MiR-467a is upregulated in radiation-induced mouse thymic lymphomas and regulates apoptosis by targeting Fas and Bax.
It has been reported dysregulation of certain microRNAs (miRNAs / miRs) is involved in tumorigenesis. However, the miRNAs associated with radiocarcinogenesis remain undefined. In this study, we validated the upregulation of miR-467a in radiation-induced mouse thymic lymphoma tissues. Then, we investigated whether miR-467a functions as an oncogenic miRNA in thymic lymphoma cells. For this purpose, we assessed the biological effect of miR-467a on thymic lymphoma cells. Using miRNA microarray, we found four miRNAs (miR-467a, miR-762, miR-455 and miR-714) were among the most upregulated (>4-fold) miRNAs in tumor tissues. Bioinformatics prediction suggests miR-467a may potentially regulate apoptosis pathway via targeting Fas and Bax. Consistently, in miR-467a-transfected cells, both proliferation and colony formation ability were significantly increased with decrease of apoptosis rate, while, in miR-467a-knockdown cells, proliferation was suppressed with increase of apoptosis rate, indicating that miR-467a may be involved in the regulation of apoptosis. Furthermore, miR-467a-knockdown resulted in smaller tumors and better prognosis in an in vivo tumor-transplanted model. To explain the mechanism of apoptosis suppression by miR-467a, we explore the expression of candidate target genes (Fas and Bax) in miR-467a-transfected relative to negative control transfected cells using flow cytometry and immunoblotting. Fas and Bax were commonly downregulated in miR-467a-transfected EL4 and NIH3T3 cells, and all of the genes harbored miR-467a target sequences in the 3'UTR of their mRNA. Fas and Bax were actually downregulated in radiation-induced thymic lymphoma tissues, and therefore both were identified as possible targets of miR-467a in thymic lymphoma. To ascertain whether downregulation of Fas and / or Bax is involved in apoptosis suppression by miR-467a, we transfected vectors expressing Fas and Bax into miR-467a-upregulated EL4 cells. Then we found that both Fas- and Bax-overexpression decreased cell viability with increase of apoptosis rate, indicating that downregulation of Fas and Bax may be at least partly responsible for apoptosis suppression by miR-467a. These data suggest that miR-467a may have oncogenic functions in radiation-induced thymic lymphoma cells and that its increased expression may confer a growth advantage on tumor cells via aberrant expression of Fas and Bax.


Kinematic alterations due to different loading schemes in early acceleration sprint performance from starting blocks.
The purpose of this study was to examine the changes to block start and early acceleration sprint kinematics with resisted sled towing. Ten male sprinters performed 12 sprints (four each of unresisted and approximately 10 and 20% body mass [BM]) for 10 m from a block start. Two-dimensional high-speed video footage (250 Hz) of the starting action and the first three steps of each sprint were recorded to enable the sagittal sprinting kinematic parameters to be obtained using APAS motion analysis software. The overall results of this study indicated that early acceleration sprint performance from starting blocks decreases with increasing load during resisted sled towing. A load of approximately 10% BM had no "negative" effect on sprint start technique or step kinematic variables measured in this study (with the exception of one variable) and was also within the "no greater than 10% decrease in speed" limits suggested by Jakalski. Towing a load of approximately 20% BM increased the time spent in the starting blocks and induced a more horizontal position during the push-off (drive) phase. The approximately 20% BM load also caused the sprinters to shorten their initial strides (length), which may have resulted from the decreased flight distances. Such results suggest that the kinematic changes produced by the 10% BM load may be more beneficial than those of the 20% BM load. Future training studies will, however, need to investigate how these acute changes in sprinting technique impact on long-term adaptations in sprinting performance from resisted sprinting.


Early death or retransplantation in adults after orthotopic liver transplantation. Can outcome be predicted?
Early, reliable outcome prediction after a liver transplant would help improve organ use by minimizing unnecessary retransplantations. At the same time, early intervention in those cases destined to fail may ameliorate the high morbidity and mortality associated with retransplantation. The purpose of this study was to analyze several parameters that have been identified in the past as being associated with patient and graft outcome, and to try to develop a model that would allow us to make predictions based on data available in the early postoperative period. A total of 148 patients were followed in a prospective, observational study. Graft failure was defined as patient death or retransplantation within 3 months of surgery. Preoperative variables studied included patient demographics, need for life support, presence of ascites, serum bilirubin, serum albumin, prothrombin time, serum creatinine, and the results of the cytotoxic crossmatch. During the first 5 postoperative days, standard measurements included serum transaminases, serum bilirubin, ketone body ratio, prothrombin time, factor V, and serum lactate. Oxygen consumption was measured shortly after surgery, once the patients had rewarmed to 36 degrees C. There were 131 successful transplants (88.5%) and 17 failures (11.5%). Most of the variables studied were found to be associated with outcome (by univariate analysis) at different points in the early postoperative period. However, receiver operating characteristic curve analysis showed that the predictive ability of even the best parameter was not adequate to make decisions on individual patients. Multivariate analysis, using stepwise logistic regression, yielded a model with an overall accuracy of 92.7%. Again, receiver operating characteristic curve analysis suggested that this model did not achieve the discriminating power needed for routine clinical use. We are still not able to accurately predict outcome in the early posttransplant period. We must be very careful when evaluating parameters, or scoring systems, that are said to accomplish this. It is especially important in this era of cost containment, with its renewed pressures to guide therapy based on our perceived understanding of a patient's future clinical course.


FOAM (Functional Ontology Assignments for Metagenomes): a Hidden Markov Model (HMM) database with environmental focus.
A new functional gene database, FOAM (Functional Ontology Assignments for Metagenomes), was developed to screen environmental metagenomic sequence datasets. FOAM provides a new functional ontology dedicated to classify gene functions relevant to environmental microorganisms based on Hidden Markov Models (HMMs). Sets of aligned protein sequences (i.e. 'profiles') were tailored to a large group of target KEGG Orthologs (KOs) from which HMMs were trained. The alignments were checked and curated to make them specific to the targeted KO. Within this process, sequence profiles were enriched with the most abundant sequences available to maximize the yield of accurate classifier models. An associated functional ontology was built to describe the functional groups and hierarchy. FOAM allows the user to select the target search space before HMM-based comparison steps and to easily organize the results into different functional categories and subcategories. FOAM is publicly available at http://portal.nersc.gov/project/m1317/FOAM/.


Comparison of EMG power during sleep from the submental and frontalis muscles.
Submentalis electromyography (sEMG) and frontalis electromyography (fEMG) muscle activities have been used to assist in the staging of sleep and detection of disruptions in sleep. This study was designed to assess the concordance between sEMG and fEMG power, by and across sleep stages. Forty-three records with simultaneous acquisition of differential signals from the submental and frontalis muscles were evaluated. Sleep stages were assigned using the poly-somnography signals based on majority agreement of five technicians. The sEMG and fEMG signals were identically filtered and aligned prior to cross-correlation analysis. A strong concordance between sEMG and fEMG power was observed, with 95% of the records exhibiting at least moderate agreement. During rapid eye movement (REM) sleep, sEMG power was significantly less than fEMG power, but exhibited four times greater across-subject variability. fEMG power during wake and non-REM (NREM) sleep was greater than sEMG power, but with 50% less variability. Differences in wake and N1 mean power and between the other sleep stages were more distinct in the fEMG recordings. Relative changes in sEMG and fEMG power across wake, NREM, and REM stages were essentially identical with median by-subject cross correlations of 0.98 and interquartile ranges of 0.97 and 0.99, respectively. The fEMG and sEMG power values were similar during wakefulness and sleep; however, the frontalis exhibits substantially less between-subject variability. This study established face validity for the use of fEMG in the detection of wake and stages of sleep, and for future applications toward assessment of quantitative REM sleep muscle activity in REM sleep behavior disorder.


Spatio-temporal modeling and optimization of a deformable-grating compressor for short high-energy laser pulses.
Monolithic large-scale diffraction gratings are desired to improve the performance of high-energy laser systems and scale them to higher energy, but the surface deformation of these diffraction gratings induce spatio-temporal coupling that is detrimental to the focusability and compressibility of the output pulse. A new deformable-grating-based pulse compressor architecture with optimized actuator positions has been designed to correct the spatial and temporal aberrations induced by grating wavefront errors. An integrated optical model has been built to analyze the effect of grating wavefront errors on the spatio-temporal performance of a compressor based on four deformable gratings. A 1.5-meter deformable grating has been optimized using an integrated finite-element-analysis and genetic-optimization model, leading to spatio-temporal performance similar to the baseline design with ideal gratings.


