Combined c-Met/Trk Inhibition Overcomes Resistance to CDK4/6 Inhibitors in Glioblastoma.
Glioblastoma (GBM) is the most common primary brain malignancy and carries an extremely poor prognosis. Recent molecular studies revealed the CDK4/6-Rb-E2F axis and receptor tyrosine kinase (RTK) signaling to be deregulated in most GBM, creating an opportunity to develop more effective therapies by targeting both pathways. Using a phospho-RTK protein array, we found that both c-Met and TrkA-B pathways were significantly activated upon CDK4/6 inhibition in GBM cells. We therefore investigated the efficacy of combined CDK4/6 and c-Met/TrkA-B inhibition against GBM. We show that both c-Met and TrkA-B pathways transactivate each other, and targeting both pathways simultaneously results in more efficient pathway suppression. Mechanistically, inhibition of CDK4/6 drove NF-κB-mediated upregulation of hepatocyte growth factor, brain-derived neurotrophic factor, and nerve growth factor that in turn activated both c-Met and TrkA-B pathways. Combining the CDK4/6 inhibitor abemaciclib with the c-Met/Trk inhibitor altiratinib or the corresponding siRNAs induced apoptosis, leading to significant synergy against GBM. Collectively, these findings demonstrate that the activation of c-Met/TrkA-B pathways is a novel mechanism involved in therapeutic resistance of GBM to CDK4/6 inhibition and that dual inhibition of c-Met/Trk with CDK4/6 should be considered in future clinical trials.Significance: CDK4/6 inhibition in glioblastoma activates the c-Met and TrkA-B pathways mediated by NF-κB and can be reversed by a dual c-Met/Trk inhibitor. Cancer Res; 78(15); 4360-9. ©2018 AACR.


Absence of arteriosclerosis in intramyocardial coronary arteries: a mystery to be solved?
Several studies show that portions of intramyocardial coronary arteries are spared of arteriosclerosis, involving morphological, embryological, biochemical and pathophysiological aspects. Endothelial function is significantly affected in the segment of transition, as estimated by the vasoactive response to Ach. These findings suggest that myocardial bridge can provide protection against arteriosclerosis by counteracting the negative effects of endothelial dysfunction. The intramyocardial portion's protection phenomenon deserves further scientific research on all research fronts. Improved morphological, biomechanical and especially physiological and embryological knowledge may be the key to a future window of opportunity for chronic arterial disease therapy and prevention. In addition, this review discusses possible therapeutic approaches for symptomatic coronary ischemia caused by myocardial bridges.


High-performance antireflective coatings with a porous nanoparticle layer for visible wavelengths.
Ghosts and flares are well-known problems that are caused by reflections from lens surfaces when we take photographs. It is more difficult to prevent such stray light in a digital camera than in a film camera because of high reflectance from the low-pass filter and diffraction from the image sensor. To prevent such stray light, we introduce an ultralow refractive index layer into the antireflective (AR) coatings. We used the solgel method to form porous fluoride layers with ultralow refractive indices, and we succeeded in developing a unique process to form AR coatings with superior performance.


Follow up of a robust meta-signature to identify Zika virus infection in Aedes aegypti: another brick in the wall.
The mosquito Aedes aegypti is the main vector of several arthropod-borne diseases that have global impacts. In a previous meta-analysis, our group identified a vector gene set containing 110 genes strongly associated with infections of dengue, West Nile and yellow fever viruses. Of these 110 genes, four genes allowed a highly accurate classification of infected status. More recently, a new study of Ae. aegypti infected with Zika virus (ZIKV) was published, providing new data to investigate whether this "infection" gene set is also altered during a ZIKV infection. Our hypothesis is that the infection-associated signature may also serve as a proxy to classify the ZIKV infection in the vector. Raw data associated with the NCBI/BioProject were downloaded and re-analysed. A total of 18 paired-end replicates corresponding to three ZIKV-infected samples and three controls were included in this study. The nMDS technique with a logistic regression was used to obtain the probabilities of belonging to a given class. Thus, to compare both gene sets, we used the area under the curve and performed a comparison using the bootstrap method. Our meta-signature was able to separate the infected mosquitoes from the controls with good predictive power to classify the Zika-infected mosquitoes.


Monitoring drug-serum protein interactions for early ADME prediction through Surface Plasmon Resonance technology.
Many molecules fail to reach the market due to poor pharmacokinetic (PK) properties, rendering the potential drug virtually unavailable for the primary target despite efficient administration to the body. PK properties of endogenous and exogenous compounds in mammals are dependent, among other factors, on their ability to interact with serum proteins. The extent of binding can greatly influence their ADME (adsorption, distribution, metabolism and execration) profile. Reliable and cost-effective bioavailability studies, early in the drug discovery process, can lead to an improvement of the success rate for compounds entering clinical trials. Optical biosensors based on surface plasmon resonance (SPR) detection emerged as an efficient approach to obtain large amounts of information about the binding of small molecules to serum proteins. Simple, automated and fast assays provide a good throughput, versatility and highly informative data output, rendering the methodology particularly suited for early screening. The ability to provide basic information on PK can be easily coupled to structure-activity relationship analysis. In this review, features of the technology and its employment for the study of serum protein-small molecule interactions are presented and discussed.


Variations in slice sensitivity profile for various height settings in tomosynthesis imaging: Phantom study.
Understanding the properties of slice sensitivity profile (SSP), or slice thickness, is crucial for an accurate and highly reproducible diagnosis using tomosynthesis imaging. The objectives of the present study are therefore to quantitatively evaluate how the SSP with the use of a small metal bead is affected by different settings of the height from the table and the height of the center of rotation (COR) in tomosynthesis imaging except for the digital breast tomosynthesis, and visually verify the effects on tomosynthesis images. The reconstruction filters used were three types of filtered back-projection and iterative reconstructions. The SSP was measured from the full width at half maximum (FWHM-SSP) of the profile curve of the bead in the perpendicular direction (z direction) relative to the table. Two types of anthropomorphic phantoms simulating the human body, with bones and soft tissues, were used to study the effects of different settings for the COR height. In all reconstruction filters, the FWHM-SSP changed as the height of the bead varied when the bead and COR were set to the same height from the table. If the bead and the COR were set to different heights, the FWHM-SSP increased (decreased) when the height of the bead was set to be greater (less) than the height of the COR. These changes were also confirmed on the anthropomorphic phantom images of the bones and soft tissues.


Role of nitric oxide in sepsis-induced hyporeactivity in isolated rat lungs.
The aim of the present study was to test the hypothesis that pulmonary microvascular reactivity is depressed in sepsis and that inducible nitric oxide synthase (iNOS) contributes to the vascular hyporeactivity. Rats were made septic by cecal ligation and puncture. After 16 h, pulmonary vascular reactivity was evaluated by measurement of perfusion pressures while the vasculature was challenged with angiotensin II and KCl. The results showed that vascular reactivity was significantly depressed in lungs from septic rats in comparison to sham-operated controls. Pretreatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) restored the depressed vasoreactivity while the nitric oxide (NO) synthase substrate L-arginine (1 mM) reversed the contraction-restoring effect of L-NAME. NO production in lungs from septic rats increased about 4-fold in comparison to sham-operated controls. iNOS protein was expressed in lung tissues, mainly the resistance vessels, from septic rats but not from sham-operated controls. Reverse transcription and polymerase chain reaction also showed a strong induction of iNOS mRNA in lung tissues from septic rats. These results suggest that increased iNOS expression and NO production may contribute to depressed pulmonary vascular reactivity in sepsis.


Optimization of municipal solid waste leaching test procedure: assessment of the part of hydrosoluble organic compounds.
Despite national recycling campaigns, the amount of municipal solid waste (MSW) to be treated remains very important in France with almost 39% of the waste produced going to landfills. Therefore with the increasing concern over sustainable development and energy valorization, it seems essential to optimize current treatment methods and develop new preparation techniques of the waste. Nevertheless an important first step to take into account is to evaluate the waste using a different method than biogas production. In this perspective, the leaching test (LT) could be used as a tool to evaluate the ability of a waste to mobilize organic and mineral compounds. This research aims at optimizing a leaching test protocol mainly adapted to organic waste in order to be used on MSW to assess the fractions of both fast and slow mobilized organic matter. Several leaching tests have thus been implemented, optimized and compared in terms of accessible organic matter in the waste. Results have shown that the test conditions have a great influence on the mobilization of pollutants. The duration of the test affects mainly the quantity and quality of organic molecules extracted. The renewal of the eluent does not properly simulate the conditions of a landfill. The results would be used to assess the performance and the efficiency of new ways of waste pretreatment.


Inducible DamID systems for genomic mapping of chromatin proteins in Drosophila.
Dam identification (DamID) is a powerful technique to generate genome-wide maps of chromatin protein binding. Due to its high sensitivity, it is particularly suited to study the genome interactions of chromatin proteins in small tissue samples in model organisms such as Drosophila Here, we report an intein-based approach to tune the expression level of Dam and Dam-fusion proteins in Drosophila by addition of a ligand to fly food. This helps to suppress possible toxic effects of Dam. In addition, we describe a strategy for genetically controlled expression of Dam in a specific cell type in complex tissues. We demonstrate the utility of the latter by generating a glia-specific map of Polycomb in small samples of brain tissue. These new DamID tools will be valuable for the mapping of binding patterns of chromatin proteins in Drosophila tissues and especially in cell lineages.


Management of aplastic anemia: the role of systematic reviews and meta-analyses.
Aplastic anemia is a rare bone marrow failure disorder. Allogeneic hematopoietic cell transplantation (alloHCT) and immunosuppressive therapy (IST) are the main therapeutic modalities currently used to treat patients with aplastic anemia. Systematic reviews and meta-analyses of randomized controlled trials (RCTs) are regarded as the highest level of evidence and as such aid practitioners in solving clinical questions. The objective of this review is to assess the base of evidence for the common practice and the current guidelines for the management of aplastic anemia. It focuses on data obtained from systematic reviews and meta-analyses of RCTs conducted in this field. Specifically, it focuses on four major therapeutic questions: the roles of alloHCT, IST, hematopoietic growth factors and supportive care.


