Genetic anchoring of whole-genome shotgun assemblies.
The recent advances in sequencing throughput and genome assembly algorithms have established whole-genome shotgun (WGS) assemblies as the cornerstone of the genomic infrastructure for many species. WGS assemblies can be constructed with comparative ease and give a comprehensive representation of the gene space even of large and complex genomes. One major obstacle in utilizing WGS assemblies for important research applications such as gene isolation or comparative genomics has been the lack of chromosomal positioning and contextualization of short sequence contigs. Assigning chromosomal locations to sequence contigs required the construction and integration of genome-wide physical maps and dense genetic linkage maps as well as synteny to model species. Recently, methods to rapidly construct ultra-dense linkage maps encompassing millions of genetic markers from WGS sequencing data of segregating populations have made possible the direct assignment of genetic positions to short sequence contigs. Here, we review recent developments in the integration of WGS assemblies and sequence-based linkage maps, discuss challenges for further improvement of the methodology and outline possible applications building on genetically anchored WGS assemblies.


Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling.
Developing tissues and growing tumours produce vascular endothelial growth factors (VEGFs), leading to the activation of the corresponding receptors in endothelial cells. The resultant angiogenic expansion of the local vasculature can promote physiological and pathological growth processes. Previous work has uncovered that the VEGF and Notch pathways are tightly linked. Signalling triggered by VEGF-A (also known as VEGF) has been shown to induce expression of the Notch ligand DLL4 in angiogenic vessels and, most prominently, in the tip of endothelial sprouts. DLL4 activates Notch in adjacent cells, which suppresses the expression of VEGF receptors and thereby restrains endothelial sprouting and proliferation. Here we show, by using inducible loss-of-function genetics in combination with inhibitors in vivo, that DLL4 protein expression in retinal tip cells is only weakly modulated by VEGFR2 signalling. Surprisingly, Notch inhibition also had no significant impact on VEGFR2 expression and induced deregulated endothelial sprouting and proliferation even in the absence of VEGFR2, which is the most important VEGF-A receptor and is considered to be indispensable for these processes. By contrast, VEGFR3, the main receptor for VEGF-C, was strongly modulated by Notch. VEGFR3 kinase-activity inhibitors but not ligand-blocking antibodies suppressed the sprouting of endothelial cells that had low Notch signalling activity. Our results establish that VEGFR2 and VEGFR3 are regulated in a highly differential manner by Notch. We propose that successful anti-angiogenic targeting of these receptors and their ligands will strongly depend on the status of endothelial Notch signalling.


Crucial role of mechanisms and modes of toxic action for understanding tissue residue toxicity and internal effect concentrations of organic chemicals.
This article reviews the mechanistic basis of the tissue residue approach for toxicity assessment (TRA). The tissue residue approach implies that whole-body or organ concentrations (residues) are a better dose metric for describing toxicity to aquatic organisms than is the aqueous concentration typically used in the external medium. Although the benefit of internal concentrations as dose metrics in ecotoxicology has long been recognized, the application of the tissue residue approach remains limited. The main factor responsible for this is the difficulty of measuring internal concentrations. We propose that environmental toxicology can advance if mechanistic considerations are implemented and toxicokinetics and toxicodynamics are explicitly addressed. The variability in ecotoxicological outcomes and species sensitivity is due in part to differences in toxicokinetics, which consist of several processes, including absorption, distribution, metabolism, and excretion (ADME), that influence internal concentrations. Using internal concentrations or tissue residues as the dose metric substantially reduces the variability in toxicity metrics among species and individuals exposed under varying conditions. Total internal concentrations are useful as dose metrics only if they represent a surrogate of the biologically effective dose, the concentration or dose at the target site. If there is no direct proportionality, we advise the implementation of comprehensive toxicokinetic models that include deriving the target dose. Depending on the mechanism of toxicity, the concentration at the target site may or may not be a sufficient descriptor of toxicity. The steady-state concentration of a baseline toxicant associated with the biological membrane is a good descriptor of the toxicodynamics of baseline toxicity. When assessing specific-acting and reactive mechanisms, additional parameters (e.g., reaction rate with the target site and regeneration of the target site) are needed for characterization. For specifically acting compounds, intrinsic potency depends on 1) affinity for, and 2) type of interaction with, a receptor or a target enzyme. These 2 parameters determine the selectivity for the toxic mechanism and the sensitivity, respectively. Implementation of mechanistic information in toxicokinetic-toxicodynamic (TK-TD) models may help explain time-delayed effects, toxicity after pulsed or fluctuating exposure, carryover toxicity after sequential pulses, and mixture toxicity. We believe that this mechanistic understanding of tissue residue toxicity will lead to improved environmental risk assessment.


Functional selectivity of orphanin FQ for its receptor coexpressed with potassium channel subunits in Xenopus laevis oocytes.
An opioid-like receptor has been cloned by several groups of researchers and recently shown to be activated by an endogenous heptadecapeptide termed orphanin FQ (or nociceptin). We isolated the corresponding mouse cDNA and coexpressed it in Xenopus laevis oocytes with the potassium channel subunits Kir3.1 (GIRK1) and Kir3.4 (CIR, rcKATP). Orphanin FQ evoked potassium currents, with 50% of the maximal effect at approximately 1 nM; [Tyr1]orphanin FQ was equally effective, and des-pheorphanin FQ was without activity. Dynorphin A, dynorphin(1-9), dynorphin(1-13), and alpha-neoendorphin were > 100 times less potent, and other agonists active at mu-, delta-, and kappa-opioid receptors had no effect. Naloxone (1 microM) and norbinaltorphimine (1 microM) had no antagonist action. Conversely, oocytes expressing kappa receptors responded to dynorphin (half-maximal concentration, 0.3 nM) but not to orphanin FQ. Thus, both kappa and orphanin FQ receptors readily couple to potassium channels, but the highly selective activation by dynorphin and orphanin FQ is consistent with distinct functional pathways in vivo.


Effect of the copepod parasite Nicothoë astaci on haemolymph chemistry of the European lobster Homarus gammarus.
The gills of the European lobster Homarus gammarus (L.) are susceptible to parasitization by the copepod Nicothoë astaci, the lobster louse. This copepod feeds on haemolymph of the host and can damage the gills, potentially affecting gaseous exchange capabilities. To investigate the host response to the parasite, haemolymph levels of total protein, haemocyanin, glucose and ammonia were quantified in adult lobsters carrying varying parasite loads. Parasite loads correlated positively with total haemolymph protein and haemocyanin concentrations but not with glucose or ammonia concentrations. The data suggest that lobsters with gills damaged by the feeding activities of N. astaci respond by producing higher levels of haemocyanin, which is both a key defence response and may compensate for their decreased respiratory functioning.


Altered O-glycan synthesis in lymphocytes from patients with Wiskott-Aldrich syndrome.
The only molecular defect reported for the X-linked immunodeficiency Wiskott-Aldrich syndrome (WAS) is the abnormal electrophoretic behavior of the major T lymphocyte sialoglycoprotein CD43. Since the 70 to 80 O-linked carbohydrate chains of CD43 are known to influence markedly its electrophoretic mobility, we analyzed the structure and the biosynthesis of O-glycans of CD43 in lymphocytes from patients with WAS. Immunofluorescence analysis with the carbohydrate dependent anti-CD43 antibody T305 revealed that in 10 out of the 12 WAS patients tested increased numbers of T lymphocytes carry on CD43 an epitope which on normal lymphocytes is expressed only after activation. Other activation antigens were absent from WAS lymphocytes. Western blots of WAS cell lysates displayed a high molecular mass form of CD43 which reacted with the T305 antibody and which could be found on in vivo activated lymphocytes but was absent from normal unstimulated lymphocytes. To examine the O-glycan structures, carbohydrate labeled CD43 was immunoprecipitated and the released oligosaccharides identified. WAS lymphocyte CD43 was found to carry predominantly the branched structure NeuNAc alpha 2----3Gal beta 1----3 (NeuNAc alpha 2----3Gal beta 1----4G1cNAc beta 1----6) GalNAcOH whereas normal lymphocytes carry the structure NeuNAc alpha 2----3Gal beta 1----3 (NeuNAc alpha 2----6) GalNAcOH. Only after activation NeuNAc alpha 2----3Gal beta 1----3 (NeuNAc alpha 2----3Gal beta 1----4GlcNAc beta 1----6) GalNAcOH becomes the principal oligosaccharide on CD43 from normal lymphocytes. Analyzing the six glycosyltransferases involved in the biosynthesis of these O-glycan structures it was found that in WAS lymphocytes high levels of beta 1----6 N-acetyl-glucosaminyl transferase are responsible for the expression of NeuNAc alpha 2----3Gal beta 1----3 (NeuNAc alpha 2----3Gal beta 1----4GlcNAc beta 1----6) GalNAcOH on CD43. The gene responsible for WAS has not yet been identified but the results presented in this study suggest that the primary defect in WAS may affect a gene which is involved in the regulation of O-glycosylation.


Paid family leave's effect on hospital admissions for pediatric abusive head trauma.
Paediatric abusive head trauma (AHT) is a leading cause of fatal child maltreatment among young children. Current prevention efforts have not been consistently effective. Policies such as paid parental leave could potentially prevent AHT, given its impacts on risk factors for child maltreatment. To explore associations between California's 2004 paid family leave (PFL) policy and hospital admissions for AHT, we used difference-in-difference analyses of 1995-2011 US state-level data before and after the policy in California and seven comparison states. Compared with seven states with no PFL policies, California's 2004 PFL showed a significant decrease in AHT admissions in both <1 and <2-year-olds. Analyses using additional data years and comparators could yield different results.