Kinetics of pronuclear development and the effects of vector type and timing of injection on the efficiency of gene transfer into rhesus macaque embryos.
A series of experiments was performed to determine the dynamics of pronuclear development as well as the efficiency of either adenovirus-associated (AAV) or lentivirus-derived vectors to introduce a green fluorescent protein (GFP) reporter gene into rhesus macaque (Macaca mulatta) embryos. Assessment of pronuclear development at various times after fertilization revealed that the appearance of pronuclei was determined by the presence of the first and the timing of the second polar body. The dynamics of pronuclear formation was a significant determinant of whether an oocyte reached the blastocyst stage, however, when the percentage of blastocysts were based on the number of zygotes, the timing of the appearance of polar bodies did not appear to have any effect on subsequent development. Injection of different AAV-derived vectors showed that the serotype of the vector did not affect development or the proportion of transgenic embryos. Moreover, all putative transgenic embryos proved to be expression mosaics. Injection of embryos with lentiviral vectors showed that timing of injection (before or after fertilization) had no effect on subsequent transgene expression, but that the type of reporter gene determined post-injection development and rate of transgenesis. The transfer of embryos following injection of a lentiviral vector into three recipients resulted in one pregnancy which was lost during the second trimester. Analysis of fetal tissues showed ubiquitous presence of the transgene and GFP expression in all tissues examined. These results show that lentivirus-derived vectors can efficiently transform rhesus embryos and are suitable for the generation of transgenic rhesus monkeys.


fMRI evidence for multisensory recruitment associated with rapid eye movements during sleep.
We studied the neural correlates of rapid eye movement during sleep (REM) by timing REMs from video recording and using rapid event-related functional MRI. Consistent with the hypothesis that REMs share the brain systems and mechanisms with waking eye movements and are visually-targeted saccades, we found REM-locked activation in the primary visual cortex, thalamic reticular nucleus (TRN), 'visual claustrum', retrosplenial cortex (RSC, only on the right hemisphere), fusiform gyrus, anterior cingulate cortex, and the oculomotor circuit that controls awake saccadic eye movements (and subserves awake visuospatial attention). Unexpectedly, robust activation also occurred in non-visual sensory cortices, motor cortex, language areas, and the ascending reticular activating system, including basal forebrain, the major source of cholinergic input to the entire cortex. REM-associated activation of these areas, especially non-visual primary sensory cortices, TRN and claustrum, parallels findings from waking studies on the interactions between multiple sensory data, and their 'binding' into a unified percept, suggesting that these mechanisms are also shared in waking and dreaming and that the sharing goes beyond the expected visual scanning mechanisms. Surprisingly, REMs were associated with a decrease in signal in specific periventricular subregions, matching the distribution of the serotonergic supraependymal plexus. REMs might serve as a useful task-free probe into major brain systems for functional brain imaging.


Violation of the intent-to-treat principle and rate of missing data in superiority trials assessing structural outcomes in rheumatic diseases.
To evaluate the methodologic quality of and identify methodologic issues in superiority trials assessing structural outcomes in rheumatic diseases. We searched Medline and the Cochrane Central Register of Controlled Trials for reports of randomized controlled trials assessing structural outcomes in osteoarthritis (OA), rheumatoid arthritis (RA), and osteoporosis (OP) published between January 1994 and December 2003 in high-impact factor general medical and specialty journals. One reader extracted data (quality assessment, intent-to-treat analysis [ITT analysis], rate of missing data, and methods of handling missing data), using a standardized form. A total of 81 reports were included in the analysis (37 on OP, 34 on RA, and 10 on OA). The mean +/- SD methodologic quality scores on the Jadad scale (possible range 0-5) and the Delphi list (possible range 0-9) were 2.9 +/- 1.2 and 6.4 +/- 1.3, respectively. Although it was reported in 54 articles (66.7%) that the analysis was done on an ITT basis, full ITT analysis was performed in only 6 of the studies (7.4%), modified ITT analysis in 11 (13.6%), and case-complete analysis in 48 (59.3%); the analysis was unclear in 16 articles (19.8%). The rate of missing data on structural outcomes could be determined in only 63 articles (77.8%) and was >20% in approximately one-third of these reports. Methods for handling missing data on structural outcomes were described in 19 articles (23.5%) and were, in general, inappropriate. Lack of ITT analysis and a high rate of missing data in superiority trials assessing structural outcomes may bias results from such trials. Our recommendations for improving these shortcomings may help researchers plan, analyze, and report the results of such trials.


Effect of cinnamon (Cinnamomum verum) bark essential oil on the halitosis-associated bacterium Solobacterium moorei and in vitro cytotoxicity.
Halitosis, also known as bad breath or oral malodour, is a condition affecting a large proportion of the population. Solobacterium moorei is a Gram-positive anaerobic bacterium that has been specifically associated with halitosis. In this study, we investigated the effects of essential oils, more particularly cinnamon bark oil, on growth, biofilm formation, eradication and killing, as well as hydrogen sulfide (H2S) production by S. moorei. A broth microdilution assay was used to determine the antibacterial activity of essential oils. Biofilm formation was assessed by a crystal violet staining assay and scanning electron microscopy. The biofilm of S. moorei was characterized by enzymatic treatments. Biofilm killing was determined by a luminescence assay monitoring ATP production. H2S production was quantified with a colorimetric assay. The biocompatibility of cinnamon oil was investigated using a gingival keratinocyte cell line. Among the ten essential oils tested, cinnamon oil was found to be the most powerful against S. moorei with MIC and MBC values of 0.039% and 0.156%, respectively. The biofilm formed by S. moorei was then characterized. The fact that DNase I and to a lesser extent proteinase K significantly reduced biofilm formation by S. moorei and induced its eradication suggests that the extracellular matrix of S. moorei biofilm may be mainly containing a DNA backbone associated with proteins. At concentrations below the MIC, cinnamon oil reduced S. moorei biofilm formation that resulted from an attenuation of bacterial growth. It was also found that treatment of a pre-formed biofilm of S. moorei with cinnamon oil significantly decreased its viability although it did not cause its eradication. Cinnamon oil had an inhibitory effect on the production of H2S by S. moorei. Lastly, it was found that at concentrations effective against S. moorei, no significant loss of viability in gingival keratinocytes occurred after a 1-h exposure. Our study brought evidence that cinnamon oil may be a promising substance to incorporate into oral hygiene products for controlling bad breath by inhibiting growth, killing biofilm, and reducing H2S production by S. moorei. Moreover, at the effective concentrations, cinnamon oil was found to have no toxic effects on oral keratinocytes.


[Weight-control intervention in overweight subjects at high risk of cardiovascular disease: a trial of a public health practical training program in a medical school].
To evaluate the effectiveness of a weight-control intervention for overweight subjects at high risk of cardiovascular disease (CVD) at a worksite conducted by medical students as a public health practical training program. A total of 45 men and women who were obese (BMI > or = 24.0 kg/m2) and found to be hypertensive (SBP > or = 140 mmHg or DBP > or = 90 mmHg) or suffering from hypercholesterolemia (total serum cholesterol > or = 220 mg/dl) in an annual health check up in November 2001 were invited to participate in a weight-control intervention program. Eight individuals agreed (intervention group) and other sixteen control subjects whose sex and age (+/- 3 years) were matched to the intervention subjects were selected. The duration of the program was three months (from July to October 2002) and a 2 kg weight reduction in that period was set as the goal. The baseline survey consisted of a dietary questionnaire and a health quiz. Subjects had two counseling sessions and received four personal letters in the three months. A semi-quantitative food frequent questionnaire, a photograph method (Diet Agent Service, Matsushita Electric Works, Ltd.) and three day food records were conducted for dietary surveys. Changes in bodyweight, BMI, blood pressure, and serum total cholesterol concentration from November 2001 to November 2002 were compared between the intervention and control groups. Food group intakes and nutrient intakes were compared between weight reduction achievers and non-achievers. Mean bodyweight changes from November 2001 to November 2002 were -2.3 kg (SD 3.3 kg) for the intervention group and +0.3 kg (SD 1.5 kg) for the control group, the difference being significant (p = 0.013). For the intervention group mean bodyweight change from July to October 2002 was -1.5 kg (SD 2.4 kg). For total serum cholesterol, the mean changes were -32.1 mg/dl vs. +0.5 mg/dl (p = 0.005), for SBP -9.5 mmHg vs. +4.7 mmHg (p = 0.083) and for DBP -2.8 mmHg vs. +1.4 mmHg (p = 0.438). These were thought to be consequences of weight-control intervention. From dietary surveys, weight reduction achievers increased fish intake and decreased fats, snacks and sweets. Those who answered the health quiz more correctly demonstrated more reduction of bodyweight. Effectiveness of a weight-control intervention for reduction of CVD risk factors was found in the present public health practical training program for medical students. Dietary advice based on various dietary surveys was indicated to be effective in the weight-control program. A population strategy to distribute health information appeared necessary for effective health education programs for high-risk subjects.


Combinational therapy for potential HIV-1 eradication and vaccination.
Eradication of HIV would avert the pandemic high rates of deaths and save the healthcare resources in treatment and prevention costs, however, it is clear that this goal is not achievable with existing anti-HIV drugs due to HIV evolvement in great magnitude and diversity. Despite recent reports of short interfering RNA-directed silencing of HIV gene activities, there remain many challenges in overcoming the complications of HIV mutation in the management of clinical HIV-infected cells. Here we describe a combinational therapy of antiviral deoxynucleotidylated RNA hybrid transfection and interleukin-2 adjuvant treatment that was able to consistently silence 99% mutant type HIV-1 infections of T lymphocytes mediated through a novel post-transcriptional gene silencing mechanism. This combined therapy not only induced strong suppression on mixed type HIV-1 replication but also boosted the immunity and proliferation of normal T lymphocytes. The outgrowth of non-infected T cells resulted in the elimination of 76% HIV-infected cells 1 week after the combinational therapy. These findings promise to provide an immediate therapy in both acute and chronic HIV infections as well as a potential vaccination strategy for AIDS eradication.


Selective potentiation of insulin-mediated glucose disposal in normal dogs by the sulfonylurea glipizide.
Investigative data have suggested that the extrapancreatic actions of the sulfonylureas may be paramount in their chronic antidiabetic action. The present study examines the effects of chronic sulfonylurea treatment on in vivo insulin action. Peripheral insulin levels, hepatic glucose production (Ra), and overall glucose disposal (Rd) were studied in six awake, normal dogs given both 0.5 and 1.0 mU/kg per min pork insulin for 2.5 h. This produces stable hyperinsulinemia from 15 to 150 min. Fasting euglycemia was held constant by the glucose clamp technique and averaged 99% basal glucose in all studies. Ra and Rd were determined from infusion of [3-(3)H]glucose, begun 90 min prior to insulin infusion. 10 mg of the sulfonylurea glipizide, was given daily to the test animals for the 10 to 20 d following appropriate control studies, then was withheld for 24 h, and the dogs were restudied. Glipizide treatment did not significantly alter basal glucose turnover, Ra, mean glucose values, or mean insulin levels as determined by radioimmunoassay. Increase in Rd above basal glucose turnover in response to insulin (delta Rd) was significantly (P less than 0.05) increased by glipizide treatment at both insulin dosage levels (paired analysis). At 1.0 mU/kg per min insulin, delta Rd rose from 2.6 mg/kg per min before glipizide to 6.5 mg/kg per min after glipizide treatment. At 0.5 mU/kg per min insulin, delta Rd went from 1.1 mg/kg per min before glipizide to 2.2 mg/kg per min after glipizide treatment. Glipizide treatment doubled the effects of insulin on Rd, while showing no significant effect upon insulin suppression of Ra. We conclude that a significant extrapancreatic chronic action of glipizide lies in its ability to selectively potentiate Rd.