Block of Kv1.7 potassium currents increases glucose-stimulated insulin secretion.
Glucose-stimulated insulin secretion (GSIS) relies on repetitive, electrical spiking activity of the beta cell membrane. Cyclic activation of voltage-gated potassium channels (K(v) ) generates an outward, 'delayed rectifier' potassium current, which drives the repolarizing phase of each spike and modulates insulin release. Although several K(v) channels are expressed in pancreatic islets, their individual contributions to GSIS remain incompletely understood. We take advantage of a naturally occurring cone-snail peptide toxin, Conkunitzin-S1 (Conk-S1), which selectively blocks K(v) 1.7 channels to provide an intrinsically limited, finely graded control of total beta cell delayed rectifier current and hence of GSIS. Conk-S1 increases GSIS in isolated rat islets, likely by reducing K(v) 1.7-mediated delayed rectifier currents in beta cells, which yields increases in action potential firing and cytoplasmic free calcium. In rats, Conk-S1 increases glucose-dependent insulin secretion without decreasing basal glucose. Thus, we conclude that K(v) 1.7 contributes to the membrane-repolarizing current of beta cells during GSIS and that block of this specific component of beta cell K(v) current offers a potential strategy for enhancing GSIS with minimal risk of hypoglycaemia during metabolic disorders such as Type 2 diabetes.


Structure-Based Discovery of Small Molecule Inhibitors of Cariogenic Virulence.
Streptococcus mutans employs a key virulence factor, three glucosyltransferase (GtfBCD) enzymes to establish cariogenic biofilms. Therefore, the inhibition of GtfBCD would provide anti-virulence therapeutics. Here a small molecule library of 500,000 small molecule compounds was screened in silico against the available crystal structure of the GtfC catalytic domain. Based on the predicted binding affinities and drug-like properties, small molecules were selected and evaluated for their ability to reduce S. mutans biofilms, as well as inhibit the activity of Gtfs. The most potent inhibitor was further characterized for Gtf binding using OctetRed instrument, which yielded low micromolar KD against GtfB and nanomolar KD against GtfC, demonstrating selectivity towards GtfC. Additionally, the lead compound did not affect the overall growth of S. mutans and commensal oral bacteria, and selectively inhibit the biofilm formation by S. mutans, indicative of its selectivity and non-bactericidal nature. The lead compound also effectively reduced cariogenicity in vivo in a rat model of dental caries. An analog that docked poorly in the GtfC catalytic domain failed to inhibit the activity of Gtfs and S. mutans biofilms, signifying the specificity of the lead compound. This report illustrates the validity and potential of structure-based design of anti-S. mutans virulence inhibitors.


Metagenome microarray for screening of fosmid clones containing specific genes.
A critical step in the process of metagenome analysis is to screen for clones that contain specific genes among a large number of clones. To form one of the sequence-based screening tools of a metagenome library, we designed a format of microarray [metagenome microarray (MGA)] that is arrayed with fosmid library clone DNA samples on a glass slide. We evaluated the MGA using random prime labeled fluorescent probes prepared from PCR products of the target gene and found that we could obtain specific hybridization signals only for the fosmid clone that contained the target gene. We found that the detection limit of the MGA was c. 10 ng microL(-1) of fosmid clone DNA, and that the MGA-based hybridization was quantitative within a concentration range of 10-200 ng microL(-1) of fosmid clone DNA. We used the MGA successfully to identify two fosmid clones that contained 16S rRNA genes from a fosmid library from the sediment of the East Sea, Korea. In conclusion, we have demonstrated that the MGA can be used for screening for fosmid clones containing specific genes in a metagenome library, and that this technology has potential application as a high-throughput metagenome screening tool.


An Evidence-Based Somatic Acupressure Intervention Protocol for Managing the Breast Cancer Fatigue-Sleep Disturbance-Depression Symptom Cluster: Development and Validation following the Medical Research Council Framework.
Somatic acupoint stimulation (SAS) has been frequently utilised as a promising intervention for individual cancer-related symptom management, such as fatigue, sleep disturbance and depression. However, research evidence regarding the role of SAS in mitigating the fatigue-sleep disturbance-depression symptom cluster (FSDSC) has been scant. This study was conducted to develop an evidence-based SAS intervention protocol that can be further implemented in a Phase II randomized controlled trial (RCT) to manage the FSDSC in breast cancer survivors. The Medical Research Council Framework for Developing and Evaluating Complex Intervention (MRC framework) was employed to guide the development procedures of the SAS intervention protocol, including the identification of an existing evidence base, the identification of theories and practice standards, and the validation of the SAS intervention protocol. A content validity study was performed through an expert panel to assess the scientific and practical appropriateness of the SAS intervention protocol. The content validity index (CVI), including item-level CVI and protocol-level CVI, were calculated to evaluate the consensus level of the expert panel. Key components of the SAS protocol, including the acupoint formula, the SAS modality, technique, intensity and frequency were identified for both a true and placebo SAS intervention based on the best available research evidence retrieved from systematic reviews, clinical trials, and relevant theories, particularly regarding the inflammatory process, yin-yang theory, zang-fu organs and meridians theory, and acupressure practical standards. The true SAS intervention was determined as daily self-administered acupressure on specific acupoints for seven weeks. The placebo SAS was designed as light acupressure on non-acupoints with the same frequency and duration as the true SAS. Excellent content validity was achieved after one round of expert panel assessment, with all the key components of the true and placebo SAS protocols rated as content valid (CVI ranged from 0.86 to 1.00). A research-informed, theory-driven and practically feasible SAS intervention protocol for the FSDSC management in breast cancer survivors was developed following the MRC framework. The feasibility and acceptability of the SAS intervention will be further tested in breast cancer survivors through a Phase II RCT.


Low Density Granulocytes and Dysregulated Neutrophils Driving Autoinflammatory Manifestations in NEMO Deficiency.
NF-κB essential modulator (NEMO, IKK-γ) deficiency is a rare combined immunodeficiency caused by mutations in the IKBKG gene. Conventionally, patients are afflicted with life threatening recurrent microbial infections. Paradoxically, the spectrum of clinical manifestations includes severe inflammatory disorders. The mechanisms leading to autoinflammation in NEMO deficiency are currently unknown. Herein, we sought to investigate the underlying mechanisms of clinical autoinflammatory manifestations in a 12-years old male NEMO deficiency (EDA-ID, OMIM #300,291) patient by comparing the immune profile of the patient before and after hematopoietic stem cell transplantation (HSCT). Response to NF-kB activators were measured by cytokine ELISA. Neutrophil and low-density granulocyte (LDG) populations were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMC) transcriptome before and after HSCT and transcriptome of sorted normal-density neutrophils and LDGs were determined using the NanoString nCounter gene expression panels. ISG15 expression and protein ISGylation was based on Immunoblotting. Consistent with the immune deficiency, PBMCs of the patient were unresponsive to toll-like and T cell receptor-activators. Paradoxically, LDGs comprised 35% of patient PBMCs and elevated expression of genes such as MMP9, LTF, and LCN2 in the granulocytic lineage, high levels of IP-10 in the patient's plasma, spontaneous ISG15 expression and protein ISGylation indicative of a spontaneous type I interferon (IFN) signature were observed, all of which normalized after HSCT. Collectively, our results suggest that type I IFN signature observed in the patient, dysregulated LDGs and spontaneously activated neutrophils, potentially contribute to tissue damage in NEMO deficiency.


[Epidemiology, treatment and prevention of type 2 diabetes in children and adolescents].
Changes in food consumption and exercise are fueling a worldwide increase in obesity in children and adolescents. As a consequence of this dramatic development an increasing rate of type 2 diabetes can be observed in children and adolescents in many countries. Development of strategies for therapy of type 2 diabetes and implementation of prevention of obesity and type 2 diabetes in this age group should be primary health care goals.


Podosome Force Generation Machinery: A Local Balance between Protrusion at the Core and Traction at the Ring.
Determining how cells generate and transduce mechanical forces at the nanoscale is a major technical challenge for the understanding of numerous physiological and pathological processes. Podosomes are submicrometer cell structures with a columnar F-actin core surrounded by a ring of adhesion proteins, which possess the singular ability to protrude into and probe the extracellular matrix. Using protrusion force microscopy, we have previously shown that single podosomes produce local nanoscale protrusions on the extracellular environment. However, how cellular forces are distributed to allow this protruding mechanism is still unknown. To investigate the molecular machinery of protrusion force generation, we performed mechanical simulations and developed quantitative image analyses of nanoscale architectural and mechanical measurements. First, in silico modeling showed that the deformations of the substrate made by podosomes require protrusion forces to be balanced by local traction forces at the immediate core periphery where the adhesion ring is located. Second, we showed that three-ring proteins are required for actin polymerization and protrusion force generation. Third, using DONALD, a 3D nanoscopy technique that provides 20 nm isotropic localization precision, we related force generation to the molecular extension of talin within the podosome ring, which requires vinculin and paxillin, indicating that the ring sustains mechanical tension. Our work demonstrates that the ring is a site of tension, balancing protrusion at the core. This local coupling of opposing forces forms the basis of protrusion and reveals the podosome as a nanoscale autonomous force generator.


Functional-cranial approach to the influence of economic strategy on skull morphology.
Environmental factors are assumed to play an important role in the shaping of craniofacial morphology. Here we propose a statistical approach which can be of utility in estimating the magnitude and localization of a particular nongenetic factor upon the specific functional components of the skull. Our analysis is a combination of previous attempts of apportionment of variance and the application of craniofunctional theory. The effect of subsistence strategy on craniofacial functional components was studied on 18 populations of hunter-gatherers and farmers from South America. Results demonstrate that the environmental factors studied likely influenced the masticatory component's size and shape. Even when this effect is not large enough to clearly differentiate among subsistence strategies (since whole craniofacial variation among populations remains greater), the method used here provides interesting clues to localize plastic or adaptive responses to external stimuli.