Transforming Regions into High-Performing Health Systems Toward the Triple Aim of Better Health, Better Care and Better Value for Canadians.
A study on the impact of regionalization on the Triple Aim of Better Health, Better Care and Better Value across Canada in 2015 identified major findings including: (a) with regard to the Triple Aim, the Canadian situation is better than before but variable and partial, and Canada continues to underperform compared with other industrialized countries, especially in primary healthcare where it matters most; (b) provinces are converging toward a two-level health system (provincial/regional); (c) optimal size of regions is probably around 350,000-500,000 population; d) citizen and physician engagement remains weak. A realistic and attainable vision for high-performing regional health systems is presented together with a way forward, including seven areas for improvement: 1. Manage the integrated regionalized health systems as results-driven health programs; 2. Strengthen wellness promotion, public health and intersectoral action for health; 3. Ensure timely access to personalized primary healthcare/family health and to proximity services; 4. Involve physicians in clinical governance and leadership, and partner with them in accountability for results including the required changes in physician remuneration; 5. Engage citizens in shaping their own health destiny and their health system; 6. Strengthen health information systems, accelerate the deployment of electronic health records and ensure their interoperability with health information systems; 7. Foster a culture of excellence and continuous quality improvement. We propose a turning point for Canada, from Paradigm Freeze to Paradigm Shift: from hospital-centric episodic care toward evidence-informed population-based primary and community care with modern family health teams, ensuring integrated and coordinated care along the continuum, especially for high users. We suggest goals and targets for 2020 and time-bound federal/provincial/regional working groups toward reaching the identified goals and targets and placing Canada on a rapid path toward the Triple Aim.


[Atorvastatin-induced drug reaction with eosinophilia and systemic symptoms (DRESS)].
Atorvastatin is a widely-used therapeutic statin given for hypercholesterolaemia and for prevention of cardiovascular events. We report herein the occurrence of a drug reaction with eosinophilia and systemic symptoms (DRESS) secondary to intake of this drug. A 58-year-old woman presented with a febrile skin rash and facial oedema, appearing 6weeks after the start of atorvastatin for dyslipidaemia. The clinical features associated disseminated polymorphic lesions, oral mucosa involvement and systemic symptoms (fever, abdominal pain, diarrhoea, polyarthralgia and adenomegaly). Blood tests showed hypereosinophilia up to 11,540/mm(3), inflammatory syndrome and anicteric cholestasis without cytolysis. Serological tests for hepatitis B and C, HIV, EBV, HHV-6, HHV-8, CMV and human Parvovirus B-19 were negative. Cutaneous histology was unspecific. A diagnosis of DRESS secondary to atorvastatin was suspected. The clinical outcome was favourable after atorvastatin discontinuation. To our knowledge, this is the first description of atorvastatin inducing DRESS, a severe life-threatening drug eruption. Atorvastatin has previously been implicated in various cutaneous adverse events. Because of their potentially serious side effects, prescription of statins must be carefully evaluated.


Deliberate practice and acquisition of expert performance: a general overview.
Traditionally, professional expertise has been judged by length of experience, reputation, and perceived mastery of knowledge and skill. Unfortunately, recent research demonstrates only a weak relationship between these indicators of expertise and actual, observed performance. In fact, observed performance does not necessarily correlate with greater professional experience. Expert performance can, however, be traced to active engagement in deliberate practice (DP), where training (often designed and arranged by their teachers and coaches) is focused on improving particular tasks. DP also involves the provision of immediate feedback, time for problem-solving and evaluation, and opportunities for repeated performance to refine behavior. In this article, we draw upon the principles of DP established in other domains, such as chess, music, typing, and sports to provide insight into developing expert performance in medicine.


Genetic variation in the chromosome 17q23 amplicon and breast cancer risk.
Gene amplification leading to overexpression is a common event in breast tumors that is linked to tumor development and progression. The 17q23 region is amplified in >40% of breast tumors and contains several candidate oncogenes. Because common genetic variation in several oncogenes has been associated with cancer risk, we assessed the relevance of common variants in the 17q23 candidate oncogenes to breast cancer. We investigated 60 polymorphisms in the TUBD1, SEPT4, PRKCA, TBX2, TBX4, TEX14, TLK2, YPEL2, and PPM1E genes from this amplicon for association with breast cancer risk among 798 Caucasian breast cancer cases and 843 unaffected Caucasian controls from the Mayo Clinic. Eight polymorphisms in PRKCA, TBX4, TLK2, and YPEL2 displayed significant dose-response associations with breast cancer risk (P(trend) < 0.05). Of these, PRKCA rs7342847 and TLK2 rs2245092 and rs733025 were also associated with hormone receptor-positive breast cancer: PRKCA rs7342847 (odds ratio, 0.7; 95% confidence interval, 0.6-0.9; P(trend) = 0.002) and TLK2 rs733025 and rs2245092 (both: odds ratio, 0.8; 95% confidence interval, 0.7-1.0; P(trend) = 0.03). Interactions between SEPT4 rs758377 and TEX14 rs302864 (P(interaction) = 0.0003) and between TLK2 rs733025 and YPEL2 rs16943468 (P(interaction) = 0.05) for risk of breast cancer were also observed. These findings suggest that single polymorphisms and combinations of polymorphisms within candidate oncogenes from the 17q23 amplicon may influence risk of breast cancer overall and possibly specific molecular subtypes of breast tumors. The findings are discussed within the context of the results from two independent data sets.


Morphology and phenotype expression of types I, II, III, and X collagen and MMP-13 of chondrocytes cultured from articular cartilage of Kashin-Beck Disease.
We investigated the characteristics of cell morphology and expression of types I, II, III, and X collagen and matrix metalloproteinase-13 (MMP-13) of chondrocytes from articular cartilage of adult patients with Kashin-Beck Disease (KBD) in vitro to understand the pathogenesis in chondrocytes. Samples of articular cartilage were divided into 2 groups: KBD group (8 samples, 8 cases) and the control (8 samples, 8 cases). KBD patients were diagnosed according to "Pathological Criteria to Diagnose KBD in China." Hyaline cartilage was digested with collagenase into cell suspensions and cultured in monolayers. Chondrocyte ultrastructure was observed by electron microscope at 10th day in vitro. Primary articular chondrocytes were seeded on microscope slides and immunostained on 12th day of cultivation for types I, II, III, and X collagens and MMP-13. Positive findings were counted by light microscopy and confirmed by flow cytometric analyses. Considerable amounts of vacuoles and distorted nuclei, as well as thickening and irregular arrangement of collagen fibrils, were seen in the KBD samples by electron microscopy. Types I, III, and X collagen were stained in the KBD, but not in the control cultures. The percentages of positive staining for type II collagen were significantly lower in KBD than those in controls (t col II = -5.54, p < 0.001), and for MMP-13 in the KBD group were significantly higher (t MMP-13 = 3.70, p < 0.01). Phenotype expressions of types I, II, III, and X collagen and MMP-13 in chondrocytes cultured in vitro were significantly different between the KBD and control cultures, indicating degenerative and hypertrophic changes in chondrocytes of KBD articular cartilage.


Wavelet-Based ECG Steganography for Protecting Patient Confidential Information in Point-of-Care Systems.
With the growing number of aging population and a significant portion of that suffering from cardiac diseases, it is conceivable that remote ECG patient monitoring systems are expected to be widely used as point-of-care (PoC) applications in hospitals around the world. Therefore, huge amount of ECG signal collected by body sensor networks from remote patients at homes will be transmitted along with other physiological readings such as blood pressure, temperature, glucose level, etc., and diagnosed by those remote patient monitoring systems. It is utterly important that patient confidentiality is protected while data are being transmitted over the public network as well as when they are stored in hospital servers used by remote monitoring systems. In this paper, a wavelet-based steganography technique has been introduced which combines encryption and scrambling technique to protect patient confidential data. The proposed method allows ECG signal to hide its corresponding patient confidential data and other physiological information thus guaranteeing the integration between ECG and the rest. To evaluate the effectiveness of the proposed technique on the ECG signal, two distortion measurement metrics have been used: the percentage residual difference and the wavelet weighted PRD. It is found that the proposed technique provides high-security protection for patients data with low (less than 1%) distortion and ECG data remain diagnosable after watermarking (i.e., hiding patient confidential data) and as well as after watermarks (i.e., hidden data) are removed from the watermarked data.


A Certified Health Physicist's Reflections on a 40-Year Career in Radiation Protection.
This is a reflection from a certified health physicist regarding his becoming aware, during his 40-year career, that the linear no-threshold (LNT) model and the associated As Low As Reasonably Achievable concept have no scientific basis and make no positive contribution to radiation safety. They should be replaced by an alternative, scientifically based model that includes a threshold, below which there is no harm, and recognition of hormesis and the adaptive response, which reflect the benefits of low-dose and low-dose-rate radiation exposure. Continued use of the unscientific LNT model is not conservative, as most regulators complacently claim but actually harmful. Examples of these harmful impacts in the areas of nuclear power, nuclear medicine, and environmental management are included.


Chronic fatigue syndrome: a qualitative investigation of patients' beliefs about the illness.
The chronic fatigue syndrome is a disabling chronic condition of uncertain cause. Previous studies have found that patients seen in hospital clinics with the syndrome often strongly believe that their illness is physical in nature and minimize the role of psychological and social factors. There is also evidence that patients cope by avoiding activity. However, almost all of these studies have assessed illness beliefs only by questionnaire. The aim of this study was to explore the nature and origin of illness beliefs in more detail using in-depth interviews and a qualitative analysis of patient responses. Sixty-six consecutive referrals meeting Oxford criteria for chronic fatigue syndrome were recruited. Analysis of responses indicated that, whereas the most commonly described explanation for the illness was a physical one, more than half the patients also believed "stress" had played a role. Patients believed that they could partially control the symptoms by reducing activity but felt helpless to influence the physical disease process and hence the course of the illness. Patients reported that they had arrived at these beliefs about the illness after prolonged reflection on their own experience combined with the reading of media reports, self help books, and patient group literature. The views of health professionals played a relatively small role. There is potentially a considerable opportunity to help patients arrive at a wider and more enabling explanation of their illness when they first present to primary care.