Interaction model based on local protein substructures generalizes to the entire structural enzyme-ligand space.
Chemogenomics is a new strategy in in silico drug discovery, where the ultimate goal is to understand molecular recognition for all molecules interacting with all proteins in the proteome. To study such cross interactions, methods that can generalize over proteins that vary greatly in sequence, structure, and function are needed. We present a general quantitative approach to protein-ligand binding affinity prediction that spans the entire structural enzyme-ligand space. The model was trained on a data set composed of all available enzymes cocrystallized with druglike ligands, taken from four publicly available interaction databases, for which a crystal structure is available. Each enzyme was characterized by a set of local descriptors of protein structure that describe the binding site of the cocrystallized ligand. The ligands in the training set were described by traditional QSAR descriptors. To evaluate the model, a comprehensive test set consisting of enzyme structures and ligands was manually curated. The test set contained enzyme-ligand complexes for which no crystal structures were available, and thus the binding modes were unknown. The test set enzymes were therefore characterized by matching their entire structures to the local descriptor library constructed from the training set. Both the training and the test set contained enzyme-ligand complexes from all major enzyme classes, and the enzymes spanned a large range of sequences and folds. The experimental binding affinities (p K i) ranged from 0.5 to 11.9 (0.7-11.0 in the test set). The induced model predicted the binding affinities of the external test set enzyme-ligand complexes with an r (2) of 0.53 and an RMSEP of 1.5. This demonstrates that the use of local descriptors makes it possible to create rough predictive models that can generalize over a wide range of protein targets.


Aspirations and realities in a North-South partnership for health promotion: lessons from a program to promote safe male circumcision in Botswana.
International donors support the partnership between the Government of Botswana and two international organisations: U.S. Centers for Disease Control and Prevention and Africa Comprehensive HIV/AIDS Partnership to implement Voluntary Medical Male Circumcision with the target of circumcising 80 % of HIV negative men in 5 years. Botswana Government had started integration of the program into its health system when international partners brought in the Models for Optimizing Volume and Efficiency to strengthen delivery of the service and push the target. The objective of this paper is to use a systems model to establish how the functioning of the partnership on Safe Male Circumcision in Botswana contributed to the outcome. Data were collected using observations, focus group discussions and interviews. Thirty participants representing all three partners were observed in a 3-day meeting; followed by three rounds of in-depth interviews with five selected leading officers over 2 years and three focus group discussions. Financial resources, "ownership" and the target influence the success or failure of partnerships. A combination of inputs by partners brought progress towards achieving set program goals. Although there were tensions between partners, they were working together in strategising to address some challenges of the partnership and implementation. Pressure to meet the expectations of the international donors caused tension and challenges between the in-country partners to the extent of Development Partners retreating and not pursuing the mission further. Target achievement, the link between financial contribution and ownership expectations caused antagonistic outcome. The paper contributes enlightenment that the functioning of the visible in-country partnership is significantly influenced by the less visible global context such as the target setters and donors.


Pattern Discovery in Brain Imaging Genetics via SCCA Modeling with a Generic Non-convex Penalty.
Brain imaging genetics intends to uncover associations between genetic markers and neuroimaging quantitative traits. Sparse canonical correlation analysis (SCCA) can discover bi-multivariate associations and select relevant features, and is becoming popular in imaging genetic studies. The L1-norm function is not only convex, but also singular at the origin, which is a necessary condition for sparsity. Thus most SCCA methods impose [Formula: see text]-norm onto the individual feature or the structure level of features to pursuit corresponding sparsity. However, the [Formula: see text]-norm penalty over-penalizes large coefficients and may incurs estimation bias. A number of non-convex penalties are proposed to reduce the estimation bias in regression tasks. But using them in SCCA remains largely unexplored. In this paper, we design a unified non-convex SCCA model, based on seven non-convex functions, for unbiased estimation and stable feature selection simultaneously. We also propose an efficient optimization algorithm. The proposed method obtains both higher correlation coefficients and better canonical loading patterns. Specifically, these SCCA methods with non-convex penalties discover a strong association between the APOE e4 rs429358 SNP and the hippocampus region of the brain. They both are Alzheimer's disease related biomarkers, indicating the potential and power of the non-convex methods in brain imaging genetics.


Characterization of the MRC OX40 antigen of activated CD4 positive T lymphocytes--a molecule related to nerve growth factor receptor.
The antigen recognized by the monoclonal antibody (mAb) MRC OX40 is present on activated rat CD4 positive T lymphocytes but not other cells. cDNA clones were isolated from an expression library using the MRC OX40 mAb and the protein sequence for the OX40 antigen deduced. It contains a typical signal sequence and a single putative transmembrane sequence of 25 predominantly hydrophobic amino acids giving an extracellular domain of 191 amino acids and a cytoplasmic domain of 36 amino acids. The sequence of the extracellular domain includes a cysteine-rich region with sequence similarities with the low affinity nerve growth factor receptor (NGFR) of neurons and the CD40 antigen present on human B cells. Within this region three cysteine-rich motifs can be recognized in OX40 compared with four similar motifs in both NGFR and CD40. OX40, CD40 and NGFR constitute a new superfamily of molecules with expression including lymphoid cells (OX40, CD40) and neuronal cells (NGFR). This is reminiscent of the immunoglobulin superfamily whose molecules are variously found at the surface of lymphoid or brain cells or both.


First- vs second-trimester ultrasound: the effect on pregnancy dating and perinatal outcomes.
The objective of the study was to examine the effect of first-trimester obstetric ultrasound (OBUS) on the measurement of the effect of complications ascribed to postterm pregnancies. We conducted a retrospective cohort study of all term, singleton pregnancies delivered at our institution who had an OBUS at a gestation of 24 weeks or less. Those women who underwent an OBUS at a gestation of 12 weeks or less (OBUS12) were compared with those who had an OBUS at 13-24 weeks of gestation (OBUS13-24). The primary outcome measures were the rates of postterm pregnancies greater than 41 or 42 weeks' gestation. Secondary outcomes were the differences between the postterm and term gestations in maternal and neonatal outcomes. In the OBUS12 group, the rate of postterm pregnancy 42 weeks or longer was lower (2.7%) as compared with the OBUS13-24 group (3.7%, P = .022). With regard to reaching 41 weeks of gestation, the OBUS12 group was again lower (18.2%) as compared with the OBUS13-24 group (22.1%, P < .001). There were also fewer postterm inductions at 42 weeks or longer in the OBUS12 group (1.8%) as compared with the OBUS13-24 group (2.6%, P = .017). When comparing perinatal outcomes between those women who reached 41 weeks of gestation and those prior to 41 weeks of gestation, the OBUS12 group demonstrated greater differences between these 2 groups. Our findings suggest that earlier obstetric ultrasound, which leads to better pregnancy dating, reduces the rate of estimated postterm pregnancies. This may, in turn, reduce unnecessary intervention and lead to better identification of postterm pregnancies at greater risk of complications.


Predicting the causative pathogen among children with osteomyelitis using Bayesian networks - improving antibiotic selection in clinical practice.
Infection of bone, osteomyelitis (OM), is a serious bacterial infection in children requiring urgent antibiotic therapy. While biological specimens are often obtained and cultured to guide antibiotic selection, culture results may take several days, are often falsely negative, and may be falsely positive because of contamination by non-causative bacteria. This poses a dilemma for clinicians when choosing the most suitable antibiotic. Selecting an antibiotic which is too narrow in spectrum risks treatment failure; selecting an antibiotic which is too broad risks toxicity and promotes antibiotic resistance. We have developed a Bayesian Network (BN) model that can be used to guide individually targeted antibiotic therapy at point-of-care, by predicting the most likely causative pathogen in children with OM and the antibiotic with optimal expected utility. The BN explicitly models the complex relationship between the unobserved infecting pathogen, observed culture results, and clinical and demographic variables, and integrates data with critical expert knowledge under a causal inference framework. Development of this tool resulted from a multidisciplinary approach, involving experts in infectious diseases, modelling, paediatrics, microbiology, computer science and statistics. The model-predicted prevalence of causative pathogens among children with osteomyelitis were 56 % for Staphylococcus aureus, 17 % for 'other' culturable bacteria (like Streptococcus pyogenes), and 27 % for bacterial pathogens that are not culturable using routine methods (like Kingella kingae). Log loss cross-validation suggests that the model performance is robust, with the best fit to culture results achieved when data and expert knowledge were combined during parameterisation. AUC values of 0.68 - 0.77 were achieved for predicting culture results of different types of specimens. BN-recommended antibiotics were rated optimal or adequate by experts in 82-98% of 81 cases sampled from the cohort. We have demonstrated the potential use of BNs in improving antibiotic selection for children with OM, which we believe to be generalisable in the development of a broader range of decision support tools. With appropriate validation, such tools might be effectively deployed for real-time clinical decision support, to promote a shift in clinical practice from generic to individually-targeted antibiotic therapy, and ultimately improve the management and outcomes for a range of serious bacterial infections.