Micro-computed Tomography versus the Cross-sectioning Method to Evaluate Dentin Defects Induced by Different Mechanized Instrumentation Techniques.
The objective of this study was to compare the methods of micro-computed tomography (micro-CT) and cross-sectioning followed by stereomicroscopy in assessing dentinal defects after instrumentation with different mechanized systems. Forty mesial roots of mandibular molars were scanned and divided into 4 groups (n = 10): Group R, Reciproc; Group PTN, ProTaper Next; Group WOG, WaveOne Gold; Group PDL, ProDesign Logic. After instrumentation, the roots were once again submitted to a micro-CT scan, and then sectioned at 3, 6, and 9 mm from the apex, and assessed for the presence of complete and incomplete dentinal defects under a stereomicroscope. The nonparametric Kruskal-Wallis, Friedman, and Wilcoxon tests were used in the statistical analysis. The study used a significance level of 5%. The total number of defects observed by cross-sectioning followed by stereomicroscopy was significantly higher than that observed by micro-CT, in all of the experimental groups (P ≤ .05). All of the defects identified in the postoperative period were already present in the corresponding preoperative period. There was no significant difference among the instrumentation systems as to the median numbers of defects, for either cross-sectioning followed by stereomicroscopy or micro-CT, at all the root levels (P > .05). In the micro-CT analysis, no significant difference was found between the median numbers of pre- and postinstrumentation defects, regardless of the instrumentation system (P > .05). None of the evaluated instrumentation systems led to the formation of new dentin defects. All of the defects identified in the stereomicroscopic analysis were already present before instrumentation, or were absent at both time points in the micro-CT analysis, indicating that the formation of new defects resulted from the sectioning procedure performed before stereomicroscopy and not from instrumentation.


Expanding Genotype-Phenotype Correlation of CLCNKA and CLCNKB Variants Linked to Hearing Loss.
The ClC-K channels CLCNKA and CLCNKB are crucial for the transepithelial transport processes required for sufficient urinary concentrations and sensory mechanoelectrical transduction in the cochlea. Loss-of-function alleles in these channels are associated with various clinical phenotypes, ranging from hypokalemic alkalosis to sensorineural hearing loss (SNHL) accompanied by severe renal conditions, i.e., Bartter's syndrome. Using a stepwise genetic approach encompassing whole-genome sequencing (WGS), we identified one family with compound heterozygous variants in the ClC-K channels, specifically a truncating variant in CLCNKA in trans with a contiguous deletion of CLCNKA and CLCNKB. Breakpoint PCR and Sanger sequencing elucidated the breakpoint junctions derived from WGS, and allele-specific droplet digital PCR confirmed one copy loss of the CLCNKA_CLCNKB contiguous deletion. The proband that harbors the CLCNKA_CLCNKB variants is characterized by SNHL without hypokalemic alkalosis and renal anomalies, suggesting a distinct phenotype in the ClC-K channels in whom SNHL predominantly occurs. These results expanded genotypes and phenotypes associated with ClC-K channels, including the disease entities associated with non-syndromic hearing loss. Repeated identification of deletions across various extents of CLCNKA_CLCNKB suggests a mutational hotspot allele, highlighting the need for an in-depth analysis of the CLCNKA_CLCNKB intergenic region, especially in undiagnosed SNHL patients with a single hit in CLCNKA.


Very early predictors of conduct problems and crime: results from a national cohort study.
Longitudinal research has produced a wealth of knowledge about individual, family, and social predictors of crime. However, nearly all studies have started after children are age 5, and little is known about earlier risk factors. The 1970 British Cohort Study is a prospective population survey of more than 16,000 children born in 1970. Pregnancy, birth, child, parent, and socioeconomic characteristics were measured from medical records, parent interviews, and child assessments at birth and age 5. Conduct problems were reported by parents at age 10, and criminal convictions were self-reported by study members at ages 30-34. Early (up to age 5) psychosocial risk factors were strong predictors of conduct problems and criminal conviction. Among pregnancy and birth measures, only prenatal maternal smoking was strongly predictive. Risk factors were similar for girls and boys. Additive risk scores predicted antisocial behaviour quite strongly. Risk factors from pregnancy to age 5 are quite strong predictors of conduct problems and crime. New risk assessment tools could be developed to identify young children at high risk for later antisocial behaviour.


Bovine milk oligosaccharides decrease gut permeability and improve inflammation and microbial dysbiosis in diet-induced obese mice.
Obesity is characterized by altered gut homeostasis, including dysbiosis and increased gut permeability closely linked to the development of metabolic disorders. Milk oligosaccharides are complex sugars that selectively enhance the growth of specific beneficial bacteria in the gastrointestinal tract and could be used as prebiotics. The aim of the study was to demonstrate the effects of bovine milk oligosaccharides (BMO) and Bifidobacterium longum ssp. infantis (B. infantis) on restoring diet-induced obesity intestinal microbiota and barrier function defects in mice. Male C57/BL6 mice were fed a Western diet (WD, 40% fat/kcal) or normal chow (C, 14% fat/kcal) for 7 wk. During the final 2 wk of the study, the diet of a subgroup of WD-fed mice was supplemented with BMO (7% wt/wt). Weekly gavage of B. infantis was performed in all mice starting at wk 3, yet B. infantis could not be detected in any luminal contents when mice were killed. Supplementation of the WD with BMO normalized the cecal and colonic microbiota with increased abundance of Lactobacillus compared with both WD and C mice and restoration of Allobaculum and Ruminococcus levels to that of C mice. The BMO supplementation reduced WD-induced increase in paracellular and transcellular flux in the large intestine as well as mRNA levels of the inflammatory marker tumor necrosis factor α. In conclusion, BMO are promising prebiotics to modulate gut microbiota and intestinal barrier function for enhanced health.


The Dietary Inflammatory Index Is Associated with Prostate Cancer Risk in French Middle-Aged Adults in a Prospective Study.
Chronic inflammation is one of the mechanisms involved in carcinogenesis. Diet is a major source of pro- and anti-inflammatory compounds. The Dietary Inflammatory Index (DII) was designed to estimate its overall inflammatory potential. Our objective was to investigate the associations between the DII and overall, breast, and prostate cancer risks. This prospective study included 6542 participants [3771 women and 2771 men with a mean ± SD age of 49.2 ± 6.4 y and a BMI (in kg/m2) of 24.0 ± 3.6 at baseline] from the Supplémentation en VItamines et Minéraux AntioXydants (SU.VI.MAX) cohort who completed at least six 24-h dietary records during the first 2 y of follow-up. The DII was based on 36 food variables. Higher scores corresponded to more proinflammatory diets. A total of 559 incident cancers were diagnosed (median follow-up, 12.6 y), including 158 female breast and 123 prostate cancers (the 2 main cancer sites in this cohort). Associations were characterized by multivariable Cox proportional hazards models. Stratified analyses were performed according to the median of usual daily alcohol intake. Sex-specific quartiles of the DII were positively associated with prostate cancer risk [quartile (Q) 4 compared with Q1, HR: 2.08; 95% CI: 1.06, 4.09] but not with overall or breast cancer risks. There was an interaction between the DII and alcohol intake (grams per day) on overall cancer risk (P-interaction = 0.02): the DII was positively associated with overall cancer risk in low-to-moderate alcohol drinkers (Q4 compared with Q1 HR: 1.75; 95% CI: 1.15, 2.68; P-trend = 0.02), whereas no association was detected in higher consumers of alcohol (P-trend = 0.8). This interaction was also observed for breast cancer (P-interaction = 0.001). Consistent with mechanistic data, findings from this study indicated that proinflammatory diets are associated with increased prostate cancer risk and, in low-to-moderate alcohol drinkers, with increased overall and breast cancer risk. The SU.VI.MAX trial was registered at clinicaltrials.gov as NCT00272428.


Clinical practice of functional electrical stimulation: from "Yesterday" to "Today".
Functional electrical stimulation (FES) is an accepted treatment method for paresis or paralysis after spinal cord and head injury as well as stroke and other neurological upper motor neuron disorders. At the beginning, FES worked like an electrophysiological brace for the correction of drop foot of patients after a stroke. When analyzing early accomplishments, it becomes evident that FES was influenced rather by technological and biomedical engineering development than by contemporary knowledge on neurocontrol of movement in individuals with upper motor neuron paralysis. Nevertheless, with better understanding of pathophysiology of spasticity and neurocontrol of impaired movement, FES advanced from an electrophysiological brace to a treatment modality for the improvement of muscle control, neuroaugmentation of residual movements, and supportive procedure for "spontaneous recovery" of motor control. In the present article we shall illustrate barriers which delayed FES to be applied in clinical practice of neuron rehabilitation from "Yesterday" to "Today." We shall discuss the importance to apply FES early after the onset of neurological conditions to prevent disuse of noninjured portions of the CNS. Moreover, FES can play a significant role in the supporting processes of neuroplasticity in the subacute phase of upper motor neuron dysfunction. Therefore, the electrophysiological brace of "Yesterday" provides "Today" a correction of missing neuromuscular function. At the same time, it is an active external device for the correction of motor deficits interacting with the somatosensory-motor integration. Thus, "Yesterday" and "Today" of the same technological approach can be very different, thanks to a different understanding and assessment of "external" and "internal" components of human motor control.


A Comprehensive Review of Sequencing and Combination Strategies of Targeted Agents in Metastatic Colorectal Cancer.
The emergence of targeted therapies for the treatment of metastatic colorectal cancer (mCRC) has considerably improved survival, but has also resulted in a dilemma of identifying the optimal sequence and combination of various agents in the mCRC treatment landscape. A number of cytotoxic agents, including irinotecan, oxaliplatin, 5-fluorouracil, capecitabine, and TAS-102, are available for treatment of mCRC. Additionally, whereas patients harboring rat sarcoma viral oncogene homolog (RAS)-wild type mCRC can be treated with the anti-epidermal growth factor receptor antibodies cetuximab and panitumumab or antiangiogenic agents (bevacizumab, ziv-aflibercept, and ramucirumab), patients with RAS-mutant mCRC are limited to antiangiogenic agents as biologic options. Regorafenib, a multikinase inhibitor, can be used in both RAS subgroups. As such, the recommended sequence of therapies that should be received by each subgroup must also be considered separately. This review provides an overview of recent clinical data for approved and investigational targeted therapies that have been studied across different mCRC treatment lines and patient subgroups. It also examines emerging trends in the treatment landscape for mCRC, including treatment with immune checkpoint inhibitors and the utilization of genomic profiling. Currently, there are no established guidelines for optimal sequencing of cytotoxic or targeted agents in metastatic colorectal cancer (mCRC). This review provides a snapshot of the current mCRC treatment paradigm and examines the latest clinical data that support the utilization of several targeted agents alone or in combination with backbone chemotherapy across different lines of treatment and patient populations, highlighting recommendations for their usage. Recent advances in the treatment landscape are also summarized, including genomic profiling and preliminary results with immune checkpoint inhibitors.