Heterologous protein production using the Pichia pastoris expression system.
The Pichia pastoris expression system is being used successfully for the production of various recombinant heterologous proteins. Recent developments with respect to the Pichia expression system have had an impact on not only the expression levels that can be achieved, but also the bioactivity of various heterologous proteins. We review here some of these recent developments, as well as strategies for reducing proteolytic degradation of the expressed recombinant protein at cultivation, cellular and protein levels. The problems associated with post-translational modifications performed on recombinant proteins by P. pastoris are discussed, including the effects on bioactivity and function of these proteins, and some engineering strategies for minimizing unwanted glycosylations. We pay particular attention to the importance of optimizing the physicochemical environment for efficient and maximal recombinant protein production in bioreactors and the role of process control in optimizing protein production is reviewed. Finally, future aspects of the use of the P. pastoris expression system are discussed with regard to the production of complex membrane proteins, such as G protein-coupled receptors, and the industrial and clinical importance of these proteins.


The Effect of Prenatal and Childhood Development on Hearing, Vision and Cognition in Adulthood.
It is unclear what the contribution of prenatal versus childhood development is for adult cognitive and sensory function and age-related decline in function. We examined hearing, vision and cognitive function in adulthood according to self-reported birth weight (an index of prenatal development) and adult height (an index of early childhood development). Subsets (N = 37,505 to 433,390) of the UK Biobank resource were analysed according to visual and hearing acuity, reaction time and fluid IQ. Sensory and cognitive performance was reassessed after ~4 years (N = 2,438 to 17,659). In statistical modelling including age, sex, socioeconomic status, educational level, smoking, maternal smoking and comorbid disease, adult height was positively associated with sensory and cognitive function (partial correlations; pr 0.05 to 0.12, p < 0.001). Within the normal range of birth weight (10th to 90th percentile), there was a positive association between birth weight and sensory and cognitive function (pr 0.06 to 0.14, p < 0.001). Neither adult height nor birth weight was associated with change in sensory or cognitive function. These results suggest that adverse prenatal and childhood experiences are a risk for poorer sensory and cognitive function and earlier development of sensory and cognitive impairment in adulthood. This finding could have significant implications for preventing sensory and cognitive impairment in older age.


A short latency vestibulomasseteric reflex evoked by electrical stimulation over the mastoid in healthy humans.
We describe EMG responses recorded in active masseter muscles following unilateral and bilateral electrical vestibular stimulation (EVS, current pulses of 5 mA intensity, 2 ms duration, 3 Hz frequency). Averaged responses in unrectified masseter EMG induced by unilateral EVS were examined in 16 healthy subjects; effects induced by bilateral (transmastoid) stimulation were studied in 10 subjects. Results showed that unilateral as well as bilateral EVS induces bilaterally a clear biphasic response (onset latency ranging from 7.2 to 8.8 ms), that is of equal amplitude and latency contra- and ipsilateral to the stimulation site. In all subjects, unilateral cathodal stimulation induced a positive-negative response termed p11/n15 according to its mean peak latency; the anodal stimulation induced a response of opposite polarity (n11/p15) in 11/16 subjects. Cathodal responses were significantly larger than anodal responses. Bilateral stimulation induced a p11/n15 response significantly larger than that induced by the unilateral cathodal stimulation. Recordings from single motor units showed that responses to cathodal stimulation corresponded to a brief (2-4 ms) silent period in motor unit discharge rate. The magnitude of EVS-induced masseter response was linearly related to current intensity and scaled with the mean level of EMG activity. The size of the p11/n15 response was asymmetrically modulated when subjects were tilted on both sides; in contrast head rotation did not exert any influence. Control experiments excluded a possible role of cutaneous receptors in generating the masseter response. We conclude that transmastoid electrical stimulation evokes vestibulomasseteric reflexes in healthy humans at latencies consistent with a di-trisynaptic pathway.


The use of microarrays to characterize neuropsychiatric disorders: postmortem studies of substance abuse and schizophrenia.
Neuropsychiatric disorders are generally diagnosed based on a classification of behavioral and, in some cases, specific neurological deficits. The lack of distinct quantitative and qualitative biological descriptors at the anatomical and cellular level complicates the search for and understanding of the neurobiology of these disorders. The advent of microarray technology has enabled large-scale profiling of transcriptional activity, allowing a comprehensive characterization of transcriptional patterns relating to the pathophysiology of neuropsychiatric disorders. We review some of the unique methodological constraints related to the use of human postmortem brain tissue in addition to the generally applicable requirements for microarray experiments. Microarray studies undertaken in neuropsychiatric disorders such as schizophrenia and substance abuse by the use of postmortem brain tissue indicate that transcriptional changes relating to synaptic function and plasticity, cytoskeletal function, energy metabolism, oligodendrocytes, and distinct intracellular signaling pathways are generally present. These have been supported by microarray studies in experimental models, and have produced multiple avenues to be explored at the functional level. The quality and specificity of information obtained from human postmortem tissue is rapidly increasing with the maturation and refinement of array-related methodologies and analysis tools, and with the use of focused cell populations. The development of experimental models of gene regulation in these disorders will serve as the initial step towards a comprehensive genome-linked analysis of the brain and associated disorders, and help characterize the integration and coordinate regulation of complex functions within the CNS.


Quantitative sodium magnetic resonance imaging of cartilage, muscle, and tendon.
Sodium magnetic resonance imaging (MRI), or imaging of the 23Na nucleus, has been under exploration for several decades, and holds promise for potentially revealing additional biochemical information about the health of tissues that cannot currently be obtained from conventional hydrogen (or proton) MRI. This additional information could serve as an important complement to conventional MRI for many applications. However, despite these exciting possibilities, sodium MRI is not yet used routinely in clinical practice, and will likely remain strictly in the domain of exploratory research for the coming decade. This paper begins with a technical overview of sodium MRI, including the nuclear magnetic resonance (NMR) signal characteristics of the sodium nucleus, the challenges associated with sodium MRI, and the specialized pulse sequences, hardware, and reconstruction techniques required. Various applications of sodium MRI for quantitative analysis of the musculoskeletal system are then reviewed, including the non-invasive assessment of cartilage degeneration in vivo, imaging of tendinopathy, applications in the assessment of various muscular pathologies, and assessment of muscle response to exercise.


Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3.
Drosophila transcription factor cubitus interruptus (Ci) and its co-activator CRE (cAMP response element)-binding protein (CBP) activate a group of target genes on the anterior-posterior border in response to hedgehog protein (Hh) signaling. In the anterior region, in contrast, the carboxyl-truncated form of Ci generated by protein processing represses Hh expression. In vertebrates, three Ci-related transcription factors (glioblastoma gene products (GLIs) 1, 2, and 3) were identified, but their functional difference in Hh signal transduction is unknown. Here, we report distinct roles for GLI1 and GLI3 in Sonic hedgehog (Shh) signaling. GLI3 containing both repression and activation domains acts both as an activator and a repressor, as does Ci, whereas GLI1 contains only the activation domain. Consistent with this, GLI3, but not GLI1, is processed to generate the repressor form. Transcriptional co-activator CBP binds to GLI3, but not to GLI1. The trans-activating capacity of GLI3 is positively and negatively regulated by Shh and cAMP-dependent protein kinase, respectively, through a specific region of GLI3, which contains the CBP-binding domain and the phosphorylation sites of cAMP-dependent protein kinase. GLI3 directly binds to the Gli1 promoter and induces Gli1 transcription in response to Shh. Thus, GLI3 may act as a mediator of Shh signaling in the activation of the target gene Gli1.


NHC copper(I) complexes bearing dipyridylamine ligands: synthesis, structural, and photoluminescent studies.
We describe the synthesis of new cationic tricoordinated copper complexes bearing bidentate pyridine-type ligands and N-heterocyclic carbene as ancillary ligands. These cationic copper complexes were fully characterized by NMR, electrochemistry, X-ray analysis, and photophysical studies in different environments. Density functional theory calculations were also undertaken to rationalize the assignment of the electronic structure and the photophysical properties. These tricoordinated cationic copper complexes possess a stabilizing CH-π interaction leading to high stability in both solid and liquid states. In addition, these copper complexes, bearing dipyridylamine ligands having a central nitrogen atom as potential anchoring point, exhibit very interesting luminescent properties that render them potential candidates for organic light-emitting diode applications.


Lipase-Catalyzed Chemoselective Ester Hydrolysis of Biomimetically Coupled Aryls for the Synthesis of Unsymmetric Biphenyl Esters.
Lipases are among the most frequently used biocatalysts in organic synthesis, allowing numerous environmentally friendly and inexpensive chemical transformations. Here, we present a biomimetic strategy based on iron(III)-catalyzed oxidative coupling and selective ester monohydrolysis using lipases for the synthesis of unsymmetric biphenyl-based esters under mild conditions. The diverse class of biphenyl esters is of pharmaceutical and technical relevance. We explored the potency of a series of nine different lipases of bacterial, fungal, and mammalian origin on their catalytic activities to cleave biphenyl esters, and optimized the reaction conditions, in terms of reaction time, temperature, pH, organic solvent, and water-organic solvent ratios, to improve the chemoselectivity, and hence control the ratio of unsymmetric versus symmetric products. Elevated temperature and increased DMSO content led to an almost exclusive monohydrolysis by the four lipases Candida rugosa lipase (CRL), Mucor miehei lipase (MML), Rhizopus niveus lipase (RNL), and Pseudomonas fluorescens lipase (PFL). The study was complemented by in silico binding predictions to rationalize the observed differences in efficacies of the lipases to convert biphenyl esters. The optimized reaction conditions were transferred to the preparative scale with high yields, underlining the potential of the presented biomimetic approach as an alternative strategy to the commonly used transition metal-based strategies for the synthesis of diverse biphenyl esters.