Congenital epulis of the newborn: a report of two cases.
Congenital epulis of the newborn is a rare lesion whose histogenesis and natural clinical history have remained obscure. Even with the advent of modern histopathological techniques, it has not been possible to depict specific cellular features unique to this lesion. However, it is important that new cases are reported from all populations so that their occurrence and frequency may be easily noted. Furthermore, the lesion is important as a differential diagnosis of other aggressive lesions early in life. This report presents two Kenyan cases.


Prognostic factors influencing the patency of hemodialysis vascular access: literature review and novel therapeutic modality by far infrared therapy.
In Taiwan, more than 85% of patients with end-stage renal disease undergo maintenance hemodialysis (HD). The native arteriovenous fistula (AVF) accounts for a prevalence of more than 80% of the vascular access in our patients. Some mechanical factors may affect the patency of hemodialysis vascular access, such as surgical skill, puncture technique and shear stress on the vascular endothelium. Several medical factors have also been identified to be associated with vascular access prognosis in HD patients, including stasis, hypercoagulability, endothelial cell injury, medications, red cell mass and genotype polymorphisms of transforming growth factor-beta1 and methylene tetrahydrofolate reductase. According to our previous study, AVF failure was associated with a longer dinucleotide (GT)n repeat (n > or = 30) in the promoter of the heme oxygenase-1 (HO-1) gene. Our recent study also demonstrated that far-infrared therapy, a noninvasive and convenient therapeutic modality, can improve access flow, inflammatory status and survival of the AVF in HD patients through both its thermal and non-thermal (endothelial-improving, anti-inflammatory, antiproliferative, antioxidative) effects by upregulating NF-E2-related factor-2-dependent HO-1 expression, leading to the inhibition of expression of E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1.


Physical and radiation hybrid mapping of canine chromosome 12, in a region corresponding to human chromosome 6p12-q12.
The positional cloning of the hypocretin receptor 2, the gene for autosomal recessive canine narcolepsy, has led to the development of a physical map spanning a large portion of canine chromosome 12 (CFA12), in a region corresponding to human chromosome 6p12-q13. More than 40 expressed sequence tags (ESTs) were used in homology search experiments, together with chromosome walking, to build both physical and radiation hybrid maps of the CFA12 13-21 region. The resulting map of bacterial artificial chromosome ends, ESTs, and microsatellite markers represents the longest continuous high-density map of the dog genome reported to date. These data further establish the dog as a system for studying disease genes of interest to human populations and highlight feasible approaches for positional cloning of disease genes in organisms where genomic resources are limited.


The effect of toluene on the vestibulo- and opto-oculomotor system in rats. A computerized nystagmographic study.
The short-term effect of exposure to toluene on the vestibulo- and opto-oculomotor system in rats was investigated. Stimulation of the vestibulo- and opto-oculomotor system was either a constant rotatory acceleration, a sinusoidal oscillation, a randomized oscillation or an optokinetic stimulation. Eye movements in response to the different stimulations were recorded by EOG and fed into a computer for analysis. Due to toluene exposure the slow phase velocity gain during constant acceleration increased and the post-acceleratory nystagmus response was prolonged. The optokinetic gain at stimulation velocities above 10 deg/sec decreased during toluene exposure. Toluene also prolonged the duration of optokinetic after- and after-afternystagmus. The findings in this study strongly suggest an effect of toluene on the cerebellum.


Pseudomonas carbonaria sp. nov., isolated from charcoal.
A beige-pigmented, oxidase-positive bacterial isolate, Wesi-4T, isolated from charcoal in 2012, was examined in detail by applying a polyphasic taxonomic approach. Cells of the isolates were rod shaped and Gram-stain negative. Examination of the 16S rRNA gene sequence of the isolate revealed highest sequence similarities to the type strains of Pseudomonas matsuisoli and Pseudomonas nosocomialis (both 97.3 %). Phylogenetic analyses on the basis of the 16S rRNA gene sequences indicated a separate position of Wesi-4T, which was confirmed by multilocus sequence analyses (MLSA) based on the three loci gyrB, rpoB and rpoD and a core genome-based phylogenetic tree. Genome sequence based comparison of Wesi-4T and the type strains of P. matsuisoli and P. nosocomialis yielded average nucleotide identity values <95 % and in silico DNA-DNA hybridization values <70 %, respectively. The polyamine pattern contains the major amines putrescine, cadaverine and spermidine. The quinone system contains predominantly ubiquinone Q-9 and in the polar lipid profile diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine are the major lipids. The fatty acid contains predominantly C16 : 0, summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c) and summed feature 8 (C18 : 1ω7c and/or C18 : 1 ω6c). In addition, physiological and biochemical tests revealed a clear phenotypic difference from P. matsuisoli. These cumulative data indicate that the isolate represents a novel species of the genus Pseudomonas for which the name Pseudomonas carbonaria sp. nov. is proposed with Wesi-4T (=DSM 110367T=CIP 111764T=CCM 9017T) as the type strain.


Inducing Social Self-Sorting in Organic Cages To Tune The Shape of The Internal Cavity.
Many interesting target guest molecules have low symmetry, yet most methods for synthesising hosts result in highly symmetrical capsules. Methods of generating lower symmetry pores are thus required to maximise the binding affinity in host-guest complexes. Herein, we use mixtures of tetraaldehyde building blocks with cyclohexanediamine to access low-symmetry imine cages. Whether a low-energy cage is isolated can be correctly predicted from the thermodynamic preference observed in computational models. The stability of the observed structures depends on the geometrical match of the aldehyde building blocks. One bent aldehyde stands out as unable to assemble into high-symmetry cages-and the same aldehyde generates low-symmetry socially self-sorted cages when combined with a linear aldehyde. We exploit this finding to synthesise a family of low-symmetry cages containing heteroatoms, illustrating that pores of varying geometries and surface chemistries may be reliably accessed through computational prediction and self-sorting.


Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer's disease.
Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive cognitive impairment and neurodegeneration. However, despite extensive clinical and genomic studies, the molecular basis of AD development and progression remains elusive. To elucidate molecular systems associated with AD, we developed a large scale gene expression dataset from 1053 postmortem brain samples across 19 cortical regions of 125 individuals with a severity spectrum of dementia and neuropathology of AD. We excluded brain specimens that evidenced neuropathology other than that characteristic of AD. For the first time, we performed a pan-cortical brain region genomic analysis, characterizing the gene expression changes associated with a measure of dementia severity and multiple measures of the severity of neuropathological lesions associated with AD (neuritic plaques and neurofibrillary tangles) and constructing region-specific co-expression networks. We rank-ordered 44,692 gene probesets, 1558 co-expressed gene modules and 19 brain regions based upon their association with the disease traits. The neurobiological pathways identified through these analyses included actin cytoskeleton, axon guidance, and nervous system development. Using public human brain single-cell RNA-sequencing data, we computed brain cell type-specific marker genes for human and determined that many of the abnormally expressed gene signatures and network modules were specific to oligodendrocytes, astrocytes, and neurons. Analysis based on disease severity suggested that: many of the gene expression changes, including those of oligodendrocytes, occurred early in the progression of disease, making them potential translational/treatment development targets and unlikely to be mere bystander result of degeneration; several modules were closely linked to cognitive compromise with lesser association with traditional measures of neuropathology. The brain regional analyses identified temporal lobe gyri as sites associated with the greatest and earliest gene expression abnormalities. This transcriptomic network analysis of 19 brain regions provides a comprehensive assessment of the critical molecular pathways associated with AD pathology and offers new insights into molecular mechanisms underlying selective regional vulnerability to AD at different stages of the progression of cognitive compromise and development of the canonical neuropathological lesions of AD.


Tree Ensembles on the Induced Discrete Space.
Decision trees are widely used predictive models in machine learning. Recently, K -tree is proposed, where the original discrete feature space is expanded by generating all orderings of values of k discrete attributes and these orderings are used as the new attributes in decision tree induction. Although K -tree performs significantly better than the proper one, their exponential time complexity can prohibit their use. In this brief, we propose K -forest, an extension of random forest, where a subset of features is selected randomly from the induced discrete space. Simulation results on 17 data sets show that the novel ensemble classifier has significantly lower error rate compared with the random forest based on the original feature space.


TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity.
The molecular mechanisms of acute kidney injury (AKI) remain unclear. Toll-like receptors (TLRs), widely expressed on leukocytes and kidney epithelial cells, regulate innate and adaptive immune responses. The present study examined the role of TLR signaling in cisplatin-induced AKI. Cisplatin-treated wild-type mice had significantly more renal dysfunction, histologic damage, and leukocytes infiltrating the kidney than similarly treated mice with a targeted deletion of TLR4 [Tlr4(-/-)]. Levels of cytokines in serum, kidney, and urine were increased significantly in cisplatin-treated wild-type mice compared with saline-treated wild-type mice and cisplatin-treated Tlr4(-/-) mice. Activation of JNK and p38, which was associated with cisplatin-induced renal injury in wild-type mice, was significantly blunted in Tlr4(-/-) mice. Using bone marrow chimeric mice, it was determined that renal parenchymal TLR4, rather than myeloid TLR4, mediated the nephrotoxic effects of cisplatin. Therefore, activation of TLR4 on renal parenchymal cells may activate p38 MAPK pathways, leading to increased production of inflammatory cytokines, such as TNF-alpha and subsequent kidney injury. Targeting the TLR4 signaling pathways may be a feasible therapeutic strategy to prevent cisplatin-induced AKI in humans.