Dicoumarol activates Ca2+-permeable cation channels triggering erythrocyte cell membrane scrambling.
Dicoumarol, a widely used anticoagulant, may cause anemia, which may result from enhanced erythrocyte loss due to bleeding or due to accelerated erythrocyte death. Erythrocytes may undergo suicidal death or eryptosis, characterized by cell shrinkage and phospholipid scrambling of the cell membrane. Eryptosis may be triggered by increase of cytosolic Ca(2+)-activity ([Ca(2+)](i)). The present study explored, whether dicoumarol induces eryptosis. [Ca(2+)](i) was estimated from Fluo3-fluorescence, cation channel activity utilizing whole cell patch clamp, cell volume from forward scatter, phospholipid scrambling from annexin-V-binding, and hemolysis from haemoglobin release. Exposure of erythrocytes for 48 hours to dicoumarol (=10 μM) significantly increased [Ca(2+)](i), enhanced cation channel activity, decreased forward scatter, triggered annexin-V-binding and elicited hemolysis. Following exposure to 30 μM dicoumarol, annexin-V-binding affected approximately 15%, and hemolysis 2% of treated erythrocytes. The stimulation of annexin-V-binding by dicoumarol was abrogated in the nominal absence of Ca(2+). In conclusion, dicoumarol stimulates suicidal death of erythrocytes by stimulating Ca(2+) entry and subsequent triggering of Ca(2+) dependent cell membrane scrambling.


The evaluation of rapidly progressive dementia.
Rapidly progressive dementia (RPD) is a unique set of disorders resulting in cognitive, behavioral, and motor decline within 2 years. A variety of etiologies may contribute to RPD including neurodegenerative, inflammatory, infectious, and toxic-metabolic conditions. Jakob-Creutzfeldt disease (CJD) is frequently the most concerning diagnosis on the differential. The challenge for the neurologist is distinguishing prion disease from reversible processes that result in dementia. This review discusses the clinical aspects and the diagnostic workup of RPD. Particular focus is given to both CJD and the potentially treatable inflammatory conditions that may cause a similar presentation. Furthermore, a standardized stepwise approach is outlined for patients presenting with RPD. Neurologists should adopt a standardized approach to the rapidly presenting disease processes that may mimic CJD in their clinical and radiologic features.


Microsurgically critical anomaly of the anterior communicating artery complex during the pterional approach to a ruptured aneurysm: double fenestration of the proximal A2 segments.
A 50-year-old man presented with a ruptured aneurysm of the anterior communicating artery (ACoA) complex anomaly with the neck of the aneurysm located in the upper ACoA. The right pterional approach was performed 2 days after admission. Retraction of the frontal lobe exposed the lower half of the ACoA complex consisting of the origins of the bilateral A2 segments, and the apparent neck of the aneurysm was clipped. However, further exposure of the bilateral A2 segments revealed double fenestration of the proximal A2 segments, a subtype of duplication of the ACoA accompanied by a bridging artery between the upper and lower ACoA. The limited visualization of this ACoA complex anomaly with an aneurysm had led to the proximal origin of the bridging artery being mistaken for the neck of the aneurysm. Such double fenestration of the proximal A2 segments is a microsurgically critical anomaly of the ACoA complex, because the bridging artery mimics the neck of an aneurysm when visualized by the pterional approach.


Role of moxibustion in inflammatory responses during treatment of rat ulcerative colitis.
To investigate the efficacy of moxibustion in ulcerative colitis (UC) rats from morphological, immunological and molecular biological perspectives. Thirty-two Sprague-Dawley rats were randomly assigned to a blank control group (normal rats, n = 6) and a model replication (MR) group (UC rats, n = 26). A UC model was established by 2,4,6-trinitrobenzenesulfonic acid/dextran sulfate sodium enema. Rats in the MR group were further randomly assigned to a 9-min moxibustion (9M) group (9 moxa-cone, n = 6), 6-min moxibustion (6M) group (6 moxa-cone, n = 6), 3-min moxibustion (3M) group (3 moxa-cone, n = 6), and a waiting list control (WLC) group (no moxibustion treatment, n = 6). Rats in the moxibustion treatment group were treated in 14 sessions over 28 d. Disease activity, local tissue morphology, serum level of interleukin (IL)-8 and IL-10, and expression of Toll-like receptor (TLR)9 as well as nuclear factor (NF)-κB p65 in colonic tissue were determined by disease activity index (DAI), hematoxylin and eosin staining, electron microscopy, enzyme-linked immunosorbent assay and Western blotting, respectively. DAI was lowest in the 9M group and highest in the WLC group. The differences in DAI between the moxibustion treatment (3M, 6M, 9M) and no treatment groups were significant for all one-to-one comparisons (0.60 ± 0.54 vs 1.20 ± 0.44, 0.60 ± 0.54 vs 1.80 ± 0.45, 0.60 ± 0.54 vs 3.0 ± 0.45, respectively, P < 0.05). Light and electron microscopy showed that the neatness of the glandular arrangement in colonic mucosal epithelia gradually increased in the WLC, 3M, 6M to 9M groups. IL-8 level successively decreased while IL-10 level increased from the WLC to 3M, 6M and 9M groups. The differences among these groups were significant for all comparisons (105.46 ± 8.75 vs 76.61 ± 3.58, 105.46 ± 8.75 vs 69.78 ± 1.87, 105.46 ± 8.75 vs 67.41 ± 1.84, respectively, P < 0.01 for IL-8; and 30.83 ± 1.29 vs 75.64 ± 1.90, 30.83 ± 1.29 vs 80.90 ± 3.16, 30.83 ± 1.29 vs 83.46 ± 2.37, respectively, P < 0.01 for IL-10), except comparison of 6M vs 9M. Expression of TLR9 and NF-κB p65 decreased in order: highest in the WLC group and lowest in the 9M group. In addition, the differences among the WLC, 3M, 6M and 9M groups were significant for all comparisons (0.492 ± 0.026 vs 0.380 ± 0.022, 0.492 ± 0.026 vs 0.355 ± 0.005, 0.492 ± 0.026 vs 0.327 ± 0.015, respectively, P < 0.05 for TLR9; and 0.436 ± 0.041 vs 0.326 ± 0.022, 0.436 ± 0.041 vs 0.293 ± 0.006, 0.436 ± 0.041 vs 0.265 ± 0.017, respectively, P < 0.05 for NF-κB p65). Moxibustion repairs damaged colonic mucosa, suppresses serum IL-8, activates serum IL-10 level, and decreases expression of TLR-9 and NF-κB p65 in UC rats.


Non-immunogenic recombinant staphylokinase versus alteplase for patients with acute ischaemic stroke 4·5 h after symptom onset in Russia (FRIDA): a randomised, open label, multicentre, parallel-group, non-inferiority trial.
Non-immunogenic staphylokinase is modified recombinant staphylokinase with low immunogenicity, high thrombolytic activity, and selectivity to fibrin. We aimed to assess the safety and efficacy of a single intravenous bolus of non-immunogenic staphylokinase compared with alteplase in patients with acute ischaemic stroke within 4·5 h after symptom onset. We did a randomised, open-label, multicentre, parallel-group, non-inferiority trial in 18 clinical sites in Russia. We included patients aged 18 years and older with a diagnosis of acute ischaemic stroke (up to 25 points on the National Institutes of Health Stroke Scale). The study drug had to be administered within 4·5 h after the onset of symptoms. Patients were randomly assigned to receive either non-immunogenic staphylokinase (10 mg) or alteplase (0·9 mg/kg, maximum 90 mg), both administered intravenously. The randomisation sequence was created by an independent biostatistician using computer-generated random numbers. 84 blocks (block size of four) of opaque sealed envelopes were numbered sequentially from 1 to 336 and were opened in numerical order. Patients were unaware of their assigned treatment and were assessed by the study investigators who were also unaware of the treatment assignment on all trial days. Emergency department staff, who administered the assigned drug and opened the envelopes, were not masked to treatment. The primary efficacy endpoint was a favourable outcome, defined as a modified Rankin scale (mRS) score of 0-1 on day 90. The margin of non-inferiority was established as 16% for the difference in mRS score of 0-1 on day 90. Non-inferiority was tested using Welch's t-test for the primary outcome only. Endpoints were analysed in the per-protocol population, which comprised all randomly assigned patients who completed treatment without any protocol violations; this population was identical to the intention-to-treat population. This trial is completed and registered at ClinicalTrials.gov, NCT03151993. Of 385 patients recruited from March 18, 2017, to March 23, 2019, 336 (87%) were included in the trial. 168 (50%) patients were randomly assigned to receive non-immunogenic staphylokinase and 168 (50%) to receive alteplase. The median duration of follow-up was 89 days (IQR 89-89). 84 (50%) of 168 patients in the non-immunogenic staphylokinase group had a favourable outcome at day 90 compared with 68 (40%) of 168 patients in the alteplase group (odds ratio [OR] 1·47, 95% CI 0·93 to 2·32; p=0·10). The difference in the rate of favourable outcome at day 90 was 9·5% (95% CI -1·7 to 20·7) and the lower limit did not cross the margin of non-inferiority (pnon-inferiority <0·0001). Symptomatic intracranial haemorrhage occurred in five (3%) patients in the non-immunogenic staphylokinase group and in 13 (8%) patients in the alteplase group (p=0·087). On day 90, 17 (10%) patients in the non-immunogenic staphylokinase group and 24 (14%) patients in the alteplase group had died (p=0·32). 22 (13%) patients in the non-immunogenic staphylokinase group had serious adverse events, compared with 37 (22%) patients in the alteplase group (p=0·044). Non-immunogenic staphylokinase was non-inferior to alteplase for patients with acute ischaemic stroke. Mortality, symptomatic intracranial haemorrhage, and serious adverse events did not differ significantly between groups. Future studies are needed to continue to assess the safety and efficacy of non-immunogenic staphylokinase in patients with acute ischaemic stroke within the 4·5 h time window, and to assess the drug in patients with acute ischaemic stroke outside this time window with reperfusion CT or magnetic resonance angiography followed by thrombectomy if necessary. The Russian Academy of Sciences.