Applying behavioral activation to sustain and enhance the effects of contingency management for reducing stimulant use among individuals with HIV infection.
There is a high prevalence of stimulant use among HIV-infected individuals, which is associated with suboptimal antiretroviral therapy (ART) adherence, HIV treatment interruptions, detectable HIV viral load, and transmission of HIV via increased sexual risk behavior. Contingency management (CM) is an initially effective treatment for stimulant use. However, the effects of CM are not sustained after the active intervention has ended. One potential contributor to the intractability of existing treatments may be a lack of attention to replacement activities or the role of depressed mood. Behavioral activation (BA) is an evidence-based approach for depression that involves identifying and participating in pleasurable, goal-directed activities. As a potential approach to address the CM rebound effect - informed by our formative qualitative research with the participant population - we conducted an open pilot trial of an intervention combining CM-BA for HIV-infected individuals with stimulant use disorder. Participants completed weekly BA therapy sessions (10-16 sessions) and thrice-weekly toxicology screenings (12 weeks); contingencies were rewarded for negative toxicology tests to support reengagement into positive life activities. Major assessments were conducted at baseline, 3-, and 6-months. Toxicology screening was repeated prior to the 6-month assessment. Eleven participants with stimulant use disorder enrolled; 7 initiated treatment and completed the full intervention. The mean age was 46 (SD = 5.03) and 14% identified as a racial/ethnic minority. Of the completers, the mean change score in self-reported stimulant use within the past 30 days (within-person change; reduction in self-reported stimulant use) was 4.14 days at 3 months and 5.0 days at 6 months [Cohen's d = 0.89]. The mean change score in weekly toxicology screens (reduction in positive toxicology screens) was .71 at 3 months and 1 at 6 months [Cohen's d = 1.05]. Exit interviews indicated that the integrated intervention was well received and acceptable. This study provides preliminary evidence that a combined CM-BA intervention for this population was feasible (100% retention at 6-months), acceptable (100% of intervention sessions attended; participants rated the intervention 'acceptable' or 'very acceptable'), and may be an option to augment the potency and sustained impact of CM for this population. Future pilot testing using a randomized controlled design is warranted.


Two colliding epidemics - obesity is independently associated with chronic pain interfering with activities of daily living in adults 18 years and over; a cross-sectional, population-based study.
Chronic pain interfering with activities of daily living is highly prevalent in the community. More than 600 million people worldwide are obese. The aim of this paper is to assess if such chronic pain is associated independently with obesity across the adult population, having controlled for other key factors. The South Australian Health Omnibus is an annual, population-based, cross-sectional study. Data on 2616 participants were analysed for episodes of daily pain for three of the preceding six months. Obesity was derived from self-reported height and weight. Multivariable logistic regression analysed the associations between chronic pain interfering with activities of daily living, body mass index (BMI) and key socio-demographic factors. Chronic pain interfering with activities of daily living peaks in people ≥75 years of age while obesity peaks in the 45-54 age group. Pain and obesity together peak in the 55-74 year age group. In the adjusted multinominal logistic regression model, compared to those with no pain, there was a strong association between obesity and pain that interfered moderately or extremely with day-to-day activities (OR 2.25; 95 % CI 1.57-3.23; p < 0.001) having controlled for respondents' age, gender, rurality, country of birth and highest educational attainment. People over 65 years of age and those with lower educational levels were more likely to experience such chronic pain related to obesity. This study demonstrates a strong association between chronic pain and obesity/morbid obesity in the South Australian population. Prospective, longitudinal data are needed to understand the dynamic interaction between these two prevalent conditions.


Alteration of lithium pharmacology through manipulation of phosphoadenosine phosphate metabolism.
Bisphosphate 3'-nucleotidase (BPNT1 in mammals and Met22/Hal2 in yeast) is one of five members of a family of signaling phosphatases united through a common tertiary structure and inhibition by subtherapeutic doses of the antibipolar drug lithium. Here we report a role for 3'-nucleotidase and its substrate, 3'-phosphoadenosine 5'-phosphate (PAP), in mediating the cellular effects of lithium. Lithium-induced inhibition of growth in yeast cells may be overcome by dose-dependent heterologous expression of human BPNT1. Disruption of the yeast 3'-nucleotidase gene or treatment of cells with lithium results in a >80-fold accumulation of PAP and leads to potent growth inhibition. These data indicate that the accumulation of a 3'-nucleotidase substrate, such as PAP, mediates the toxicity of lithium. To further probe this model we examined the growth inhibitory effects of lithium under conditions in which PAP biosynthetic machinery was concomitantly down-regulated. Disruption of met3 or met14 genes (ATP sulfurylase or phosphosulfate kinase), transcriptional down-regulation of MET3 through methionine addition, or administration of chlorate, a widely used cell-permeable sulfurylase inhibitor, function to reduce lithium-induced intracellular PAP accumulation and lithium toxicity; all of these effects were reversed by heterologous expression of human sulfurylase and kinase. Collectively, our data support a role for 3'-nucleotidase activity and PAP metabolism in aspects of lithium's mechanism of action and provide a platform for development of novel pharmacological modulators aimed at improving therapies for the treatment of bipolar disorder.


Intragenic duplication in the PKHD1 gene in autosomal recessive polycystic kidney disease.
In the present study, we report on a couple who underwent prenatal genetic diagnosis for autosomal recessive polycystic kidney disease (ARPKD). This healthy couple had previously had a healthy boy but had experienced two consecutive neonatal deaths due to respiratory distress resulting from pulmonary hypoplasia caused by oligohydramnios. The woman consulted our facility after she realized she was pregnant again. We promptly performed a carrier test for the PKHD1 gene by target exome sequencing of samples from the couple. A pathogenic mutation was identified only in the paternal allele (c.9008C>T, p.S3003F). The mutation was confirmed by Sanger sequencing of the DNA from formalin-fixed, paraffin-embedded, kidney tissue of the second neonate patient and was not found in the healthy sibling. We then performed haplotype analyses using microsatellite markers scattered throughout the PKHD1 gene. DNA from the amniocentesis was determined to belong to a carrier, and the couple decided to continue with the pregnancy, obtaining a healthy newborn. Subsequent detailed examination of the exome data suggested higher read depth at exons 45 and 46. Multiplex ligation-dependent probe amplification allowed identification of duplication of these two exons. This case suggests the potential usefulness of target exome sequencing in the prenatal diagnosis of the PKHD1 gene in ARPKD. This is the first report of intragenic duplication in the PKHD1 gene in ARPKD.


The Association Between Analgesic Treatment Beliefs and Electronically Monitored Adherence for Cancer Pain.
To determine whether clusters based on analgesic treatment beliefs among patients with cancer predict objective analgesic adherence. 207 patients with cancer in the outpatient setting who were aged 18 years or older, self-identified as White or African American, were diagnosed with solid tumor or multiple myeloma, and were prescribed at least one around-the-clock analgesic prescription for reported cancer pain. This study is a secondary analysis of an existing dataset. General linear modeling with a backward elimination approach was applied to determine whether previously identified analgesic treatment belief clusters, as well as sociodemographic, clinical, and pain variables, were associated with adherence behaviors. Significant explanatory factors were experiential in nature and included sociodemographic, clinical, and pain-related variables, explaining 21% of the variance in analgesic adherence. Analgesic belief clusters were not predictive of adherence. Future research should examine sociodemographic and other clinical factors, as well as the influence of analgesic treatment beliefs, to better understand adherence behaviors among patients with cancer.


The histopathology of chronic gastritis.
Chronic gastritis is a multifactorial disorder thought to be influenced by bacterial and host genetic factors. Histopathological examination is the mainstay of diagnosis, however features like the presence of Helicobacter pylori are difficult to evaluate on biopsy. We evaluated 120 gastric antral biopsies using the revised Sydney system. The density of the inflammatory infiltrate, H pylori and mast cells were evaluated. It was seen that the presence of H pylori is strongly associated with an acute and a chronic inflammatory infiltrate. The presence of neutrophils on biopsy is strongly associated with the presence of H pylori and with the density and the grade of the chronic inflammatory infiltrate. The chronic inflammatory response is an intermediary between the acute inflammatory process and glandular atrophy. The lymphocytic infiltrate is also a precursor lesion of the lymphoid follicles. The presence of mast cells does not appear to be related to any of the other inflammatory parameters. The presence of one feature is a strong indicator for the presence of other inflammatory features.


Moth tails divert bat attack: evolution of acoustic deflection.
Adaptations to divert the attacks of visually guided predators have evolved repeatedly in animals. Using high-speed infrared videography, we show that luna moths (Actias luna) generate an acoustic diversion with spinning hindwing tails to deflect echolocating bat attacks away from their body and toward these nonessential appendages. We pit luna moths against big brown bats (Eptesicus fuscus) and demonstrate a survival advantage of ∼ 47% for moths with tails versus those that had their tails removed. The benefit of hindwing tails is equivalent to the advantage conferred to moths by bat-detecting ears. Moth tails lured bat attacks to these wing regions during 55% of interactions between bats and intact luna moths. We analyzed flight kinematics of moths with and without hindwing tails and suggest that tails have a minimal role in flight performance. Using a robust phylogeny, we find that long spatulate tails have independently evolved four times in saturniid moths, further supporting the selective advantage of this anti-bat strategy. Diversionary tactics are perhaps more common than appreciated in predator-prey interactions. Our finding suggests that focusing on the sensory ecologies of key predators will reveal such countermeasures in prey.


A Postnatal Pax7 Progenitor Gives Rise to Pituitary Adenomas.
Pituitary adenomas are classified into functioning and nonfunctioning (silent) tumors on the basis of hormone secretion. However, the mechanism of tumorigenesis and the cell of origin for pituitary adenoma subtypes remain to be elucidated. Employing a tamoxifen-inducible mouse model, we demonstrate that a novel postnatal Pax7(+) progenitor cell population in the pituitary gland gives rise to silent corticotroph macro-adenomas when the retinoblastoma tumor suppressor is conditionally deleted. While Pax transcriptional factors are critical for embryonic patterning as well as postnatal stem cell renewal for many organs, we have discovered that Pax7 marks a restricted cell population in the postnatal pituitary intermediate lobe. This Pax7(+) early progenitor cell population is overlapping but ontologically downstream of the Nestin(+) pituitary stem cell population, yet upstream of another newly discovered Myf6(+) late progenitor cell population. Interestingly, the Pax7(+) progenitor cell population is evolutionarily conserved in primates and humans, and Pax7 expression is maintained not only in murine tumors but also in human functioning and silent corticotropinomas. Taken together, our results strongly suggest that human silent corticotroph adenomas may in fact arise from a Pax7 lineage of the intermediate lobe, a region of the human pituitary bearing closer scientific interest as a reservoir of pituitary progenitor cells.