Parasite epidemiology in a changing world: can molecular phylogeography help us tell the wood from the trees?
SUMMARY Molecular phylogeography has revolutionised our ability to infer past biogeographic events from cross-sectional data on current parasite populations. In ecological parasitology, this approach has been used to address fundamental questions concerning host-parasite co-evolution and geographic patterns of spread, and has raised many technical issues and problems of interpretation. For applied parasitologists, the added complexity inherent in adding population genetic structure to perceived parasite distributions can sometimes seem to cloud rather than clarify approaches to control. In this paper, we use case studies firstly to illustrate the potential extent of cryptic diversity in parasite and parasitoid populations, secondly to consider how anthropogenic influences including movement of domestic animals affect the geographic distribution and host associations of parasite genotypes, and thirdly to explore the applied relevance of these processes to parasites of socio-economic importance. The contribution of phylogeographic approaches to deeper understanding of parasite biology in these cases is assessed. Thus, molecular data on the emerging parasites Angiostrongylus vasorum in dogs and wild canids, and the myiasis-causing flies Lucilia spp. in sheep and Cochliomyia hominovorax in humans, lead to clear implications for control efforts to limit global spread. Broader applications of molecular phylogeography to understanding parasite distributions in an era of rapid global change are also discussed.


In Operando X-ray Studies of High-Performance Lithium-Ion Storage in Keplerate-Type Polyoxometalate Anodes.
Polyoxometalates (POMs) have emerged as potential anode materials for lithium-ion batteries (LIBs) owing to their ability to transfer multiple electrons. Although POM anode materials exhibit notable results in LIBs, their energy-storage mechanisms have not been well-investigated. Here, we utilize various in operando and ex situ techniques to verify the charge-storage mechanisms of a Keplerate-type POM Na2K23{[(MoVI)MoVI5O21(H2O)3(KSO4)]12 [(VIVO)30(H2O)20(SO4)0.5]}·ca200H2O ({Mo72V30}) anode in LIBs. The {Mo72V30} anode provides a high reversible capacity of up to ∼1300 mA h g-1 without capacity fading for up to 100 cycles. The lithium-ion storage mechanism was studied systematically through in operando synchrotron X-ray absorption near-edge structure, ex situ X-ray diffraction, ex situ extended X-ray absorption fine structure, ex situ transmission electron microscopy, in operando synchrotron transmission X-ray microscopy, and in operando Raman spectroscopy. Based on the abovementioned results, we propose that the open hollow-ball structure of the {Mo72V30} molecular cluster serves as an electron/ion sponge that can store a large number of lithium ions and electrons reversibly via multiple and reversible redox reactions (Mo6+ ↔ Mo1+ and V5+/V4+↔ V1+) with fast lithium diffusion kinetics (DLi+: 10-9-10-10 cm2 s-1). No obvious volumetric expansion of the microsized {Mo72V30} particle is observed during the lithiation/delithiation process, which leads to high cycling stability. This study provides comprehensive analytical methods for understanding the lithium-ion storage mechanism of such complicated POMs, which is important for further studies of POM electrodes in energy-storage applications.


Shape of diffraction orders of centered and decentered pixelated lenses.
We consider diffraction by pixelated lenses when the lens size is significantly smaller than the diffraction pattern of single pixels. In that case, the diffraction orders show shapes that have not been identified in earlier studies and that are quite sensitive to the pixel filling ratio as well as to decentering.


Extensive cochleotopic mapping of human auditory cortical fields obtained with phase-encoding FMRI.
The primary sensory cortices are characterized by a topographical mapping of basic sensory features which is considered to deteriorate in higher-order areas in favor of complex sensory features. Recently, however, retinotopic maps were also discovered in the higher-order visual, parietal and prefrontal cortices. The discovery of these maps enabled the distinction between visual regions, clarified their function and hierarchical processing. Could such extension of topographical mapping to high-order processing regions apply to the auditory modality as well? This question has been studied previously in animal models but only sporadically in humans, whose anatomical and functional organization may differ from that of animals (e.g. unique verbal functions and Heschl's gyrus curvature). Here we applied fMRI spectral analysis to investigate the cochleotopic organization of the human cerebral cortex. We found multiple mirror-symmetric novel cochleotopic maps covering most of the core and high-order human auditory cortex, including regions considered non-cochleotopic, stretching all the way to the superior temporal sulcus. These maps suggest that topographical mapping persists well beyond the auditory core and belt, and that the mirror-symmetry of topographical preferences may be a fundamental principle across sensory modalities.


A statistical approach to volume data quality assessment.
Quality assessment plays a crucial role in data analysis. In this paper, we present a reduced-reference approach to volume data quality assessment. Our algorithm extracts important statistical information from the original data in the wavelet domain. Using the extracted information as feature and predefined distance functions, we are able to identify and quantify the quality loss in the reduced or distorted version of data, eliminating the need to access the original data. Our feature representation is naturally organized in the form of multiple scales, which facilitates quality evaluation of data with different resolutions. The feature can be effectively compressed in size. We have experimented with our algorithm on scientific and medical data sets of various sizes and characteristics. Our results show that the size of the feature does not increase in proportion to the size of original data. This ensures the scalability of our algorithm and makes it very applicable for quality assessment of large-scale data sets. Additionally, the feature could be used to repair the reduced or distorted data for quality improvement. Finally, our approach can be treated as a new way to evaluate the uncertainty introduced by different versions of data.


A central role for a single c-Myb binding site in a thymic locus control region.
Locus control regions (LCRs) are powerful assemblies of cis elements that organize the actions of cell-type-specific trans-acting factors. A 2.3-kb LCR in the human adenosine deaminase (ADA) gene first intron, which controls expression in thymocytes, is composed of a 200-bp enhancer domain and extended flanking sequences that facilitate activation from within chromatin. Prior analyses have demonstrated that the enhancer contains a 28-bp core region and local adjacent augmentative cis elements. We now show that the core contains a single critical c-Myb binding site. In both transiently cotransfected human cells and stable chromatin-integrated yeast cells, c-Myb strongly transactivated reporter constructs that contained polymerized core sequences. c-Myb protein was strongly evident in T lymphoblasts in which the enhancer was active and was localized within discrete nuclear structures. Fetal murine thymus exhibited a striking concordance of endogenous c-myb expression with that of mouse ADA and human ADA LCR-directed transgene expression. Point mutation of the c-Myb site within the intact 2.3-kb LCR severely attenuated enhancer activity in transfections and LCR activity in transgenic thymocytes. Within the context of a complex enhancer and LCR, c-Myb can act as an organizer of thymocyte-specific gene expression via a single binding site.


New class of monoclonal antibodies against severe influenza: prophylactic and therapeutic efficacy in ferrets.
The urgent medical need for innovative approaches to control influenza is emphasized by the widespread resistance of circulating subtype H1N1 viruses to the leading antiviral drug oseltamivir, the pandemic threat posed by the occurrences of human infections with highly pathogenic avian H5N1 viruses, and indeed the evolving swine-origin H1N1 influenza pandemic. A recently discovered class of human monoclonal antibodies with the ability to neutralize a broad spectrum of influenza viruses (including H1, H2, H5, H6 and H9 subtypes) has the potential to prevent and treat influenza in humans. Here we report the latest efficacy data for a representative antibody of this novel class. We evaluated the prophylactic and therapeutic efficacy of the human monoclonal antibody CR6261 against lethal challenge with the highly pathogenic avian H5N1 virus in ferrets, the optimal model of human influenza infection. Survival rates, clinically relevant disease signs such as changes in body weight and temperature, virus replication in lungs and upper respiratory tract, as well as macro- and microscopic pathology were investigated. Prophylactic administration of 30 and 10 mg/kg CR6261 prior to viral challenge completely prevented mortality, weight loss and reduced the amount of infectious virus in the lungs by more than 99.9%, abolished shedding of virus in pharyngeal secretions and largely prevented H5N1-induced lung pathology. When administered therapeutically 1 day after challenge, 30 mg/kg CR6261 prevented death in all animals and blunted disease, as evidenced by decreased weight loss and temperature rise, reduced lung viral loads and shedding, and less lung damage. These data demonstrate the prophylactic and therapeutic efficacy of this new class of human monoclonal antibodies in a highly stringent and clinically relevant animal model of influenza and justify clinical development of this approach as intervention for both seasonal and pandemic influenza.


Cell-mediated immunity to human CMV infection: a brief overview.
The cellular immune response to human cytomegalovirus (HCMV) has different components originating from both the adaptive and innate immune systems. There is a significant global interest in understanding how the immune system keeps HCMV under control, in particular with a view to situations where HCMV infection causes severe damage. Such settings include HIV infection, transplantation, and maybe most importantly perinatal medicine, HCMV being a major cause of sometimes catastrophic birth defects. The development of an active HCMV vaccine has proven very difficult but some recent successes raise hope that this might be available in the future. However, adoptive transfer of HCMV-specific T cells has been successfully used to prevent CMV disease after bone marrow transplantation for many years. In fact, the CD8 T cell response has been thought to be the most important effector response, with numerous reports focusing on specific T cell subsets recognizing select peptides in select human leukocyte antigen (HLA) contexts. However, it is becoming increasingly clear now that other cells, first and foremost CD4 T cells, but also gamma/delta (γ/δ) T cells and natural killer cells, are critically involved in the cellular immune response to HCMV. This commentary aims to provide a brief overview of the field.