Nonalcoholic fatty liver disease epidemic and its implications for liver transplantation.
Nonalcoholic steatohepatitis (NASH) is increasingly recognized as the most common chronic liver disease worldwide. The aim of this study is to investigate the transplantation trends of liver transplant (LT) recipients with NASH. Using the United Network for Organ Sharing database, we found a steady increase in LT rate especially in those more than 65 years old. We identified differences across ethnic groups and United Network for Organ Sharing regions. This study highlights the impact of the rising prevalence of NASH on the demand for LT and provides invaluable information to healthcare policymakers and the transplant community about the target groups and geographic location for focused and early intervention.


Enzymes as bionanoreactors: glucose oxidase for the synthesis of catalytic Au nanoparticles and Au nanoparticle-polyaniline nanocomposites.
The use of biomaterials such as enzymes for the synthesis of functional materials is important because such biologically guided processes can significantly reduce energy consumption in manufacturing processes. Glucose oxidase (GOx) has been exploited as a reducing as well as a stabilising agent for the green chemical synthesis of Au nanoparticles at pH 7.0 under ambient conditions. The synthesized Au nanoparticle-GOx composite was found to act as a highly-effective catalyst towards the reduction of p-nitrophenol to p-aminophenol in the presence of NaBH4. The catalytic activity of GOx was largely inhibited after its participation in the reduction of metal salt to form nanoparticles. A detailed mechanistic investigation was carried out using fluorescence spectroscopy, Fourier transform infra-red (FTIR) spectroscopy and circular dichroism (CD) to gain insights into the conformational changes in the enzyme structure. The catalytic activity of GOx towards the oxidation of glucose was taken advantage of to form a Au nanoparticle-polyaniline (Au NP-PANI) composite at room temperature. The production of the green emeraldine salt form of polyaniline (PANI) was extremely low in case of Au nanoparticle-GOx composite, where GOx was involved as a reducing agent. However, H2O2 generated during the catalytic reaction of GOx acted as a simultaneous reducing and oxidizing agent, leading to the formation of an Au NP-PANI core-shell composite in a controlled fashion.


Bone marrow transplantation.
The goals in bone marrow transplantation are its application to the treatment of diseases arising in the blood-forming tissues of man. Techniques for procuring and grafting marrow are of the needle-and-syringe type and are based on the normal physiological processes in which stem cells circulate through blood and other fluids of the mammalian organism. Destruction of bone marrow by irradiation, chemicals, or unknown agencies provides the immediate experimental system for demonstrating the therapeutic value of marrow transplants. Genetic diseases characterized by abnormal marrow function are also modifiable by grafts of blood-forming tissues. Studies with identical twins are critical experiments for showing the clinical value of grafts, even though the transplanted cells cannot be identified by the usual marker techniques. Among the best results seen with marrow grafting is the presumed cure of certain rare hereditary immune-deficiency disorders of children. A major problem in bone marrow transplantation-one that delays its wider clinical application-is the immune reaction from cells growing out of the foreign transplant which attack the host (the graft-versus-host reaction). Attempts to use a graft-versus-host response to eliminate tumor cells is a part of the marrow research program. The history of the processes that led to some of the achieved goals in marrow grafting shows the usual multicentric origin of an idea. Certain individuals play critical roles in developing the idea. Finally, a body of knowledge is accumulated that opens up or limits prospects for the future. In bone marrow transplantati on, future achievements will depend in part on the progress that is made in the areas of cell separation, bone marrow banking, and tissue culture.


Latency of unit responses in cochlear nucleus determined in two different ways.
The latency revealed by poststimulus time histograms of the responses of single units in the cochlear nucleus to tone bursts was compared with the latency of the change in discharge frequency in response to small increments in the amplitude of the stimulus. The latter was derived on the basis of statistical signal analysis of the discharge pattern in response to tones amplitude modulated with pseudorandom noise. The "step response" of the system was computed by time integration of the cross covariance between modulation and spike density. The following observations can be made: 1. The latency of the responses to tone bursts always decreased with increasing sound intensity, whereas the latency of the step response was almost constant for intensities from immediately above threshold to the highest intensity used (60-70 dB above threshold). 2. In most units the latency revealed by the PST histogram of the responses to tone bursts approached the value of latency of the step response asymptotically. 3. In some units with longer latency, the latency of the response to tone bursts was many times greater than the latency of the step response, even at high sound intensities. 4. A histogram of latency values of the step response of the units studied showed narrow peaks at 2.8 and 4.7 ms. 5. On the basis of the present results it is concluded that the latency values of the step response represent the true sum of synaptic and axon dendritical propagation delay, whereas the latency of the responses to tone bursts also includes the temporal summation at the synaptic level.


A survey for selected viral, chlamydial, and parasitic diseases in wild dusky-headed parakeets (Aratinga weddellii) and tui parakeets (Brotogeris sanctithomae) in Peru.
Thirty-eight free-ranging dusky-headed parakeets (Aratinga weddellii) and 13 tui parakeets (Brotogeris sanctithomae) were caught and released in Parque Nacional del Manu in southeastern Peru from 19 July to 5 August 1993. Blood and fecal samples were collected and sera were evaluated for titers to Pacheco's disease herpesvirus, psittacine polyomavirus, paramyxovirus-1, and Chlamydia psittaci. Fecal samples were examined for evidence of ascarid or coccidial infection by fecal flotation, and blood smears were examined for hemoparasites. Five (50%) of 10 A. weddellii serum samples tested by complement fixation (CF) for psittacine polyomavirus antibodies were positive, and three (19%) of 16 A. weddellii samples tested by virus neutralization (VN) for psittacine polyomavirus antibodies were positive, yielding a total of 8 (38%) of the 21 A. weddellii samples positive for psittacine polyomavirus. Based on CF for herpesvirus, four (11%) of 38 A. weddellii samples had antibodies against herpesvirus. All B. sanctithomae were negative for psittacine polyomavirus and psittacine herpesvirus. Thirty-five of the A. weddellii tested were negative for Chlamydia psittaci by CF, latex agglutination, and elementary body agglutination, and all B. sanctithomae were negative for Chlamydia psittaci by the CF test. Nine A. weddellii and eight B. sanctithomae evaluated for paramyxovirus-1 titers by the hemagglutination inhibition test were negative. All fecal samples were negative for ascarids or coccidia by fecal flotation, and all blood smears were negative for hemoparasites by direct microscopic examination. This is the first known description of psittacine polyomavirus and psittacine herpesvirus in free-ranging parrots. Serologic evidence of Pacheco's disease herpesvirus in wild A. weddellii is interesting in light of the fact that Aratinga spp. are considered to be possible carriers of this virus in captivity.


Clinical and radiographic analysis of Perthes deformity in the adolescent and young adult.
The residual deformity of Perthes disease can present with a wide variety of proximal femoral pathomorphology with associated intra- and extra-articular sources of pain. A systematic clinical and radiographic analysis is critical to understanding the deformity and identifying the source of pain. Groin pain and lateral hip pain are the most common complaints but patients can present with buttock, thigh, knee or even low back pain. Each location can suggest a different source of pain. Understanding the potential associated deformities can also help one identify the source of the clinical complaints as intra- or extra-articular. A thorough physical examination of the hip and lower extremities is critical and should include evaluation of the patient standing, supine, prone and in the lateral position. Each examination element can help link the clinical complaint to the underlying proximal femoral deformity. Radiographic evaluation should utilize a standard technique and the initial imaging should include an anteroposterior pelvis, lateral of the proximal femur and false-profile of the hip. Advanced imaging, including computed tomographic scans and gadolinium enhanced arthro-magnetic resonance imaging, can be helpful in delineating the three dimensional deformity and labral and articular cartilage injury. A thorough understanding of all three elements (clinical complaints, physical examination, radiographs) is critical to tailoring a treatment plan for the symptomatic patient with residual Perthes disease.


Expression of tubulin beta II in neural stem/progenitor cells and radial fibers during human fetal brain development.
Recent studies revealed that the "radial glia" in fetal rodent brains are dividing neuronal precursor cells. However, in fetal primate brains, this issue remains unclear, with previous reports indicating that radial glia are a specialized form of astroglia. To investigate the relationship between radial fibers (RFs) and neural stem/progenitor cells in the fetal human brain, we generated polyclonal antibodies to human nestin protein and developed a new mAb, KNY-379, by screening for antibodies that immunostained RFs on paraffin-embedded human fetal brain specimens (12 gestational weeks). The immunostaining for KNY-379 antigen and nestin was seen over the RFs in brains at 8 gestational weeks. Furthermore, KNY-379 antigen and nestin were also detected in human neural stem/progenitor cells in neurosphere cultures. At 12 to 15 gestational weeks, the KNY-379 immunostaining of RFs remained in the periventricular zone and the deep part of the intermediate zone, but it also appeared in outgrowing axons in the cortical plate, in the superficial portion of the intermediate zone, and in apical dendrites in the molecular layer. In the later stages of fetal development (18-40 gestational weeks), this antigen remained in the outgrowing axons and dendrites, but was no longer associated with RFs. Expression cloning and immunoblot analysis demonstrated the antigen to be tubulin beta II, which would thus be a good marker for studying RFs and neural stem/progenitor cells in the early developing human brain.


Effects of natural images on the detectability of simple and compound wavelet subband quantization distortions.
Quantization of the coefficients within a discrete wavelet transform subband gives rise to distortions in the reconstructed image that are localized in spatial frequency and orientation and are spatially correlated with the image. We investigated the detectability of these distortions: Contrast thresholds were measured for both simple and compound distortions presented in the unmasked paradigm and against two natural-image maskers. Simple and compound distortions were generated through uniform scalar quantization of one or two subbands. Unmasked detection thresholds for simple distortions yielded contrast sensitivity functions similar to those reported for 1-octave Gabor patches. Detection thresholds for simple distortions presented against two natural-image backgrounds revealed that thresholds were elevated across the frequency range of 1.15-18.4 cycles per degree with the greatest elevation for low-frequency distortions. Unmasked thresholds for compound distortions revealed relative sensitivities of 1.1-1.2, suggesting that summation of responses to wavelet distortions is similar to summation of responses to gratings. Masked thresholds for compound distortions revealed relative sensitivities of 1.5-1.7, suggesting greater summation when distortions are masked by natural images.