Lyme disease in children: Data from the Canadian Paediatric Surveillance Program.
Lyme disease (LD) is an infectious disease that is emerging in eastern and central Canada associated with the spread of the tick vector Ixodes scapularis. National surveillance shows that children are an at-risk age group. To study the epidemiology of LD in Canadian children using the Canadian Paediatric Surveillance Program (CPSP) to better understand exposure history, clinical manifestations, diagnosis and treatment of paediatric LD cases in Canada. A structured questionnaire was completed by paediatricians for each LD case reported as part of the Canadian Paediatric Surveillance Program from 2014 to 2017. There were 95 cases that met inclusion criteria as confirmed or probable cases. The median age was 7 years; 38 % were 5-9 years and 35 % were 10-15 years of age. Most cases were acquired in known Canadian endemic locations; 5 were acquired during travel to the US. Most cases were reported from Nova Scotia and Ontario (46 % and 38 % respectively). The most common clinical presentation was arthritis (59 % of all cases), which is a manifestation of the late disseminated stage of LD. Late disseminated disease presented through the year, whereas early LD (Erythema migrans) and early disseminated LD presented during the summer and fall. Antibiotic choice and duration of therapy generally followed accepted guidelines. This study of the clinical spectrum of LD in Canadian children underlines the need for preventive measures to protect children in Canada from emerging LD, and the need for health care provider awareness.


Common path in-line holography using enhanced joint object reference digital interferometers.
Joint object reference digital interferometer (JORDI) is a recently developed system capable of recording holograms of various types [Opt. Lett. 38(22), 4719 (2013)]. Presented here is a new enhanced system design that is based on the previous JORDI. While the previous JORDI has been based purely on diffractive optical elements, displayed on spatial light modulators, the present design incorporates an additional refractive objective lens, thus enabling hologram recording with improved resolution and increased system applicability. Experimental results demonstrate successful hologram recording for various types of objects, including transmissive, reflective, three-dimensional, phase and highly scattering objects. The resolution limit of the system is analyzed and experimentally validated. Finally, the suitability of JORDI for microscopic applications is verified as a microscope objective based configuration of the system is demonstrated.


Extended LazyNav: Virtual 3D Ground Navigation for Large Displays and Head-Mounted Displays.
This paper presents the extended work on LazyNav, a head-free, eyes-free and hands-free mid-air ground navigation control model presented at the IEEE 3D User Interfaces (3DUI) 2015, in particular with a new application to the head-mounted display (HMD). Our mid-air interaction metaphor makes use of only a single pair of the remaining tracked body elements to tailor the navigation. Therefore, the user can navigate in the scene while still being able to perform other interactions with her hands and head, e.g., carrying a bag, grasping a cup of coffee, or observing the content by moving her eyes and locally rotating her head. We design several body motions for navigation by considering the use of non-critical body parts and develop assumptions about ground navigation techniques. Through the user studies, we investigate the motions that are easy to discover, easy to control, socially acceptable, accurate and not tiring. Finally, we evaluate the desired ground navigation features with a prototype application in both a large display (LD) and a HMD navigation scenarios. We highlight several recommendations for designing a particular mid-air ground navigation technique for a LD and a HMD.


Effects of tail docking and docking length on neuroanatomical changes in healed tail tips of pigs.
In pig production, piglets are tail docked at birth in order to prevent tail biting later in life. In order to examine the effects of tail docking and docking length on the formation of neuromas, we used 65 pigs and the following four treatments: intact tails (n=18); leaving 75% (n=17); leaving 50% (n=19); or leaving 25% (n=11) of the tail length on the pigs. The piglets were docked between day 2 and 4 after birth using a gas-heated apparatus, and were kept under conventional conditions until slaughter at 22 weeks of age, where tails were removed and examined macroscopically and histologically. The tail lengths and diameters differed at slaughter (lengths: 30.6±0.6; 24.9±0.4; 19.8±0.6; 8.7±0.6 cm; P<0.001; tail diameter: 0.5±0.03; 0.8±0.02; 1.0±0.03; 1.4±0.04 cm; P<0.001, respectively). Docking resulted in a higher proportion of tails with neuromas (64 v. 0%; P<0.001), number of neuromas per tail (1.0±0.2 v. 0; P<0.001) and size of neuromas (1023±592 v. 0 μm; P<0.001). The results show that tail docking piglets using hot-iron cautery causes formation of neuromas in the outermost part of the tail tip. The presence of neuromas might lead to altered nociceptive thresholds, which need to be confirmed in future studies.


Quantitative morphometric analysis of single gold nanoparticles by optical extinction microscopy: Material permittivity and surface damping effects.
Quantifying the optical extinction cross section of a plasmonic nanoparticle has recently emerged as a powerful means to characterize the nanoparticle morphologically, i.e., to determine its size and shape with a precision comparable to electron microscopy while using a simple optical microscope. In this context, a critical piece of information to solve the inverse problem, namely, calculating the particle geometry from the measured cross section, is the material permittivity. For bulk gold, many datasets have been reported in the literature, raising the question of which one is more adequate to describe specific systems at the nanoscale. Another question is how the nanoparticle interface, not present in the bulk material, affects its permittivity. In this work, we have investigated the role of the material permittivities on the morphometric characterization of defect-free ultra-uniform gold nanospheres with diameters of 10 nm and 30 nm, following a quantitative analysis of the polarization- and spectrally-resolved extinction cross section on hundreds of individual nanoparticles. The measured cross sections were fitted using an ellipsoid model. By minimizing the fit error or the variation of the fitted dimensions with color channel selection, the material permittivity dataset and the surface damping parameter g best describing the nanoparticles are found to be the single crystal dataset by Olmon et al. [Phys. Rev. B 86, 235147 (2012)] and g ≈ 1, respectively. The resulting nanoparticle geometries are in good agreement with transmission electron microscopy of the same sample batches, including both 2D projection and tomography.


Patterns of positive selection in six Mammalian genomes.
Genome-wide scans for positively selected genes (PSGs) in mammals have provided insight into the dynamics of genome evolution, the genetic basis of differences between species, and the functions of individual genes. However, previous scans have been limited in power and accuracy owing to small numbers of available genomes. Here we present the most comprehensive examination of mammalian PSGs to date, using the six high-coverage genome assemblies now available for eutherian mammals. The increased phylogenetic depth of this dataset results in substantially improved statistical power, and permits several new lineage- and clade-specific tests to be applied. Of approximately 16,500 human genes with high-confidence orthologs in at least two other species, 400 genes showed significant evidence of positive selection (FDR<0.05), according to a standard likelihood ratio test. An additional 144 genes showed evidence of positive selection on particular lineages or clades. As in previous studies, the identified PSGs were enriched for roles in defense/immunity, chemosensory perception, and reproduction, but enrichments were also evident for more specific functions, such as complement-mediated immunity and taste perception. Several pathways were strongly enriched for PSGs, suggesting possible co-evolution of interacting genes. A novel Bayesian analysis of the possible "selection histories" of each gene indicated that most PSGs have switched multiple times between positive selection and nonselection, suggesting that positive selection is often episodic. A detailed analysis of Affymetrix exon array data indicated that PSGs are expressed at significantly lower levels, and in a more tissue-specific manner, than non-PSGs. Genes that are specifically expressed in the spleen, testes, liver, and breast are significantly enriched for PSGs, but no evidence was found for an enrichment for PSGs among brain-specific genes. This study provides additional evidence for widespread positive selection in mammalian evolution and new genome-wide insights into the functional implications of positive selection.


Toxic proteins in neurodegenerative disease.
A broad range of neurodegenerative disorders is characterized by neuronal damage that may be caused by toxic, aggregation-prone proteins. As genes are identified for these disorders and cell culture and animal models are developed, it has become clear that a major effect of mutations in these genes is the abnormal processing and accumulation of misfolded protein in neuronal inclusions and plaques. Increased understanding of the cellular mechanisms for disposal of abnormal proteins and of the effects of toxic protein accumulation on neuronal survival may allow the development of rational, effective treatment for these disorders.


Gene set analysis in the cloud.
Cloud computing offers low cost and highly flexible opportunities in bioinformatics. Its potential has already been demonstrated in high-throughput sequence data analysis. Pathway-based or gene set analysis of expression data has received relatively less attention. We developed a gene set analysis algorithm for biomarker identification in the cloud. The resulting tool, YunBe, is ready to use on Amazon Web Services. Moreover, here we compare its performance to those obtained with desktop and computing cluster solutions. YunBe is open-source and freely accessible within the Amazon Elastic MapReduce service at s3n://lrcv-crp-sante/app/yunbe.jar. Source code and user's guidelines can be downloaded from http://tinyurl.com/yunbedownload.


Add-on amlodipine improves arterial function and structure in hypertensive patients treated with an angiotensin receptor blocker.
The present study was designed to determine whether adding amlodipine further improved functional and structural cardiovascular damage in hypertensive patients whose blood pressure was already well controlled with an angiotensin II type 1 receptor blocker (ARB). The cardiothoracic ratio on chest radiographs, level of urinary albumin excretion, pulse wave velocity (PWV), intima-media thickness (IMT) of the carotid arteries, and 24 hour ambulatory blood pressure (BP) were evaluated before and 12 months after the start of add-on of amlodipine or placebo in 50 hypertensive patients being treated with an ARB. The add-on amlodipine therapy significantly improved the PWV from 1689 +/- 61 to 1447 +/- 47 cm/s and the IMT from 0.88 +/- 0.08 to 0.75 +/- 0.06 mm in the hypertensive patients treated with an ARB without altering their mean 24 hour ambulatory BP values, but did not alter the cardiothoracic ratio or urinary albumin excretion. Amlodipine also significantly decreased the variability of ambulatory BP, but the decrease did not significantly contribute to the changes in PWV or IMT. Thus, the add-on low-dose amlodipine therapy had benefits in terms of the vascular function and vascular structure of hypertensive patients treated with an ARB that were independent of its depressor effects. The antiatherogenic pleiotropic properties of amlodipine have a preventive effect on the progression of arterial stiffness in hypertensive patients treated with an ARB.