Comparison of different chondrocytes for use in tissue engineering of cartilage model structures.
This study compares bovine chondrocytes harvested from four different animal locations--nasoseptal, articular, costal, and auricular--for tissue-engineered cartilage modeling. While the work serves as a preliminary investigation for fabricating a human ear model, the results are important to tissue- engineered cartilage in general. Chondrocytes were cultured and examined to determine relative cell proliferation rates, type II collagen and aggrecan gene expression, and extracellular matrix production. Respective chondrocytes were then seeded onto biodegradable poly(L-lactide-epsilon-caprolactone) disc-shaped scaffolds. Cell-copolymer constructs were cultured and subsequently implanted in the subcutaneous space of athymic mice for up to 20 weeks. Neocartilage development in harvested constructs was assessed by molecular and histological means. Cell culture followed over periods of up to 4 weeks showed chondrocyte proliferation from the tissue sources varied, as did levels of type II collagen and aggrecan gene expression. For both genes, highest expression was found for costal chondrocytes, followed by nasoseptal, articular, and auricular cells. Retrieval of 20-week discs from mice revealed changes in construct dimensions with different chondrocytes. Greatest disc diameter was found for scaffolds seeded with auricular chondrocytes, followed by those with costal, nasoseptal, and articular cells. Greatest disc thickness was measured for scaffolds containing costal chondrocytes, followed by those with nasoseptal, auricular, and articular cells. Retrieved copolymer alone was smallest in diameter and thickness. Only auricular scaffolds developed elastic fibers after 20 weeks of implantation. Type II collagen and aggrecan were detected with differing expression levels on quantitative RT-PCR of discs implanted for 20 weeks. These data demonstrate that bovine chondrocytes obtained from different cartilaginous sites in an animal may elicit distinct responses during their respective development of a tissue-engineered neocartilage. Thus, each chondrocyte type establishes or maintains its particular developmental characteristics, and this observation is critical in the design and elaboration of any tissue-engineered cartilage model.


Choice and birth method: mixed-method study of caesarean delivery for maternal request.
To explore whether women view decision-making surrounding vaginal or caesarean birth as their choice. Longitudinal cohort study utilising quantitative (questionnaire, routinely collected data) and qualitative (in-depth interviews) methods simultaneously. A large hospital providing National Health Service maternity care in the UK. Four-hundred and fifty-four primigravid women. Women completed up to three questionnaires between their antenatal booking appointment and delivery. Amongst these women, 153 were interviewed at least once during pregnancy (between 24 and 36 weeks) and/or after 12 moths after birth. Data were also obtained from women's hospital delivery records. Descriptive statistical analysis was performed (survey and delivery data). Interview data were analysed using a seven-stage sequential form of qualitative analysis. Whilst many women supported the principle of choice, they identified how, in practice their autonomy was limited by individual circumstance and available care provision. All women felt that concerns about their baby's or their own health should take precedence over personal preference. Moreover, expressing a preference for either vaginal or caesarean birth was inherently problematic as choice until the time of delivery was neither static nor final. Women did not have autonomous choice over their actual birth method, but neither did they necessarily want it. The results of this large exploratory study suggest that choice may not be the best concept through which to approach the current arrangements for birth in the UK. Moreover, they challenge the notion of choice that currently prevails in international debates about caesarean delivery for maternal request.


The rise and fall of Hox gene clusters.
Although all bilaterian animals have a related set of Hox genes, the genomic organization of this gene complement comes in different flavors. In some unrelated species, Hox genes are clustered; in others, they are not. This indicates that the bilaterian ancestor had a clustered Hox gene family and that, subsequently, this genomic organization was either maintained or lost. Remarkably, the tightest organization is found in vertebrates, raising the embarrassingly finalistic possibility that vertebrates have maintained best this ancestral configuration. Alternatively, could they have co-evolved with an increased ;organization' of the Hox clusters, possibly linked to their genomic amplification, which would be at odds with our current perception of evolutionary mechanisms? When discussing the why's and how's of Hox gene clustering, we need to account for three points: the mechanisms of cluster evolution; the underlying biological constraints; and the developmental modes of the animals under consideration. By integrating these parameters, general conclusions emerge that can help solve the aforementioned dilemma.


Cochrane Rehabilitation: 2018 annual report.
During its second year of existence, Cochrane Rehabilitation worked hard to accomplish new and old goals. The Review Committee completed the massive task of identifying and "tagging" all rehabilitation reviews in the Cochrane library. The Publication Committee signed agreements with several international journals and started the publication of Cochrane Corners. The Education Committee performed educational activities such as workshops in International Meetings. The Methodology Committee has completed a two days Cochrane Rehabilitation Methodological Meeting in Paris of which the results will soon be published. The Communication Committee reaches almost 5,000 rehabilitation professionals through social media, and is working on the translation of contents in Italian, Spanish, French, Dutch, Croatian and Japanese. Memoranda of Understanding have been signed with several National and International Rehabilitation Scientific Societies, Universities, Hospitals, Research Centres and other organizations. The be4rehab (best evidence for rehabilitation) project has been started with the World Health Organisation (WHO) to extract from Cochrane reviews and clinical guidelines the best currently available evidence to produce the WHO Minimum Package of Rehabilitation Interventions. The Cochrane Rehabilitation ebook is under development as well as a priority setting exercise with 39 countries from all continents.


Natural Modulators of Endosomal Toll-Like Receptor-Mediated Psoriatic Skin Inflammation.
Psoriasis is a chronic inflammatory autoimmune disease that can be initiated by excessive activation of endosomal toll-like receptors (TLRs), particularly TLR7, TLR8, and TLR9. Therefore, inhibitors of endosomal TLR activation are being investigated for their ability to treat this disease. The currently approved biological drugs adalimumab, etanercept, infliximab, ustekinumab, ixekizumab, and secukizumab are antibodies against effector cytokines that participate in the initiation and development of psoriasis. Several immune modulatory oligonucleotides and small molecular weight compounds, including IMO-3100, IMO-8400, and CPG-52364, that block the interaction between endosomal TLRs and their ligands are under clinical investigation for their effectiveness in the treatment of psoriasis. In addition, several chemical compounds, including AS-2444697, PF-05387252, PF-05388169, PF-06650833, ML120B, and PHA-408, can inhibit TLR signaling. Although these compounds have demonstrated anti-inflammatory activity in animal models, their therapeutic potential for the treatment of psoriasis has not yet been tested. Recent studies demonstrated that natural compounds derived from plants, fungi, and bacteria, including mustard seed, Antrodia cinnamomea extract, curcumin, resveratrol, thiostrepton, azithromycin, and andrographolide, inhibited psoriasis-like inflammation induced by the TLR7 agonist imiquimod in animal models. These natural modulators employ different mechanisms to inhibit endosomal TLR activation and are administered via different routes. Therefore, they represent candidate psoriasis drugs and might lead to the development of new treatment options.


Sputum PGP is reduced by azithromycin treatment in patients with COPD and correlates with exacerbations.
Proline-glycine-proline (PGP), a neutrophil chemoattractant derived from the enzymatic breakdown of collagen, is elevated in sputum of patients with chronic obstructive pulmonary disease (COPD) and may contribute to disease progression. Whether sputum levels of PGP respond to therapy for COPD or predict outcomes is unknown. We conducted a study ancillary to a multicenter trial of the efficacy of azithromycin treatment for 1 year in preventing COPD exacerbations to test whether sputum levels of PGP were altered by treatment or associated with exacerbation frequency. We collected remnant sputa from trial participants and assayed them in a blinded fashion for PGP, myeloperoxidase and matrix metalloproteinase (MMP)-9 and for the ability to generate PGP from collagen ex vivo. Once the parent trial was unblinded, the results were correlated with use of azithromycin or placebo and exacerbations in participants. Azithromycin treatment significantly reduced sputum levels of PGP and myeloperoxidase in patients with COPD, particularly with increased duration of therapy. We found no difference in sputum MMP-9 or PGP generation between participants taking azithromycin or placebo. Sputum PGP levels were highest around the time of an exacerbation and declined with successful treatment. These data support a role for PGP in the airway and parenchymal neutrophilic inflammation that drives COPD progression and exacerbations, and provide new information on the anti-inflammatory properties of macrolides. PGP may have potential as a target for novel anti-inflammatory therapies in COPD and as a biomarker for clinical trials.


Targeting the T-Lak cell originated protein kinase by OTS964 shrinks the size of power-law coded heterogeneous glioma stem cell populations.
Glioblastoma resists chemoradiotherapy, then, recurs to be a fatal space-occupying lesion. The recurrence is caused by re-growing cell populations such as glioma stem cells (GSCs), suggesting that GSC populations should be targeted. This study addressed whether a novel anti-cancer drug, OTS964, an inhibitor for T-LAK cell originated protein kinase (TOPK), is effective in reducing the size of the heterogeneous GSC populations, a power-law coded heterogeneous GSC populations consisting of glioma sphere (GS) clones, by detailing quantitative growth properties. We found that OTS964 killed GS clones while suppressing the growth of surviving GS clones, thus identifying clone-eliminating and growth-disturbing efficacies of OTS964. The efficacies led to a significant size reduction in GS populations in a dose-dependent manner. The surviving GS clones reconstructed GS populations in the following generations; the recovery of GS populations fits a recurrence after the chemotherapy. The recovering GS clones resisted the clone-eliminating effect of OTS964 in sequential exposure during the growth recovery. However, surprisingly, the resistant properties of the recovered-GS clones had been plastically canceled during self-renewal, and then the GS clones had become re-sensitive to OTS964. Thus, OTS964 targets GSCs to eliminate them or suppress their growth, resulting in shrinkage of the power-law coded GSC populations. We propose a therapy focusing on long-term control in recurrence of glioblastoma via reducing the size of the GSC populations by OTS964.


How to embed ethics into laboratory research.
Health-related innovation in biotechnology requires anticipating potential bioethical implications. In this article, we present a strategy to embed ethics in a group of early-stage researchers performing research in gene therapy and regenerative medicine in the laboratory phase. We conducted a series of focus group meetings with early-stage researchers who work in biotechnology laboratories. The objective was to reflect on the bioethical challenges of their own work and to promote the integration of research ethics with laboratory practice. The activity was assessed with questionnaires completed by the researchers before and after the meetings, and the analyses of the focus groups' content. As a result of the focus group series, all participants changed their perspectives about ethical issues regarding their planned research, developed the ability to reflect and debate on research ethics and had increased awareness of ethical issues in their own research activities. Half of them made changes in their research work. The study provides a concrete strategy to embed ethics and to strengthen responsibility in laboratory research. It is a strategy that allows to perform ethics reflection "on site" and in "real time" and complements the classic strategy of ethics assessment of the research protocol before starting the research procedure.


