). RKF is a hybrid scan matching technique comprised of feature-to-feature and point-to-point approaches. This algorithm aims at mitigating errors accumulation using the key frame technique, which is inspired from video streaming broadcast process. The algorithm depends on the iterative closest point algorithm during the lack of linear features which is typically exhibited in unstructured environments. The algorithm switches back to the RKF once linear features are detected. To validate and evaluate the algorithm, the mapping performance and time consumption are compared with various algorithms in static and dynamic environments. The performance of the algorithm exhibits promising navigational, mapping results and very short computational time, that indicates the potential use of the new algorithm with real-time systems.


The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases.
Mutations in isocitrate dehydrogenases (IDHs) have a gain-of-function effect leading to R(-)-2-hydroxyglutarate (R-2HG) accumulation. By using biochemical, structural and cellular assays, we show that either or both R- and S-2HG inhibit 2-oxoglutarate (2OG)-dependent oxygenases with varying potencies. Half-maximal inhibitory concentration (IC(50)) values for the R-form of 2HG varied from approximately 25 μM for the histone N(ɛ)-lysine demethylase JMJD2A to more than 5 mM for the hypoxia-inducible factor (HIF) prolyl hydroxylase. The results indicate that candidate oncogenic pathways in IDH-associated malignancy should include those that are regulated by other 2OG oxygenases than HIF hydroxylases, in particular those involving the regulation of histone methylation.


Gender effects in children's beliefs about school performance: a cross-cultural study.
Do young boys and girls understand what leads to academic success (e.g., talent, effort, good teaching, luck) in the same way? Do young girls and boys have equivalent perceptions of their academic competence? Are these beliefs engendered in the same way across sociocultural contexts? In a cross-cultural study of over 3,000 children in grades 2 to 6, ages 7.2 to 13.6, we discovered that boys and girls around the world have very similar ideas about what generally leads to academic success. Moreover, in the few contexts where boys' and girls' academic performances were equal, their beliefs were also equal. However, when girls outperformed boys, their beliefs in their own talent were no greater than boys' beliefs, even though they did have stronger beliefs than boys in other facets of their achievement potential (e.g., putting forth effort, being lucky, getting their teacher's help). Our findings support the generally close correspondence between children's achievement and their competence-related beliefs, with the exception that young girls appear to specifically discount their talent. The effects held regardless of the children's achievement, intelligence, or age (approximately 8 to 13 years). Girls were more biased in some contexts than in others, however, suggesting that competence-related biases are rooted in culture-specific aspects of school settings.


The involvement of a protein kinase in phototaxis and gravitaxis of Euglena gracilis.
The unicellular flagellate Euglena gracilis shows positive phototaxis at low-light intensities (<10 W/m(2)) and a negative one at higher irradiances (>10 W/m(2)). Phototaxis is based on blue light-activated adenylyl cyclases, which produce cAMP upon irradiation. In the absence of light the cells swim upward in the water column (negative gravitaxis). The results of sounding rocket campaigns and of a large number of ground experiments led to the following model of signal perception and transduction in gravitaxis of E. gracilis: The body of the cell is heavier than the surrounding medium, sediments and thereby exerts a force onto the lower membrane. Upon deviation from a vertical swimming path mechano-sensitive ion channels are activated. Calcium is gated inwards which leads to an increase in the intracellular calcium concentration and causes a change of the membrane potential. After influx, calcium activates one of several calmodulins found in Euglena, which in turn activates an adenylyl cyclase (different from the one involved in phototaxis) to produce cAMP from ATP. One further element in the sensory transduction chain of both phototaxis and gravitaxis is a specific protein kinase A. We found five different protein kinases A in E. gracilis. The blockage of only one of these (PK.4, accession No. EU935859) by means of RNAi inhibited both phototaxis and gravitaxis, while inhibition of the other four affected neither phototaxis nor gravitaxis. It is assumed that cAMP directly activates this protein kinase A which may in turn phosphorylate a protein involved in the flagellar beating mechanism.


Nut consumption on all-cause, cardiovascular, and cancer mortality risk: a systematic review and meta-analysis of epidemiologic studies.
Recent pooled analyses supported a beneficial impact of nut consumption on health, but to our knowledge, whether nuts are associated with overall decreased mortality has not been previously reviewed. We aimed to systematically review prospective studies that explored the effects of nut consumption on all-cause, cardiovascular disease (CVD), and cancer mortality and quantify the size effect through a meta-analysis. We also reviewed confounding factors associated with nut consumption to assess potential clustering with other covariates. We searched PubMed and EMBASE for studies published up to June 2014. Study characteristics, HRs, and 95% CIs were generated on the basis of quantitative analyses. A dose-response analysis was performed when data were available. Seven studies for all-cause mortality, 6 studies for CVD mortality, and 2 studies for cancer mortality were included in the meta-analysis with a total of 354,933 participants, 44,636 cumulative incident deaths, and 3,746,534 cumulative person-years. Nut consumption was associated with some baseline characteristics such as lower body mass index and smoking status as well as increased intakes of fruit, vegetables, and alcohol. One-serving of nuts per week and per day resulted in 4% (RR: 0.96; 95% CI: 0.93, 0.98) and 27% (RR: 0.73; 95% CI: 0.60, 0.88) decreased risk of all-cause mortality, respectively, and decreased risk of CVD mortality [RR: 0.93 (95% CI: 0.88, 0.99) and 0.61 (95% CI: 0.42, 0.91), respectively]. Effects were primarily driven by decreased coronary artery disease deaths rather than stroke deaths. Nut consumption was also associated with decreased risk of cancer deaths when highest compared with lowest categories of intake were compared (RR: 0.86; 95% CI: 0.75, 0.98), but no dose-effect was shown. Nut consumption is associated with lower risk of all-cause, CVD, and cancer mortality, but the presence of confounding factors should be taken into account when considering such findings.