Widely tunable electro-optic distributed Bragg reflector in liquid crystal waveguide.
We propose and numerically investigate a versatile and easy-to-realize configuration for a guided-wave voltage-tunable distributed feedback grating based on reorientation in nematic liquid crystal and coplanar comb electrodes. The device has a wide tuning range exceeding 100 nm and covers C and L bands for wavelength division multiplexing.


CD8 beta chain influences CD8 alpha chain-associated Lck kinase activity.
The CD8 molecule plays an important role in the differentiation of CD8+ T cells in the thymus and in their normal function in the periphery. CD8 exists on the cell surface in two forms, the alpha alpha homodimer and the alpha beta heterodimer. Recent studies indicate an important role for the CD8 beta chain in thymic development of CD8+ T cells and suggest that signaling via CD8 alpha beta may be distinct from CD8 alpha alpha. To better understand these differences, we introduced the CD8 beta gene into a T cell hybridoma which only expressed the CD8 alpha alpha homodimer. In the parent hybridoma, cross-linking of the CD8 alpha chain led to minimal enhancement of CD8-associated Lck tyrosine kinase activity. In the CD8 beta+ transfectants, several observations suggested that CD8 beta modifies CD8 alpha-associated Lck tyrosine kinase activity: (a) in in vitro kinase assays, antibody-mediated crosslinking of CD8 alone, or CD8 cross-linking with the TCR, resulted in 10-fold greater activation of Lck kinase activity, compared to cells expressing CD8 alpha alpha alone; (b) in vivo, markedly enhanced tyrosine phosphorylation of several intracellular proteins was observed upon CD8 cross-linking with the TCR in CD8 alpha beta-expressing cells, compared to cells expressing CD8 alpha alpha alone; and (c) Lck association with CD8 alpha was stabilized by the coexpression of CD8 beta. Thus, the differential Lck kinase activation and tyrosine phosphorylation seen with CD8 alpha alpha vs. CD8 alpha beta may reflect the unique signaling capabilities of the CD8 beta molecule. These differences in signaling may, in part, account for the diminished ability to generate CD8 single positive thymocytes in mice bearing a homozygous disruption of the CD8 beta gene.


Motivation dynamically increases noise resistance by internal feedback during movement.
Motivation improves performance, pushing us beyond our normal limits. One general explanation for this is that the effects of neural noise can be reduced, at a cost. If this were possible, reward would promote investment in resisting noise. But how could the effects of noise be attenuated, and why should this be costly? Negative feedback may be employed to compensate for disturbances in a neural representation. Such feedback would increase the robustness of neural representations to internal signal fluctuations, producing a stable attractor. We propose that encoding this negative feedback in neural signals would incur additional costs proportional to the strength of the feedback signal. We use eye movements to test the hypothesis that motivation by reward improves precision by increasing the strength of internal negative feedback. We find that reward simultaneously increases the amplitude, velocity and endpoint precision of saccades, indicating true improvement in oculomotor performance. Analysis of trajectories demonstrates that variation in the eye position during the course of saccades is predictive of the variation of endpoints, but this relation is reduced by reward. This indicates that motivation permits more aggressive correction of errors during the saccade, so that they no longer affect the endpoint. We suggest that such increases in internal negative feedback allow attractor stability, albeit at a cost, and therefore may explain how motivation improves cognitive as well as motor precision.


Use of immunofluorescence to visualize cell-specific gene expression during sporulation in Bacillus subtilis.
We have adapted immunofluorescence microscopy for use in Bacillus subtilis and have employed this procedure for visualizing cell-specific gene expression at early to intermediate stages of sporulation. Sporangia were doubly stained with propidium iodide to visualize the forespore and mother cell nucleoids and with fluorescein-conjugated antibodies to visualize the location of beta-galactosidase produced under the control of the sporulation RNA polymerase sigma factors sigma E and sigma F. In confirmation and extension of earlier reports, we found that expression of a lacZ fusion under the control of sigma E was confined to the mother cell compartment of sporangia at the septation (II) and engulfment (III) stages of morphogenesis. Conversely, sigma F-directed gene expression was confined to the forespore compartment of sporangia at postseptation stages of development. Little indication was found for sigma E- or sigma F-directed gene expression prior to septation or in both compartments of postseptation sporangia. Gene expression under the control of the forespore sigma factor sigma G also exhibited a high level of compartmentalization. A high proportion of sporangia exhibited fluorescence in our immunostaining protocol, which should be suitable for the subcellular localization of sporulation proteins for which specific antibodies are available.


[Analysis of spatial diffusion patterns for AIDS cases in some Brazilian States].
Despite new improvements in AIDS treatment, preventive measures are still essential to control the epidemic. Effective programs almost always depend on correct and efficient allocation of scarce health resources. Detailed information on the epidemic, such as where, when, and how the epidemic will spread are of great value. This study was conducted to obtain a better understanding of the dissemination of AIDS cases in four important Brazilian States. Spatial diffusion patterns were evaluated qualitatively by studying sequential maps and quantitatively by analyzing spatial correlograms. Ten years were analyzed, grouped in three periods (1987-1989, 1990-1992, and 1993-1996). The diffusion process was studied for both total AIDS cases and male and female cases. Diffusion of AIDS cases presented specific characteristics for each of the four States. Information derived from the study, especially the results of the correlogram analysis, improve our understanding of the epidemic's spatial diffusion in different parts of the country and can also be used to determine parameters for other AIDS epidemiological models.


Gestural communication in young gorillas (Gorilla gorilla): gestural repertoire, learning, and use.
In the present study we investigated the gestural communication of gorillas (Gorilla gorilla). The subjects were 13 gorillas (1-6 years old) living in two different groups in captivity. Our goal was to compile the gestural repertoire of subadult gorillas, with a special focus on processes of social cognition, including attention to individual and developmental variability, group variability, and flexibility of use. Thirty-three different gestures (six auditory, 11 tactile, and 16 visual gestures) were recorded. We found idiosyncratic gestures, individual differences, and similar degrees of concordance between and within groups, as well as some group-specific gestures. These results provide evidence that ontogenetic ritualization is the main learning process involved, but some form of social learning may also be responsible for the acquisition of special gestures. The present study establishes that gorillas have a multifaceted gestural repertoire, characterized by a great deal of flexibility with accommodations to various communicative circumstances, including the attentional state of the recipient. The possibility of assigning Seyfarth and Cheney's [1997] model for nonhuman primate vocal development to the development of nonhuman primate gestural communication is discussed.


Migraine history and breast cancer risk among postmenopausal women.
PURPOSE Both migraine and breast cancer are hormonally mediated. Two recent reports indicate that women with a migraine history may have a lower risk of postmenopausal breast cancer than those who never suffered migraines. This finding requires confirmation; in particular, an assessment of the influence of use of nonsteroidal anti-inflammatory drugs (NSAID) is needed, because many studies indicate that NSAID use also may confer a reduction in breast cancer risk. METHODS We assessed the relationship between self-reported history of migraine and incidence of postmenopausal breast cancer in 91,116 women enrolled on the Women's Health Initiative Observational Study prospective cohort from 1993 to 1998 at ages 50 to 79 years. Through September 15, 2005, there were 4,006 eligible patients with breast cancer diagnosed. Results Women with a history of migraine had a lower risk of breast cancer (hazard ratio [HR], 0.89; 95% CI, 0.80 to 98) than women without a migraine history. This risk did not vary by recent NSAID use. The lower risk was somewhat more pronounced for invasive estrogen-receptor-positive and progesterone-receptor-positive tumors (HR, 0.83; 95% CI, 0.71 to 0.97), as no reduction in risk was observed for invasive ER-negative/PR-negative tumors (HR, 1.16; 95% CI, 0.86 to 1.57), and this difference in risk estimates was borderline statistically significant (P = .06). CONCLUSION This study supports the hypothesis that a history of migraine is associated with a lower risk of breast cancer and that this relationship is independent of recent NSAID use.


Imputing cognitive impairment in SPARK, a large autism cohort.
Diverse large cohorts are necessary for dissecting subtypes of autism, and intellectual disability is one of the most robust endophenotypes for analysis. However, current cognitive assessment methods are not feasible at scale. We developed five commonly used machine learning models to predict cognitive impairment (FSIQ<80 and FSIQ<70) and FSIQ scores among 521 children with autism using parent-reported online surveys in SPARK, and evaluated them in an independent set (n = 1346) with a missing data rate up to 70%. We assessed accuracy, sensitivity, and specificity by comparing predicted cognitive levels against clinical IQ data. The elastic-net model has good performance (AUC = 0.876, sensitivity = 0.772, specificity = 0.803) using 129 predictive features to impute cognitive impairment (FSIQ<80). Top-ranked predictive features included parent-reported language and cognitive levels, age at autism diagnosis, and history of services. Prediction of FSIQ<70 and FSIQ scores also showed good performance. We show cognitive levels can be imputed with high accuracy for children with autism, using commonly collected parent-reported data and standardized surveys. The current model offers a method for large-scale autism studies seeking estimates of cognitive ability when standardized psychometric testing is not feasible. LAY SUMMARY: Children with autism who have more severe learning challenges or cognitive impairment have different needs that are important to consider in research studies. When children in our study were missing standardized cognitive testing scores, we were able to use machine learning with other information to correctly "guess" when they have cognitive impairment about 80% of the time. We can use this information in research in the future to develop more appropriate treatments for children with autism and cognitive impairment.


Folate receptor-beta expression as a diagnostic target in human & rodent nonalcoholic steatohepatitis.
Nonalcoholic steatohepatitis (NASH) afflicts 20-36% of individuals with nonalcoholic fatty liver disease (NAFLD). A lipotoxic hepatic environment, altered innate immune signaling and inflammation are defining features of progression to NASH. Activated resident liver macrophages express folate receptor beta (FR-β) which may be an indicator of progression from steatosis to NASH. The goals of this study were to characterize FR-β protein expression in human NAFLD and rodent models of NASH, and demonstrate liver targeting of an FR-β imaging agent to the liver of a rodent NASH model using FR-β. Rat liver lysates from methionine choline deficient (MCD) fed rats, high fat diet (HFD) and methionine choline sufficient (MC+) rat controls were analyzed for hepatic FR-β protein. The FR-β-targeted agent, Etarfolatide was injected into MCD and MC + -fed C57BL/6 mice for efficient FastSPECT hepatic imaging. Additionally, FR-β expression across the stages of human NAFLD from normal to NASH was assessed. FastSPECT images show targeting of Etarfolatide to the liver of mice fed 8 weeks of MCD diet but not control-fed mice. The MCD rat model exhibited significantly increased protein expression of hepatic FR-β in contrast to HFD or normal samples. Similarly human liver samples categorized as NASH Fatty or NASH Not Fatty showed elevated FR-β protein when compared to normal liver. FR-β transcript expression levels were elevated across both NASH Fatty and NASH Not Fatty samples. The findings in this study indicate that FR-β expression in NASH may be harnessed to target agents directly to the liver.