X-ray structures of the signal recognition particle receptor reveal targeting cycle intermediates.
The signal recognition particle (SRP) and its conjugate receptor (SR) mediate cotranslational targeting of a subclass of proteins destined for secretion to the endoplasmic reticulum membrane in eukaryotes or to the plasma membrane in prokaryotes. Conserved active site residues in the GTPase domains of both SRP and SR mediate discrete conformational changes during formation and dissociation of the SRP.SR complex. Here, we describe structures of the prokaryotic SR, FtsY, as an apo protein and in two different complexes with a non-hydrolysable GTP analog (GMPPNP). These structures reveal intermediate conformations of FtsY containing GMPPNP and explain how the conserved active site residues position the nucleotide into a non-catalytic conformation. The basis for the lower specificity of binding of nucleotide in FtsY prior to heterodimerization with the SRP conjugate Ffh is also shown. We propose that these structural changes represent discrete conformational states assumed by FtsY during targeting complex formation and dissociation.


Direction-specific interactions control crystal growth by oriented attachment.
The oriented attachment of molecular clusters and nanoparticles in solution is now recognized as an important mechanism of crystal growth in many materials, yet the alignment process and attachment mechanism have not been established. We performed high-resolution transmission electron microscopy using a fluid cell to directly observe oriented attachment of iron oxyhydroxide nanoparticles. The particles undergo continuous rotation and interaction until they find a perfect lattice match. A sudden jump to contact then occurs over less than 1 nanometer, followed by lateral atom-by-atom addition initiated at the contact point. Interface elimination proceeds at a rate consistent with the curvature dependence of the Gibbs free energy. Measured translational and rotational accelerations show that strong, highly direction-specific interactions drive crystal growth via oriented attachment.


Membrane-mediated neuroprotection by curcumin from amyloid-β-peptide-induced toxicity.
Amyloid-β peptide (Aβ)-membrane interactions have been implicated in the formation of toxic oligomers that permeabilize membranes, allowing an influx of calcium ions and triggering cell death in the pathogenesis of Alzheimer's disease (AD). Curcumin, a small dietary polyphenolic molecule, has been shown to reduce Aβ-induced toxicity and AD pathology. We investigate here the effect of curcumin on Aβ40-induced toxicity in cultured human neuroblastoma SH-SY5Y cells and test a novel neuroprotection mechanism in which curcumin reduces Aβ-membrane interactions and attenuates Aβ-induced membrane disruptions. Predominantly monomeric Aβ40 exerts toxicity toward SH-SY5Y cells and has been shown to insert spontaneously into anionic lipid monolayers at the air/water interface, resulting in the misfolding and assembly of Aβ into β-sheet-enriched oligomers. Concomitantly, membrane morphology and lipid packing are disrupted. Curcumin dose-dependently ameliorates Aβ-induced neurotoxicity and reduces either the rate or extent of Aβ insertion into anionic lipid monolayers. Moreover, curcumin reduces Aβ-induced dye leakage from lipid-bilayer-covered, dye-loaded, porous silica microspheres. Because curcumin neither affects the inherent surface activity of Aβ nor modifies the membrane properties, it reduces Aβ insertion by directly attenuating Aβ-membrane interactions and reducing Aβ-induced membrane disruption. Although the exact molecular mechanism of curcumin's membrane protective effect remains unclear, this effect could in part contribute to curcumin's neuroprotective effect with respect to Aβ-induced toxicity. Our work reveals a novel molecular mechanism by which curcumin reduces Aβ-related pathology and toxicity and suggests a therapeutic strategy for preventing or treating AD by targeting the inhibition of Aβ-induced membrane disruption.


Attitudes of Medicare-eligible Americans toward mail service pharmacy.
For many years, community pharmacies provided mail delivery as a convenience for a small segment of special circumstance patients who requested it. Fueled by a movement among plan sponsors and prescription benefit managers to encourage or require its use, growth in mail service pharmacy began to accelerate in the 1980s and now accounts for nearly 25% of the market in the general population and a much higher percentage of seniors. To assess the attitudes of Medicare-eligible Americans toward concerns that have been raised about mail service pharmacy and its mandated use in the prescription benefit plans of public and private insurance programs. Existing published literature was reviewed, and interviews were conducted with Medicare-eligible persons aged 65 and older to identify potential areas of concern with mail order pharmacy services. A survey was constructed and mailed to a nationally representative random sample of 6,500 persons between the ages of 65 and 79 in July 2012. By the cutoff date, 669 completed surveys had been received, and an additional 221 had been returned as undeliverable, resulting in an overall response rate of 10.7%. Nearly half of respondents listed chain pharmacy as their primary source of prescription medications (47.7%) followed by mail service (34.1%), independent pharmacy (13.1%), and other (5.1%). Responses of seniors residing in rural zip codes compared with those in nonrural zip codes demonstrated significantly higher agreement with several concerns, including lost or stolen medications, receiving the exact medication the physician prescribed, and the effects of exposure to heat, cold, or moisture. Two additional concerns approached statistical significance: the ability to speak with a pharmacist face-to-face and the ability to obtain medications quickly if needed. A total of 533 (83.7%) indicated they would oppose mandated mail order in their current benefit plan if it would cause the local community pharmacy they rely on for immediate medication needs to close. The mean risk of such an eventuality that respondents were willing to accept was 42.2%, indicating they would oppose mandatory mail order if there were greater than about a 4-in-10 chance it would cause the loss of their local pharmacy. Seniors appear to be practical and pragmatic about the sources of their prescription medications. While most see a role for mail service pharmacy, they are also aware of its limitations. Many have needs they believe cannot be adequately met by mail service or have relationships with local pharmacies and pharmacists they believe are important for maintaining their health and well-being. As a result, seniors are relatively risk averse when it comes to the loss of their local community pharmacy, even if they routinely use mail order for most of their medications. Beyond their specific concerns, most seniors oppose any restrictions on their freedom to use the pharmacy of their choice on general principle.


Effect of growth differentiation factor 5 on the proliferation and tenogenic differentiation potential of human mesenchymal stem cells in vitro.
The use of growth differentiation factor 5 (GDF-5) in damaged tendons has been shown to improve tendon repair. It has been hypothesized that further improvements may be achieved when GDF-5 is used to promote cell proliferation and induce tenogenic differentiation in human bone marrow-derived mesenchymal stem cells (hMSCs). However, the optimal conditions required to produce these effects on hMSCs have not been demonstrated in previous studies. A study to determine cell proliferation and tenogenic differentiation in hMSCs exposed to different concentrations of GDF-5 (0, 5, 25, 50, 100 and 500 ng/ml) was thus conducted. No significant changes were observed in the cell proliferation rate in hMSCs treated at different concentrations of GDF-5. GDF-5 appeared to induce tenogenic differentiation at 100 ng/ml, as reflected by (1) a significant increase in total collagen expression, similar to that of the primary native human tenocyte culture; (2) a significant upregulation in candidate tenogenic marker gene expression, i.e. scleraxis, tenascin-C and type-I collagen; (3) the ratio of type-I collagen to type-III collagen expression was elevated to levels similar to that of human tenocyte cultures, and (4) a significant downregulation of the non-tenogenic marker genes runt-related transcription factor 2 and sex determining region Y (SRY)-box 9 at day 7 of GDF-5 induction, further excluding hMSC differentiation into other lineages. In conclusion, GDF-5 does not alter the proliferation rates of hMSCs, but, instead, induces an optimal tenogenic differentiation response at 100 ng/ml.


PRD--a protein domain involved in PTS-dependent induction and carbon catabolite repression of catabolic operons in bacteria.
Several operon-specific transcriptional regulators, including antiterminators and activators, contain a duplicated conserved domain, the PTS regulation domain (PRD). These duplicated domains modify the activity of the transcriptional regulators both positively and negatively. PRD-containing regulators are very common in Gram-positive bacteria. In contrast, antiterminators controlling beta-glucoside utilization are the only functionally characterized members of this family from gram-negative bacteria. PRD-containing regulators are controlled by PTS-dependent phosphorylation with different consequences: (i) In the absence of inducer, the phosphorylated EIIB component of the sugar permease donates its phosphate to a PRD, thereby inactivating the regulator. In the presence of the substrate, the regulator is dephosphorylated, and the phosphate is transferred to the sugar, resulting in induction of the operon. (ii) In gram-positive bacteria, a novel mechanism of carbon catabolite repression mediated by PRD-containing regulators has been demonstrated. In the absence of PTS substrates, the HPr protein is phosphorylated by enzyme I at His-15. This form of HPr can, in turn, phosphorylate PRD-containing regulators and stimulate their activity. In the presence of rapidly metabolizable carbon sources, ATP-dependent phosphorylation of HPr at Ser-46 by HPr kinase inhibits phosphorylation by enzyme I, and PRD-containing regulators cannot, therefore, be stimulated and are inactive. All regulators of this family contain two copies of PRD, which are functionally specialized in either induction or catabolite repression.