Commentary: lawyer phobia.
Fear of being involved in a malpractice lawsuit has spawned various defensive attitudes and behaviors in physicians. Despite the relative low rate of malpractice suits against psychiatrists, they too engage in defensive medicine. Simon's and Shuman's paper reviews the hidden danger to clinical care that defensive psychiatric practices can pose to both patients and doctors. This commentary further endorses the paper's position that the study of defensive medicine should be included in psychiatric residency training much like the study of countertransference.


Cerebral protection by barbiturate anesthesia. Use after middle cerebral artery occlusion in Java monkeys.
Regional cerebral ischemia was produced in 18 Java monkeys by permanent middle cerebral artery (MCA) occlusion. All monkeys were thereafter paralyzed (pancuronium bromide, 0.05 mg/kg/hr) and sedated (diazepam, 0.1 mg/kg/hr) for a 48-hour period. Thirty minutes after MCA occlusion, pentobarbital sodium anesthesia was induced in nine of the monkeys (14 mg/kg) and maintained for 48 hours (7 mg/kg every two hours), with continuous supportive care. After 48 hours, all drugs were discontinued; the monkeys were observed for five days, and then killed. Seven of the control monkeys developed a cerebral infarction, three did not survive past the 48 hours of intensive care, and the other four had a notable neurologic deficit. All pentobarbital monkeys survived the seven days, but four had a cerebral infarction and two of these had a notable neurologic deficit. These differences were statistically significant.


[Sonographic diagnosis of fetal liver cysts].
The authors report on prenatal ultrasonic diagnosis of foetal liver cysts with a massively thickened and cystic placenta in the twenty-third week of pregnancy. Karyotyping and serological examination of foetal blood samples of the umbilical vein gave normal results. The liver cysts were tapped twice subsequently, because they displaced other foetal abdominal and thoracic organs. In the thirty-fifth week of pregnancy the foetus died due to malnutrition resulting from the changes of the placenta, the origin of which remained unclear.


Predicting rhesus monkey eye movements during natural-image search.
There are three prominent factors that can predict human visual-search behavior in natural scenes: the distinctiveness of a location (salience), similarity to the target (relevance), and features of the environment that predict where the object might be (context). We do not currently know how well these factors are able to predict macaque visual search, which matters because it is arguably the most popular model for asking how the brain controls eye movements. Here we trained monkeys to perform the pedestrian search task previously used for human subjects. Salience, relevance, and context models were all predictive of monkey eye fixations and jointly about as precise as for humans. We attempted to disrupt the influence of scene context on search by testing the monkeys with an inverted set of the same images. Surprisingly, the monkeys were able to locate the pedestrian at a rate similar to that for upright images. The best predictions of monkey fixations in searching inverted images were obtained by rotating the results of the model predictions for the original image. The fact that the same models can predict human and monkey search behavior suggests that the monkey can be used as a good model for understanding how the human brain enables natural-scene search.


Q selection for an electro-optical earth imaging system: theoretical and experimental results.
This paper explores practical design considerations for selecting Q for an electro-optical earth imaging system, where Q is defined as (λ FN) / pixel pitch. Analytical methods are used to show that, under imaging conditions with high SNR, increasing Q with fixed aperture cannot lead to degradation of image quality regardless of the angular smear rate of the system. The potential for degradation of image quality under low SNR is bounded by an increase of the detector noise scaling as Q. An imaging test bed is used to collect representative imagery for various Q configurations. The test bed includes real world errors such as image smear and haze. The value of Q is varied by changing the focal length of the imaging system. Imagery is presented over a broad range of parameters.


Distal limb radiography, ossification, and growth plate closure in the juvenile Asian elephant (Elephas maximus).
Eleven juvenile Asian elephants (Elephas maximus) were evaluated radiographically to determine the relative times of growth plate closure and phalangeal ossification in the bones of the distal forelimb. Specifically, the first, second, and third phalanges of the third digit (D3) were evaluated, as well as the third phalanx of digits 1, 2, 4, and 5. All elephants were healthy at the time of examination. A retrospective evaluation of radiographs from six of the 11 juvenile elephants was also completed to augment the data set. This study reports the methods used to obtain high-quality radiographs of the distal juvenile elephant limb, ossification characteristics of the phalanges, relative times of growth plate closure within the proximal phalanges of D3, and a method for age estimation based on radiographic findings. This study will help clinicians in conducting elephant foot radiography, in evaluating foot radiographs in juvenile elephants, in recognizing normal versus pathologic change, and in estimating juvenile elephant age based on radiographic ossification characteristics and growth plate closure times. Consistent use of the proposed foot radiograph technique is recommended to facilitate foot disease recognition and as part of the annual examination of captive Asian elephants.


The inhibition of VDAC1 oligomerization promotes pigmentation through the CaMK-CRTCs/CREB-MITF pathway.
The voltage-dependent anion channel 1 (VDAC1) forms an oligomeric structure on the mitochondrial outer membrane, which plays critical roles in many physiological processes. Research studies have demonstrated that the knockout of VDAC1 increases pigment content and up-regulates the expression of melanogenic genes. Due to its involvement in various physiological processes, the depletion of VDAC1 has significant detrimental effects on cellular functions and the inhibition of VDAC1 oligomerization has recently emerged as a promising strategy for the treatment of several diseases. In this study, we found that VDAC1 oligomerization inhibitors, VBIT-12 and NSC-15364, promote melanogenesis, dendrite formation and melanosome transport in human epidermal melanocytes (HEMCs). Mechanistically, treatment of HEMCs with an oligomerization inhibitor increased the level of cytoplasmic calcium ions, which activated calcium-calmodulin dependent protein kinase (CaMK) and led to the phosphorylation of CREB and the nuclear translocation of CREB-regulated transcription coactivators (CRTCs). Subsequently, CRTCs, p-CREB and CREB-binding protein (CBP) in the nucleus cooperatively recruit the transcription machinery to initiate the transcription of MITF thus promoting pigmentation. Importantly, our study also demonstrates that VDAC1 oligomerization inhibitors increase pigmentation in zebrafish and in human skin explants, highlighting their potential as a therapeutic strategy for skin pigmentation disorders.


Impaired retention of visual discriminated escape training produced by subseizure amygdala stimulation.
These experiments examined the effects on memory of posttrial, subseizure, electrical stimulation of the amygdala. Rats were trained in a visual discriminated avoidance Y-maze. Each animal received 6 tirals on the training day. Retention, tested the following day, was measured both by the number of correct choices on the first 6 retraining trials and by the number of trials to a criterion of 5 of 6 correct choices. If administered 2 min, 1 h, or 4 h, but not 10 h, after training, bilateral amygdala stimulation significantly impaired retention as measured 24 h after training. In a second experiment, rats received unilateral amygdala stimulation in order to examine better the anatomical localization of effective stimulation sites. The unilateral stimulation was administered either 2 min, 10 min, 1 h, or 4 h after training. The behavioral procedures were the same as those used in the first experiment. For animals stimulated 2 min after training, the optimal stimulation region was one which extended rostrally from the ventrolateral portion of the basomedial nucleus to the dorsomedial region of the amygdala near the stria terminalis and nucleus centralis. For animals stimulated after a 10 min training-treatment interval, this amygdala region was not an effective stimulation site. However, in these animals, stimulation of the basolateral nucleus impaired later retention. Unilateral, posttraining amygdala stimulation administered 1 or 4 h after training did not appear to produce retention deficits. The findings of these experiments thus indicate that posttrial unilateral or bilateral amygdala stimulation impairs retention of discriminated avoidance training. Furthermore, the specific amygdala site at which posttrial stimulation impairs later retention varies with the training-treatment interval.


[Neurointensive care of severe traumatic brain injury].
We present a Danish algorithm for the neurointensive care of patients with severe traumatic brain injury. The primary goal is to avoid cerebral ischaemia and hypoxia and secondarily brain injury. Patient evaluation by a neurosurgeon is mandatory, and decision-making concerning extended cerebral monitoring should take place immediately. Treatment aiming at diminishing increased intracranial pressure should be initiated early. Early critical care management of patients with severe traumatic brain injury should be performed in a teamwork comprising various specialties.


Changing the game: exploring infants' participation in early play routines.
Play has proved to have a central role in children's development, most notably in rule learning (Piaget, 1965; Sutton-Smith, 1979) and negotiation of roles and goals (Garvey, 1974; Bruner et al., 1976). Yet very little research has been done on early play. The present study focuses on early social games, i.e., vocal-kinetic play routines that mothers use to interact with infants from very early on. We explored 3-month-old infants and their mothers performing a routine game first in the usual way, then in two violated conditions: without gestures and without sound. The aim of the study is to investigate infants' participation and expectations in the game and whether this participation is affected by changes in the multimodal format of the game. Infants' facial expressions, gaze, and body movements were coded to measure levels of engagement and affective state across the three conditions. Results showed a significant decrease in Limbs Movements and expressions of Positive Affect, an increase in Gaze Away and in Stunned Expression when the game structure was violated. These results indicate that the violated game conditions were experienced as less engaging, either because of an unexpected break in the established joint routine, or simply because they were weaker versions of the same game. Overall, our results suggest that structured, multimodal play routines may constitute interactional contexts that only work as integrated units of auditory and motor resources, representing early communicative contexts which prepare the ground for later, more complex multimodal interactions, such as verbal exchanges.


Bilateral Exudative Retinal Detachments and Panuveitis in a Patient with Multiple Myeloma.
To report a case of bilateral exudative retinal detachments and panuveitis in a patient with multiple myeloma (MM). A 54-year-old patient with non-proliferative diabetic retinopathy was referred with blurred vision and scotomas in both eyes (OU). Three months prior to the onset of ocular symptoms, he was diagnosed with systemic MM and was receiving chemotherapy. Clinical examination revealed best-corrected visual acuities of 20/80 OU, rare anterior chamber cell, 2+ vitreous cell, diffuse intraretinal hemorrhages, and exudative retinal detachments (RD). Optical coherence tomography of the macula showed central subretinal fluid with cystic intraretinal fluid OU. The findings were consistent with panuveitis and exudative RD in the setting of MM. He reported symptomatic improvement after plasmapheresis and oral prednisone initiation. Extensive, bilateral exudative RD and panuveitis are rare but potentially sight-threatening findings in patients with MM.