An active murine transposon family pair: retrotransposition of "master" MusD copies and ETn trans-mobilization.
The ETn (Early Transposon) elements are among the most active murine mobile sequences, being responsible for a series of mutations by insertion in vivo. Yet they are noncoding, and it had long been suspected that ETn are mobilized in trans by coding-competent elements, most probably from the closely related MusD family of LTR-retrotransposons. A genome-wide in silico search for coding-competent MusD elements identified a total of nine such copies, which we cloned and marked to test their transpositional activity, using an ex vivo assay in heterologous cells. Three copies were found to be autonomous for transposition, with each gag, pro, and pol MusD gene absolutely required for mobility. These active MusD copies specifically trigger retrotransposition of marked ETn elements with high efficiency, by complementation in trans. Characterization of the structures of de novo transposed MusD and ETn marked elements, as well as of their integration sites, disclosed canonical retroviral-like retrotransposition, with 6-bp target site duplications common to both elements. These results highlight the parasitic molecular strategies that are used by the ETn elements for their mobility, and unambiguously identify their "master genes."


Maximal potential energy transport: a variational principle for solidification problems.
We analyze numerically the mechanisms controlling the spacing of chimneys--channels devoid of solid--in two-dimensional mushy layers formed by solidifying a binary alloy. Chimneys are the principal conduits through which buoyancy effects material transport out of the mushy layer and into the liquid from which it formed. Experiments show a coarsening of chimney spacing; we pursue the hypothesis that the spacing adjusts to optimize material transport and hence maximize the rate of removal of potential energy stored in the mushy layer. The optimal solute flux increases approximately linearly with the mush Rayleigh number. However, for spacings below a critical value, the chimneys collapse and solute fluxes cease, revealing a hysteresis between chimney convection and no flow. The results are consistent with a variational principle controlling the dynamics of this dissipative system.


Avoidance of the Plant Hormone Cis-Jasmone by Aedes aegypti Depends On Mosquito Age in Both Plant and Human Odor Backgrounds.
Adults of many mosquito species feed on plants to obtain metabolic energy and to enhance reproduction. Mosquitoes primarily rely on olfaction to locate plants and are known to respond to a range of plant volatiles. We studied the olfactory response of the yellow fever mosquito Aedes aegypti to methyl jasmonate (MeJA) and cis-jasmone (CiJA), volatile compounds originating from the octadecanoid signaling pathway that plays a key role in plant defense against herbivores. Specifically, we investigated how Ae. aegypti of different ages responded to elevated levels of CiJA in two attractive odor contexts, either derived from Lima bean plants or human skin. Aedes aegypti females landed significantly less often on a surface with CiJA and MeJA compared to the solvent control, CiJA exerting a stronger reduction in landing than MeJA. Odor context (plant or human) had no significant main effect on the olfactory responses of Ae. aegypti females to CiJA. Mosquito age significantly affected the olfactory response, older females (7-9 d) responding more strongly to elevated levels of CiJA than young females (1-3 d) in either odor context. Our results show that avoidance of CiJA by Ae. aegypti is independent of odor background, suggesting that jasmonates are inherently aversive cues to these mosquitoes. We propose that avoidance of plants with elevated levels of jasmonates is adaptive to mosquitoes to reduce the risk of encountering predators that is higher on these plants, i.e. by avoiding 'enemy-dense-space'.


Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables.
To define the efficacy of venetoclax with extended follow-up and identify clinical or biological treatment effect modifiers, updated data for previously treated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in 4 early-phase trials were pooled. Rates of response, complete remission (CR/CRi), and undetectable minimal residual disease (U-MRD) were analyzed for all patients (n = 436) and for those patients who were planned to receive 400 mg/day monotherapy (n = 347). Univariate and multiple regression analyses were performed to identify the pretreatment factors associated with response rates and duration of response (DoR). Objective responses were documented in 75% of all patients, including 22% CR/CRi. Overall, 27% and 16% of the patients achieved U-MRD in blood and marrow, respectively. Estimated median progression-free survival (PFS), DoR, and time to progression were 30.2, 38.4, and 36.9 months, respectively. Similar efficacy outcomes were observed within the 400 mg/day monotherapy subset. For those who achieved CR/CRi, the 3-year PFS estimate was 83%. DoR was superior for patients achieving CR/CRi or U-MRD in landmark analyses. In multiple regression analyses, bulky lymphadenopathy (≥5 cm) and refractoriness to B-cell receptor inhibitor (BCRi) therapy were significantly associated with lower CR rate and shorter DoR. Fewer prior therapies were associated with higher CR rate, but not DoR. Chromosome 17p deletion and/or TP53 mutation and NOTCH1 mutation were consistently associated with shorter DoR, but not probability of response. Thus, both pretreatment factors and depth of response correlated with DoR with venetoclax. Patients without bulky lymphadenopathy, BCRi-refractory CLL, or an adverse mutation profile had the most durable benefit.


Enhancement of Lymphatic Vessels in the Superficial Layer in a Rat Model of a Lymphedematous Response.
The morphologic and histologic behavior of lymphatic vessels in lymphedema has not been well analyzed using laboratory animals. The purpose of the present study was to elucidate the regeneration process of lymphatic vessels after acute lymphedema in a rat model. The acute lymphedema was induced by an amputation and a replantation surgery on a rat hind limb. Recovery of lymphatic flow was traced using fluorescent lymphography with dye injection. The morphology and number of lymphatic vessels were immunohistochemically detected and quantified in both superficial and deep layers. The swelling was the most severe, and the number of lymphatic vessels in the superficial layer was significantly and maximally increased on postoperative day 3. Backflows and overflows were also detectable in the superficial layer on postoperative day 3. The number of lymphatic vessels had decreased but remained significantly higher than that in the controls on postoperative day 14, when the swelling decreased to the levels in the controls. In contrast, the number of lymphatic vessels in the deep layer showed a tendency toward increased numbers; however, it was not statistically significant on postoperative day 3, 7, or 14. We have obtained solid evidence showing the differential potency of lymphatic vessels between the superficial and the deep layers after temporal lymphedematous induction. Further analysis of lymphedematous responses in animal models could provide new insights into the challenges associated with the clinical treatment of lymphedema.


Probing the interactions of phenol with oxygenated functional groups on curved fullerene-like sheets in activated carbon.
The mechanism(s) of interactions of phenol with oxygenated functional groups (OH, COO and COOH) in nanopores of activated carbon (AC) is a contentious issue among researchers. This mechanism is of particular interest because a better understanding of the role of such groups in nanopores would essentially translate to advances in AC production and use, especially in regard to the treatment of organic-based wastewaters. We therefore attempt to shed more light on the subject by employing density functional theory (DFT) calculations in which fullerene-like models integrating convex or concave structure, which simulate the eclectic porous structures on AC surface, are adopted. TEM analysis, EDS mapping and Boehm titration are also conducted on actual phenol-adsorbed AC. Our results suggest the widely-reported phenomenon of decreased phenol uptake on AC due to increased concentration of oxygenated functional groups is possibly attributed to the increased presence of the latter on the convex side of the curved carbon sheets. Such a system effectively inhibits phenol from getting direct contact with the carbon sheet, thus constraining any available π-π interaction, while the effect of groups acting on the concave part of the curved sheet does not impart the same detriment.


Genome-wide effects of MELK-inhibitor in triple-negative breast cancer cells indicate context-dependent response with p53 as a key determinant.
Triple-negative breast cancer (TNBC) is an aggressive, highly recurrent breast cancer subtype, affecting approximately one-fifth of all breast cancer patients. Subpopulations of treatment-resistant cancer stem cells within the tumors are considered to contribute to disease recurrence. A potential druggable target for such cells is the maternal embryonic leucine-zipper kinase (MELK). MELK expression is upregulated in mammary stem cells and in undifferentiated cancers, where it correlates with poor prognosis and potentially mediates treatment resistance. Several MELK inhibitors have been developed, of which one, OTSSP167, is currently in clinical trials. In order to better understand how MELK and its inhibition influence TNBC, we verified its anti-proliferative and apoptotic effects in claudin-low TNBC cell lines MDA-MB-231 and SUM-159 using MTS assays and/or trypan blue viability assays together with analysis of PARP cleavage. Then, using microarrays, we explored which genes were affected by OTSSP167. We demonstrate that different sets of genes are regulated in MDA-MB-231 and SUM-159, but in both cell lines genes involved in cell cycle, mitosis and protein metabolism and folding were regulated. We identified p53 (TP53) as a potential upstream regulator of the regulated genes. Using western blot we found that OTSSP167 downregulates mutant p53 in all tested TNBC cell lines (MDA-MB-231, SUM-159, and BT-549), but upregulates wild-type p53 in the luminal A subtype MCF-7 cell line. We propose that OTSSP167 might have context-dependent or off-target effects, but that one consistent mechanism of action could involve the destabilization of mutant p53.