Reducing Qubit Requirements for Quantum Simulations Using Molecular Point Group Symmetries.
Simulating molecules is believed to be one of the early stage applications for quantum computers. Current state-of-the-art quantum computers are limited in size and coherence; therefore, optimizing resources to execute quantum algorithms is crucial. In this work, we develop the second quantization representation of spatial symmetries, which are then transformed to their qubit operator representation. These qubit operator representations are used to reduce the number of qubits required for simulating molecules. We present our results for various molecules and elucidate a formal connection of this work with a previous technique that analyzed generic Z2 Pauli symmetries.


[Changes in undergraduate education in the health professions from the perspective of comprehensive training].
This article discusses the issue of legal, technical, and political legitimacy for formulating a public policy aimed at organizing the training of health professionals in accordance with the population's health needs, while highlighting the competencies of the education and health sectors in this construction. Comprehensiveness is viewed as the main thrust for proposing and supporting the changes needed in the training of professionals in education and health, since it involves an expanded understanding of health, the linkage among multi-professional and interdisciplinary knowledge and practices, and dialogue/exchange with health system users, aimed at innovation of practices in all scenarios of health care and health sector management.


The development of the sensory neuron pattern in the antennal disc of wild-type and mutant (lz3, ssa) Drosophila melanogaster.
The development of the sensory neuron pattern in the antennal disc of Drosophila melanogaster was studied with a neuron-specific monoclonal antibody (22C10). In the wild type, the earliest neurons become visible 3 h after pupariation, much later than in other imaginal discs. They lie in the center of the disc and correspond to the neurons of the adult aristal sensillum. Their axons join the larval antennal nerve and seem to establish the first connection towards the brain. Later on, three clusters of neurons appear in the periphery of the disc. Two of them most likely give rise to the Johnston's organ in the second antennal segment. Neurons of the olfactory third antennal segment are formed only after eversion of the antennal disc (clusters t1-t3). The adult pattern of antennal neurons is established at about 27% of metamorphosis. In the mutant lozenge3 (lz3), which lacks basiconic antennal sensilla, cluster t3 fails to develop. This indicates that, in the wild type, a homogeneous group of basiconic sensilla is formed by cluster t3. The possible role of the lozenge gene in sensillar determination is discussed. The homeotic mutant spineless-aristapedia (ssa) transforms the arista into a leg-like tarsus. Unlike leg discs, neurons are missing in the larval antennal disc of ssa. However, the first neurons differentiate earlier than in normal antennal discs. Despite these changes, the pattern of afferents in the ectopic tarsus appears leg specific, whereas in the non-transformed antennal segments a normal antennal pattern is formed. This suggests that neither larval leg neurons nor early aristal neurons are essential for the outgrowth of subsequent afferents.


Recovery from macular photostress and slow retinal potentials in cured retinal detachment.
After successful surgery for retinal detachment, a series of functional tests was performed, which primarily concerned the contact between photoreceptors and pigment epithelium. Even several months after reattachment the EOG still remained lower than in the fellow eye, when the macula was involved. If maximal visual acuity was reached with a formerly detached retinal area, the photostress recovery time was found to be delayed. The dc-coupled ERG showed distinct impairment of the c-wave in the eye with the reattached retina.


Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress.
The innate immune response is the first line of defence against invading microorganisms and it is also activated in different neurologic/neurodegenerative pathological scenarios. As a result, the family of the innate immune toll-like receptors (TLRs) and, in particular, the genetic/pharmacological manipulation of the TLR-4 signalling pathway emerges as a potential therapeutic strategy. Growing evidence relates stress exposure with altered immune responses, but the precise role of TLR-4 remains partly unknown. The present study aimed to elucidate whether the elements of the TLR-4 signalling pathway are activated after acute stress exposure in rat brain frontal cortex and its role in the regulation of the stress-induced neuroinflammatory response, by means of its pharmacological modulation with the intravenous administration of the TLR-4 specific inhibitor TAK-242. Considering that TLR-4 responds predominantly to lipopolysaccharide from gram-negative bacteria, we checked whether increased intestinal permeability and a resultant bacterial translocation is a potential regulatory mechanism of stress-induced TLR-4 activation. Acute restraint stress exposure upregulates TLR-4 expression both at the mRNA and protein level. Stress-induced TLR-4 upregulation is prevented by the protocol of antibiotic intestinal decontamination made to reduce indigenous gastrointestinal microflora, suggesting a role for bacterial translocation on TLR-4 signalling pathway activation. TAK-242 pre-stress administration prevents the accumulation of potentially deleterious inflammatory and oxidative/nitrosative mediators in the brain frontal cortex of rats. The use of TAK-242 or other TLR-4 signalling pathway inhibitory compounds could be considered as a potential therapeutic adjuvant strategy to constrain the inflammatory process taking place after stress exposure and in stress-related neuropsychiatric diseases.


Abstract and reduced-context representations in fault-finding training.
The ability to transfer problem-solving expertise to new situations is regarded as an important practical skill but it is known to be sensitive to contextual differences. Employing abstract and reduced-context training tasks has been proposed as a method of fostering transferable skill but the evidence supporting this approach is limited. The research reported here aimed at assessing the effectiveness of training with diagnostic tasks of varying degrees of contextual detail. The criterion test used to measure training effectiveness was a context-rich diagnostic task that involved locating faults in a representation of a water supply and drainage system (WSDS). In the first study reported (baseline study), subjects were trained and tested on the WSDS task. Various training interventions were employed and a set of diagnostic heuristics proved to be the most effective. Two pilot studies were then carried out to determine whether training with abstract diagnostic tasks could produce transfer to the criterion test, the WSDS. Little evidence of transfer was found; therefore, it was decided to incorporate some context into training but not so much as to obscure important, conceptual task features. This was achieved by constructing reduced-context representations (RCO) of the WSDS at more than one level of abstraction (main study). Training with those representations took less time than training with the WSDS but transfer to the criterion test (the WSDS) was equally efficient. During training with the RCO representations, a technique of refusing costly test information was employed which is thought to have helped subjects discover efficient search strategies and consistently transfer them to the criterion test. This was contrasted with the verbal diagnostic heuristics of the baseline study, which had proved to be effective, but which were not always transferred consistently to the criterion test. This raises the question as to whether diagnostic strategies are necessarily best conveyed solely in verbal form, if the intention is to train transferable skill.


Tracing brain genotoxic stress in Parkinson's disease with a novel single-cell genetic sensor.
To develop an in vivo tool to probe brain genotoxic stress, we designed a viral proxy as a single-cell genetic sensor termed PRISM that harnesses the instability of recombinant adeno-associated virus genome processing and a hypermutable repeat sequence-dependent reporter. PRISM exploits the virus-host interaction to probe persistent neuronal DNA damage and overactive DNA damage response. A Parkinson's disease (PD)-associated environmental toxicant, paraquat (PQ), inflicted neuronal genotoxic stress sensitively detected by PRISM. The most affected cell type in PD, dopaminergic (DA) neurons in substantia nigra, was distinguished by a high level of genotoxic stress following PQ exposure. Human alpha-synuclein proteotoxicity and propagation also triggered genotoxic stress in nigral DA neurons in a transgenic mouse model. Genotoxic stress is a prominent feature in PD patient brains. Our results reveal that PD-associated etiological factors precipitated brain genotoxic stress and detail a useful tool for probing the pathogenic significance in aging and neurodegenerative disorders.


Emergence of event cascades in inhomogeneous networks.
There is a commonality among contagious diseases, tweets, and neuronal firings that past events facilitate the future occurrence of events. The spread of events has been extensively studied such that the systems exhibit catastrophic chain reactions if the interaction represented by the ratio of reproduction exceeds unity; however, their subthreshold states are not fully understood. Here, we report that these systems are possessed by nonstationary cascades of event-occurrences already in the subthreshold regime. Event cascades can be harmful in some contexts, when the peak-demand causes vaccine shortages, heavy traffic on communication lines, but may be beneficial in other contexts, such that spontaneous activity in neural networks may be used to generate motion or store memory. Thus it is important to comprehend the mechanism by which such cascades appear, and consider controlling a system to tame or facilitate fluctuations in the event-occurrences. The critical interaction for the emergence of cascades depends greatly on the network structure in which individuals are connected. We demonstrate that we can predict whether cascades may emerge, given information about the interactions between individuals. Furthermore, we develop a method of reallocating connections among individuals so that event cascades may be either impeded or impelled in a network.


Cholesterol attenuates linoleic acid-induced endothelial cell activation.
Vascular endothelial cell activation and dysfunction are critical early events in atherosclerosis. Even though very low or high levels of cholesterol can compromise cellular functions, cholesterol is a critical membrane component and may protect the vascular endothelium from oxidative stress and polyunsaturated fatty acid-mediated inflammatory responses. We have previously shown that the parent omega-6 fatty acid linoleic acid can markedly activate vascular endothelial cells. We now propose that membrane cholesterol can modify and inhibit linoleic acid-mediated endothelial cell dysfunction. To test this hypothesis, pulmonary artery endothelial cells were incubated with cholesterol (0 to 100 micromol/L) for 24 hours and then treated with 90 micromol/L of linoleic acid (18:2n-6) for 6 to 24 hours. In control cells, treatment with linoleic acid reduced intracellular glutathione levels and induced the DNA binding activity of nuclear factor-kappaB (NF-kappaB) leading to the upregulation of interleukin-6 (IL-6). In addition, the expression of endothelial nitric oxide synthase (eNOS) was altered, with linoleic acid increasing eNOS activity. In contrast, enrichment with cholesterol enhanced glutathione levels and reduced the linoleic acid-induced activation of NF-kappaBand the production of IL-6. Prior exposure to 50 micromol/L cholesterol also prevented the fatty acid-induced increase in eNOS activation. Cholesterol loading activated peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear receptor that can decrease inflammatory responses. Furthermore, the PPAR-gamma agonist thiazolidinedione markedly downregulated the NF-kappaB activation mediated by linoleic acid. Our data suggest that signaling pathways linked to endothelial cell activation by prooxidant and proinflammatory insults may be influenced by cellular cholesterol levels.


Sentinel node detection in patients with thyroid carcinoma: a meta-analysis.
This study was designed to review the diagnostic performance of sentinel node (SN) detection for assessment of the nodal status in thyroid carcinoma patients and to determine the technique (using blue dye or Technetium-99m colloid (99mTc) that demonstrated the highest success rate with regard to the detection rate and sensitivity. A comprehensive computer literature search of studies published in English language through December 2007 and regarding SN procedures in patients with thyroid disorders was performed in MEDLINE. Pooled values regarding the SN detection rate and the pooled sensitivity values of the SN procedure were presented with a 95% confidence interval (CI) for the different SN detection techniques. Ultimately, we identified 14 studies comprising a total of 457 patients. Of these, ten studies (n = 329 patients) used the blue dye technique with a pooled SN detection of 83% (95% CI, 79-87%). The remaining four studies (n = 128) used 99mTc-colloid with a pooled SN detection of 96% (95% CI, 91-99%; p < 0.05 vs. blue dye technique). In patients with suspected thyroid carcinoma, SN biopsy demonstrated a higher SN detection rate when 99mTc was used (96%) instead of the blue dye technique (83%).


Tropical Laboratory Initiative: An innovative model for laboratory medicine in rural areas.
Communities in rural, low-resource settings often lack access to reliable diagnostics. This leads to missed and misdiagnosed cases of disease and contributes to morbidity and mortality. This paper describes a model for providing local laboratory services to rural areas of Ghana, and provides suggestions on how it could be adapted and expanded to serve populations in a range of rural communities. The Tropical Laboratory Initiative (TLI) system in Ghana comprises one central laboratory where samples delivered from clinics by motorbike riders are analysed. Test requests and results are communicated on a mHealth application, and the patient does not have to visit the laboratory or travel beyond the clinic to receive a test. The TLI also serves as a research base. The laboratory is accredited by the National Health Insurance Authority, and accepts the national health insurance. The TLI serves several communities in Amansie West, Ashanti region, and currently works with 10 clinics. The nearest hospital is a one-hour drive away and is the only other nearby facility for diagnostics beyond basic rapid tests. Demand for services has increased yearly since the launch in 2010, and the TLI currently provides over 1000 tests to approximately 350 patients monthly. The majority of patients are female, and the most common tests are for antenatal care. Our experience demonstrates that laboratory services can be affordable and most components already exist, even in rural areas. Ministries of health in low-resource settings should consider this model to complement the rapid tests available in clinics. Integrating with an insurance system promotes financial sustainability.


The impact of hearing protection on sound localization and orienting behavior.
The effect of hearing protection devices (HPDs) on sound localization was examined in the context of an auditory-cued visual search task. Participants were required to locate and identify a visual target in a field of 5, 20, or 50 visual distractors randomly distributed on the interior surface of a sphere. Four HPD conditions were examined: earplugs, earmuffs, both earplugs and earmuffs simultaneously (double hearing protection), and no hearing protection. In addition, there was a control condition in which no auditory cue was provided. A repeated measures analysis of variance revealed significant main effects of HPD for both search time and head motion data (p < .05), indicating that the degree to which localization is disrupted by HPDs varies with the type of device worn. When both earplugs and earmuffs are worn simultaneously, search times and head motion are more similar to those found when no auditory cue is provided than when either earplugs or earmuffs alone are worn, suggesting that sound localization cues are so severely disrupted by double hearing protection the listener can recover little or no information regarding the direction of sound source origin. Potential applications of this research include high-noise military, aerospace, and industrial settings in which HPDs are necessary but wearing double protection may compromise safety and/or performance.


Berberine alleviates adipose tissue fibrosis by inducing AMP-activated kinase signaling in high-fat diet-induced obese mice.
Adipose tissue fibrosis is a novel mechanism for the development of obesity related insulin resistance. Berberine (BBR) has been shown to relieve several metabolic disorders, including obesity and type 2 diabetes. However, the effects of BBR on obesity related adipose fibrosis remain poorly understood. The objective of this study was to assess the effects of BBR on adipose tissue fibrosis in high fat diet (HFD)-induced obese mice. The results showed that BBR reduced animal body weight and significantly improved glucose tolerance in HFD mice. In addition, BBR treatment markedly attenuated collagen deposition and reversed the up-regulation of fibrosis associated genes in the adipose tissue of HFD mice. Moreover, BBR treatment activated AMP-activated kinase signaling and reduced TGF-β1 and Smad3 phosphorylation. Of note, the inhibitory effects of BBR on adipose tissue fibrosis were significantly blocked by AMPK inhibition with compound C, an AMPK inhibitor. Macrophage infiltration and polarization induced by HFD were also reversed after BBR administration. These findings suggest that BBR displays beneficial effects in the treatment of obesity, in part via improvement of adipose tissue fibrosis.


Green gravel: a novel restoration tool to combat kelp forest decline.
Kelp forests are in decline globally and large-scale intervention could be required to halt the loss of these valuable ecosystems. To date kelp forest restoration has had limited success and been expensive and unable to address the increasing scale of ecosystem deterioration. Here we developed and tested a new approach: "green gravel". Small rocks were seeded with kelp and reared in the laboratory until 2-3 cm, before out-planting to the field. The out-planted kelp had high survival and growth over 9 months, even when dropped from the surface. This technique is cheap, simple, and does not require scuba diving or highly trained field workers. It can be up-scaled to treat large areas or even used to introduce genes from more resilient kelp populations onto vulnerable reefs. Green gravel thus overcomes some of the current major limitations of kelp restoration and provides a promising new defense against kelp forest decline.


On robust nonlinear modeling of a complex process with large number of inputs using m-QRcp factorization and C(p) statistic.
The problem of modeling complex processes with a large number of inputs is addressed. A new method is proposed for the optimization of the models in minimum C(p) statistic sense using QR with a modified scheme of column pivoting (m-QRcp) factorization. Two different classes of multilayer nonlinear modeling problems are explored: 1) in the first class of models, each layer comprises multiple linearly parameterized submodels or cells; the individual cells are optimally modeled using QR factorization, and m-QRcp factorization ensures optimal selection of variables across the layers. 2) The nonhomogeneous feed-forward neural network is chosen as the second class of models, where the network architecture and structure are optimized in terms of best set of hidden links (and nodes) using m-QPcp factorization. In both the cases, the optimization is shown to be direct and conclusive. The proposed is a generic approach to the optimal modeling of complex multilayered architectures, which leads to computationally fast and numerically robust parsimonious designs, free from collinearity problems. The method is largely free from heuristics and is amenable to automated modeling.


Attention Allocation to Financial Information: The Role of Color and Impulsivity Personality Trait.
In order to raise the level of investor's protection, the European Commission has recently introduced the key investor information document (KIID), a standard, plainly worded, and consumer-friendly document which should provide individuals with essential information for their investment decisions. KIID layout has been delineated relying on results from focus groups, surveys and telephone interviews, ignoring the reliable, and unbiased insights offered by neuroscientific approaches. The current study aims to elucidate the patterns of eye movements in the early phases of information acquisition during the reading of financial disclosure documents, disentangling the independent role of color and impulsivity at modulating attention distribution toward the different sources of financial information. Oculomotor behavior was monitored in eighty-one healthy adults through the eye tracking technology (SMI REDn Scientific 60 Hz). An ecological protocol exploiting KIIDs was developed to control for several individual variables, through delivering standard visual stimuli based on official financial documents. Participants performed a passive exploration task (with the only specific instruction of visually exploring the document), followed by an active task where they were asked to rate the financial attractiveness of the products, as low, medium or high. The Barratt impulsiveness scale (BIS-11) was administered to each participant, to score such personality trait. Attention distribution over the different information sources, included in the KIIDs, has been quantified and found to be independently modulated by both color and impulsivity, with a greater role of the former over the latter. The addition of either red or blue information to some KIID's sections increases attention allocation toward the whole document, compared to the usual black and white version. BIS-11 total scores were inversely related to the first and average fixation duration in the neutral, though not in the colored condition. Bottom-up, stimulus-related mechanisms of attention allocation influence information acquisition during the reading of financial prospectuses to the point that the increased attention induced by color compensates for individual impulsivity. Such evidence should be considered by regulators when devising the disclosure documents in order to increase investors' protection.


Haemodynamic responses in chronically painful, human trapezius muscle to cold pressor stimulation.
The aim was to compare haemodynamic responses in trapezius muscles to cold pressor stimulation in individuals with localized trapezius myalgia and asymptomatic controls. Nine males with chronic localized pain in the trapezius (mean age, 23.2 years) and nine male controls (mean age, 24.6 years) who had no medical history of migraine, hypertension or sustained pain in the trapezius region were investigated. Two experimental (cold pressor and mock) trials were performed in a randomly assigned sequence. In the cold pressor trial the participant's left foot and ankle were immersed in 4 degrees C cold water for 2 min; the mock trial was done without that stimulus. Blood volume was continuously recorded 1 min before, 2 min during, and 5 min after cold pressor stimulation using near-infrared spectroscopy. Each participant's blood-volume data were baseline-corrected and submitted to statistical analysis. Results showed that the individuals with muscle pain exhibited a significantly lower mean blood volume than the controls during cold pressor stimulation (p = 0.0367). Upon withdrawal of that stimulation, the mean blood volume in both groups fell below the baseline. These results suggest that individuals with chronic regional trapezius myalgia have less capacity to vasodilate this muscle during cold pressor stimulation than those without such myalgia. It is not yet known if this difference in the haemodynamic response is a cause or an effect of the myalgia.


Menopausal hormone therapy use and risk of ovarian cancer by race: the ovarian cancer in women of African ancestry consortium.
Most studies examining post-menopausal menopausal hormone therapy (MHT) use and ovarian cancer risk have focused on White women and few have included Black women. We evaluated MHT use and ovarian cancer risk in Black (n = 800 cases, 1783 controls) and White women (n = 2710 cases, 8556 controls), using data from the Ovarian Cancer in Women of African Ancestry consortium. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of MHT use with ovarian cancer risk, examining histotype, MHT type and duration of use. Long-term MHT use, ≥10 years, was associated with an increased ovarian cancer risk for White women (OR = 1.38, 95%CI: 1.22-1.57) and the association was consistent for Black women (OR = 1.20, 95%CI: 0.81-1.78, pinteraction = 0.4). For White women, the associations between long-term unopposed estrogen or estrogen plus progesterone use and ovarian cancer risk were similar; the increased risk associated with long-term MHT use was confined to high-grade serous and endometroid tumors. Based on smaller numbers for Black women, the increased ovarian cancer risk associated with long-term MHT use was apparent for unopposed estrogen use and was predominately confined to other epithelial histotypes. The association between long-term MHT use and ovarian cancer risk was consistent for Black and White women.