Characterization of cancer stem-like cells derived from mouse induced pluripotent stem cells transformed by tumor-derived extracellular vesicles.
Several studies have shown that cancer niche can perform an active role in the regulation of tumor cell maintenance and progression through extracellular vesicles-based intercellular communication. However, it has not been reported whether this vesicle-mediated communication affects the malignant transformation of normal stem cells/progenitors. We have previously reported that the conditioned medium derived from the mouse Lewis Lung Carcinoma (LLC) cell line can convert mouse induced pluripotent stem cells (miPSCs) into cancer stem cells (CSCs), indicating that normal stem cells when placed in an aberrant microenvironment can give rise to functionally active CSCs. Here, we focused on the contribution of tumor-derived extracellular vesicles (tEVs) that are secreted from LLC cells to induce the transformation of miPSCs into CSCs. We isolated tEVs from the conditioned medium of LLC cells, and then the differentiating miPSCs were exposed to tEVs for 4 weeks. The resultant tEV treated cells (miPS-LLCev) expressed Nanog and Oct3/4 proteins comparable to miPSCs. The frequency of sphere formation of the miPS-LLCev cells in suspension culture indicated that the self-renewal capacity of the miPS-LLCev cells was significant. When the miPS-LLCev cells were subcutaneously transplanted into Balb/c nude mice, malignant liposarcomas with extensive angiogenesis developed. miPS-LLCevPT and miPS-LLCevDT, the cells established from primary site and disseminated liposarcomas, respectively, showed their capacities to self-renew and differentiate into adipocytes and endothelial cells. Moreover, we confirmed the secondary liposarcoma development when these cells were transplanted. Taken together, these results indicate that miPS-LLCev cells possess CSC properties. Thus, our current study provides the first evidence that tEVs have the potential to induce CSC properties in normal tissue stem cells/progenitors.


Neuroprotective and Symptomatic Effects of Cannabidiol in an Animal Model of Parkinson's Disease.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia Nigra pars compacta, leading to classical PD motor symptoms. Current therapies are purely symptomatic and do not modify disease progression. Cannabidiol (CBD), one of the main phytocannabinoids identified in Cannabis Sativa, which exhibits a large spectrum of therapeutic properties, including anti-inflammatory and antioxidant effects, suggesting its potential as disease-modifying agent for PD. The aim of this study was to evaluate the effects of chronic treatment with CBD (10 mg/kg, i.p.) on PD-associated neurodegenerative and neuroinflammatory processes, and motor deficits in the 6-hydroxydopamine model. Moreover, we investigated the potential mechanisms by which CBD exerted its effects in this model. CBD-treated animals showed a reduction of nigrostriatal degeneration accompanied by a damping of the neuroinflammatory response and an improvement of motor performance. In particular, CBD exhibits a preferential action on astrocytes and activates the astrocytic transient receptor potential vanilloid 1 (TRPV1), thus, enhancing the endogenous neuroprotective response of ciliary neurotrophic factor (CNTF). These results overall support the potential therapeutic utility of CBD in PD, as both neuroprotective and symptomatic agent.


Low resolution electromagnetic tomography: a new method for localizing electrical activity in the brain.
This paper presents a new method for localizing the electric activity in the brain based on multichannel surface EEG recordings. In contrast to the models presented up to now the new method does not assume a limited number of dipolar point sources nor a distribution on a given known surface, but directly computes a current distribution throughout the full brain volume. In order to find a unique solution for the 3-dimensional distribution among the infinite set of different possible solutions, the method assumes that neighboring neurons are simultaneously and synchronously activated. The basic assumption rests on evidence from single cell recordings in the brain that demonstrates strong synchronization of adjacent neurons. In view of this physiological consideration the computational task is to select the smoothest of all possible 3-dimensional current distributions, a task that is a common procedure in generalized signal processing. The result is a true 3-dimensional tomography with the characteristic that localization is preserved with a certain amount of dispersion, i.e., it has a relatively low spatial resolution. The new method, which we call Low Resolution Electromagnetic Tomography (LORETA) is illustrated with two different sets of evoked potential data, the first showing the tomography of the P100 component to checkerboard stimulation of the left, right, upper and lower hemiretina, and the second showing the results for the auditory N100 component and the two cognitive components CNV and P300. A direct comparison of the tomography results with those obtained from fitting one and two dipoles illustrates that the new method provides physiologically meaningful results while dipolar solutions fail in many situations. In the case of the cognitive components, the method offers new hypotheses on the location of higher cognitive functions in the brain.


The Bedford Alzheimer Nursing Severity scale for the severely demented: validation study.
We evaluated the floor effect and convergent, discriminant, and known-group validity of the Bedford Alzheimer Nursing Severity scale (BANS-s), a rating scale comprising cognitive and functional items recently developed for grading severe dementia. Ninety-nine demented patients (81 females and 18 males aged 55-100 years) in two nursing homes were assessed with the BANS-s, established cognitive and functional scales [Mini Mental State Examination, the extended version of the Clinical Dementia Rating (CDR), Katz's basic activities of daily living, Tinetti balance and gait, and Crichton scales], a behavioral scale (UCLA Neuropsychiatric Inventory), and indicators of malnutrition (Prognostic Nutritional Index). A relevant proportion (40%) of patients scored close to the floor of all scales except BANS-s and CDR, which showed a more uniform distribution of scores throughout the possible range. Convergent validity of BANS-s with the other cognitive and functional scales was good, with Pearson's r ranging from 0.62 to 0.79. Discriminant validity analysis of BANS-s versus the UCLA Neuropsychiatric Inventory showed that the two scales measure different domains (Pearson's r = 0.36). To test known-group validity, all patients were divided into two groups of different severity as defined by the Prognostic Nutritional Index. BANS-s and CDR were the scales with the best ability to discriminate malnourished from nonmalnourished patients. As a further validity test, the 37 patients reaching the floor on other cognitive and functional scales were divided into two subgroups of different dementia severity as defined by the Tinetti scale. BANS-s but not CDR was able to differentiate the two groups.


[Updated treatment of peritoneal carcinomas: a review].
Peritoneal surface malignancy (PSM) is a clinical entity with an unfavourable prognosis, which characterizes the evolution of neoplastic diseases from the abdominal and/or pelvic organs and could also be the terminal stage of extra-abdominal tumors. Examples of diseases that can spread mainly within the peritoneal cavity are appendiceal tumors, ovarian cancer, colorectal cancer, abdominal sarcomatosis, gastric cancer and peritoneal mesothelioma. The locoregional therapy is defined as the combination of cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP). The rationale of this combined therapy for PSM is based on the natural history of this clinical entity that remains confined in the peritoneal cavity for most of its natural history. This pattern of spread would seem to indicate the potential usefulness of selectively increasing drug concentration in the tumour-bearing area by direct intraperitoneal chemotherapy instillation. This approach led to these outcomes: the median survival of colorectal carcinoma and ovarian cancer was 32 months; patients with peritoneal mesothelioma showed 57% survival at 5 years, while in patients with appendiceal mucinous tumors and pseudomyxoma peritonei (PMP) the 10 years overall survival was 78%. A significant improvement in survival was associated with hyperthermic intra-peritoneal chemotherapy (HIPEC) in patients with gastric cancer. Considering the constant increasing of diseases treatable with this procedure, more centres should be activated. The establishment of a clear policy and scientific guidelines is mandatory, in order to perform the CRS+HIPEC safely, minimizing treatment-related morbidity and mortality and maximizing the results in terms of survival and quality of life.


Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells.
The retinoblastoma tumor suppressor protein pRb restricts cell growth through inhibition of cell cycle progression. Increasing evidence suggests that pRb also promotes differentiation, but the mechanisms are poorly understood, and the key question remains as to how differentiation in tumor cells can be enhanced in order to diminish their aggressive potential. Previously, we identified the histone demethylase KDM5A (lysine [K]-specific demethylase 5A), which demethylates histone H3 on Lys4 (H3K4), as a pRB-interacting protein counteracting pRB's role in promoting differentiation. Here we show that loss of Kdm5a restores differentiation through increasing mitochondrial respiration. This metabolic effect is both necessary and sufficient to induce the expression of a network of cell type-specific signaling and structural genes. Importantly, the regulatory functions of pRB in the cell cycle and differentiation are distinct because although restoring differentiation requires intact mitochondrial function, it does not necessitate cell cycle exit. Cells lacking Rb1 exhibit defective mitochondria and decreased oxygen consumption. Kdm5a is a direct repressor of metabolic regulatory genes, thus explaining the compensatory role of Kdm5a deletion in restoring mitochondrial function and differentiation. Significantly, activation of mitochondrial function by the mitochondrial biogenesis regulator Pgc-1α (peroxisome proliferator-activated receptor γ-coactivator 1α; also called PPARGC1A) a coactivator of the Kdm5a target genes, is sufficient to override the differentiation block. Overexpression of Pgc-1α, like KDM5A deletion, inhibits cell growth in RB-negative human cancer cell lines. The rescue of differentiation by loss of KDM5A or by activation of mitochondrial biogenesis reveals the switch to oxidative phosphorylation as an essential step in restoring differentiation and a less aggressive cancer phenotype.


Presynaptic effects of NMDA in cerebellar Purkinje cells and interneurons.
NMDA receptors (NMDARs) are generally believed to mediate exclusively postsynaptic effects at brain synapses. Here we searched for presynaptic effects of NMDA at inhibitory synapses in rat cerebellar slices. In Purkinje cells, application of NMDA enhanced the frequency of miniature IPSCs (mIPSCs) but not that of miniature EPSCs (mEPSCs). This increase in frequency was dependent on the external Mg2+ concentration. In basket and stellate cells, NMDA induced an even larger mIPSC frequency increase than in Purkinje cells, whereas mEPSCs were again not affected. Moreover, NMDA induced an inward current in both types of interneuron, which translated into a small depolarization (approximately 10 mV for 30 microM NMDA) under current-clamp conditions. In paired recordings of connected basket cell-Purkinje cell synapses, depolarizations of 10-30 mV applied to the basket cell soma enhanced the frequency of postsynaptic mIPSCs, suggesting that somatic depolarization was partially transmitted to the terminals in the presence of tetrodotoxin. However, this effect was small and unlikely to account fully for the effects of NMDA on mIPSCs. Consistent with a small number of dendritic NMDARs, evoked EPSCs in interneurons had a remarkably small NMDA component. Evoked IPSCs at interneuron-interneuron synapses were inhibited by NMDA, and the rate of failures was increased, indicating again a presynaptic site of action. We conclude that activation of NMDARs in interneurons exerts complex presynaptic effects, and that the corresponding receptors are most likely located in the axonal domain of the cell.