Fertility transition in Bangladesh: understanding the role of the proximate determinants.
Bangladesh has been passing through a crucial phase of fertility transition. The level of fertility declined dramatically during the early 1990s without any remarkable improvement in socioeconomic and health status, and then remained constant at a high level of 3.3, despite the increased use of contraception. Such fertility transition can be traced to variations in one or more of the proximate or direct determinants of fertility. This paper critically analyses the fertility levels in Bangladesh with a view to exploring the possible explanations of fertility decline in the 1990s and then its stabilization. The main focus of the study is to examine the role of the major proximate determinants of fertility in bringing about the change in fertility level in Bangladesh. The data for the study come from a series of nationally representative surveys over the period of 1975 to 1999-2000. The analysis indicates that fertility has temporarily ceased to decline in recent years due to the 'tempo' effect of high past fertility, but in general a declining trend in fertility is underway. The analysis suggests that the fall in fertility is consistent with the underlying trends in most important proximate determinants of fertility. In recent years contraception has emerged as the highest fertility reducing factor in Bangladesh and its effect is greatest in middle and older age groups. Although until the early 1990s postpartum lactational infecundability was the most important and strongest fertility reducing factor in Bangladesh, in recent years its fertility inhibiting effect has gradually decreasing owing to the declining trend in the lactational infecundability period. The analysis reveals that although the fertility reducing effect of the marriage pattern is increasing, its effect is offset by the declining trend in the lactational infecundability period. A review of these two variables suggests that their effect cannot be raised much for prevailing socioeconomic and cultural reasons, and any future reduction in fertility in Bangladesh may be largely dependent on increased use of effective birth control methods.


Performance scaling comparison for free-space optical and electrical interconnection approaches.
Projected performance metrics of free-space optical and electrical interconnections are estimated and compared in terms of smart-pixel input-output bandwidth density and practical geometric packaging constraints. The results suggest that three-dimensional optical interconnects based on smart pixels provide the highest volume, latency, and power-consumption benefits for applications in which globally interconnected networks are required to implement links across many integrated-circuit chips. It is further shown that interconnection approaches based on macro-optical elements achieve better scaling than those based on micro-optical elements. The scaling limits of micro-optical-based architectures stem from the need for repeaters to overcome diffraction losses in multichip architectures with high bisection bandwidth. The overall results provide guidance in determining whether and how strongly a free-space optical interconnection approach can be applied to a given multiprocessor problem.


Nodulisporol and Nodulisporone, novel specific inhibitors of human DNA polymerase lambda from a fungus, Nodulisporium sp.
Tetralols 1 and 2, dihydroisocoumarins 3-6, and chromone 7 are natural compounds isolated from cultures of fungi, and their structures were determined by spectroscopic analyses. Compounds 1 and 2 from Nodulisporium sp. are novel tetralols, 1,2,3,4-tetrahydro-5-methoxynaphthalene-1,4-diol (nodulisporol) and 3,4-dihydro-4-hydroxy-8-methoxynaphthalen-1(2H)-one (nodulisporone), respectively. All isolated compounds selectively inhibited the activity of human DNA polymerase lambda (pol lambda), and compound 5 (3,5-dimethyl-8-methoxy-3,4-dihydroisocoumarin) was the strongest inhibitor of pol lambda in the tested compounds with an IC(50) value of 49 microM. New tetralols (1 and 2) are the third and second strongest inhibitors of pol lambda, but did not influence the activities of mammalian pols alpha to kappa, and showed no effect even on the activities of plant pols alpha and beta, prokaryotic pols, and other DNA metabolic enzymes such as calf terminal deoxynucleotidyl transferase, human immunodeficiency virus type-1 (HIV-1) reverse transcriptase, human telomerase, T7 RNA polymerase, and bovine deoxyribonuclease I. The structure-activity relationships of isolated compounds such as novel tetralols, dihydroisocoumarins, and chromone are discussed.


The second transmembrane domain of P2X7 contributes to dilated pore formation.
Activation of the purinergic receptor P2X7 leads to the cellular permeability of low molecular weight cations. To determine which domains of P2X7 are necessary for this permeability, we exchanged either the C-terminus or portions of the second transmembrane domain (TM2) with those in P2X1 or P2X4. Replacement of the C-terminus of P2X7 with either P2X1 or P2X4 prevented surface expression of the chimeric receptor. Similarly, chimeric P2X7 containing TM2 from P2X1 or P2X4 had reduced surface expression and no permeability to cationic dyes. Exchanging the N-terminal 10 residues or C-terminal 14 residues of the P2X7 TM2 with the corresponding region of P2X1 TM2 partially restored surface expression and limited pore permeability. To further probe TM2 structure, we replaced single residues in P2X7 TM2 with those in P2X1 or P2X4. We identified multiple substitutions that drastically changed pore permeability without altering surface expression. Three substitutions (Q332P, Y336T, and Y343L) individually reduced pore formation as indicated by decreased dye uptake and also reduced membrane blebbing in response to ATP exposure. Three others substitutions, V335T, S342G, and S342A each enhanced dye uptake, membrane blebbing and cell death. Our results demonstrate a critical role for the TM2 domain of P2X7 in receptor function, and provide a structural basis for differences between purinergic receptors.


Surgical management of neonatal atrioventricular septal defect with aortic arch obstruction.
For neonates with atrioventricular septal defect and aortic arch obstruction including coarctation of the aorta, we sought to determine whether a difference in outcomes exists after a primary neonatal versus staged surgical repair (neonatal arch repair with delayed intracardiac repair). This retrospective cohort study included consecutive neonates with atrioventricular septal defect and aortic arch obstruction who underwent cardiac surgery before 28 days of age at six centers from 1990 to 2009. Characteristics and outcomes between patients undergoing neonatal versus staged repair were compared. Of 66 study patients, 31 (47%) underwent primary neonatal repair and 35 (53%) underwent staged repair. At baseline echocardiogram, a greater percentage of neonatal repair patients had relative unbalanced ventricular size (56% versus 35%, p = 0.02). There were no other differences in demographic characteristics, cardiac anatomical or functional details, or surgical technique. Those undergoing neonatal repair tended to be more likely to have at least moderate left atrioventricular valve regurgitation early after repair (42% versus 19%, p = 0.05) and to have at least one major in-hospital complication (42% versus 20%, p = 0.06). After the initial cardiac operation, compared with the neonatal repair group, patients undergoing staged repair had greater survival (87% versus 57% at 6 years, log-rank p = 0.02) and freedom from the first unplanned cardiac reoperation (69% versus 45% at 6 years, log-rank p = 0.005). For neonates with atrioventricular septal defect and aortic arch obstruction, when compared with neonatal repair, a staged approach was associated with improved survival and lower morbidity.


Early gonadal development: exploring Wt1 and Sox9 function.
Prior to sex determination the gonadal anlage is formed as a bipotential primordium with the capacity to differentiate into either testes or ovaries depending on the presence or absence of the Sry gene. Knockout experiments have implicated five genes in the formation or survival of the gonadal primordium: Wt1, Sf1, Lim1, Lhx9 and Emx2. We are particularly interested in the Wilms tumour suppressor, WT1, which is characterized by complex posttranscriptional modifications. Here we will focus on published in vitro evidence suggesting distinct functions for the various isoforms and present our own results from in vivo experiments. Our data suggest that WT1 is an important regulator of the transcription or stability of the sex-determining gene Sry. One of the first genes expressed after the initial male sex-determining signal is the Sox9 gene. Human SOX9 has been implicated in male-to-female sex reversal. To analyse Sox9 function in mouse development we have performed transgenic experiments and ectopically expressed this gene in XX gonads. Our data indicate that Sox9 is sufficient to induce testis formation in mice. Here we will discuss our new data and present an updated model for Wt1 and Sox9 function in gonad formation and sex determination.


The Growing Curvilinear Component Analysis (GCCA) neural network.
Big high dimensional data is becoming a challenging field of research. There exist a lot of techniques which infer information. However, because of the curse of dimensionality, a necessary step is the dimensionality reduction (DR) of the information. DR can be performed by linear and nonlinear algorithms. In general, linear algorithms are faster because of less computational burden. A related problem is dealing with time-varying high dimensional data, where the time dependence is due to nonstationary data distribution. Data stream algorithms are not able to project in lower dimensional spaces. Indeed, only linear projections, like principal component analysis (PCA), are used in real time while nonlinear techniques need the whole database (offline). The Growing Curvilinear Component Analysis (GCCA) neural network addresses this problem; it has a self-organized incremental architecture adapting to the changing data distribution and performs simultaneously the data quantization and projection by using CCA, a nonlinear distance-preserving reduction technique. This is achieved by introducing the idea of "seed", pair of neurons which colonize the input domain, and "bridge", a novel kind of edge in the manifold graph, which signals the data non-stationarity. Some artificial examples and a real application are given, with a comparison with other existing techniques.


Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer's disease: results of a randomized, double-blind, placebo-controlled phase 2a study.
PQ912 is an inhibitor of the glutaminyl cyclase enzyme that plays a central role in the formation of synaptotoxic pyroglutamate-A-beta oligomers. We report on the first clinical study with PQ912 in subjects with biomarker-proven Alzheimer's disease (AD). The aim was to determine the maximal tolerated dose, target occupancy and treatment-related pharmacodynamic effects. The exploratory efficacy readouts selected were tailored to the patient population with early AD. The therapeutic approach focuses on synaptic dysfunction as captured by various measures such as electroencephalography (EEG), synaptic biomarkers and sensitive cognitive tests. This was a randomized, double-blind, placebo-controlled trial evaluating the safety, tolerability and efficacy of PQ912 800 mg twice daily (bid) for 12 weeks in subjects with mild cognitive impairment or mild dementia due to AD. The 120 enrolled subjects were treatment-naïve at the start of the study, had confirmed AD biomarkers in their cerebrospinal fluid at screening and had a Mini Mental State Examination score between 21 and 30. After 1 week of treatment with 400 mg bid, patients were up-titrated to 800 mg bid for 11 weeks. Patients were randomized 1:1 to either PQ912 or placebo. The primary composite endpoints were to assess safety and tolerability based on the number of patients who discontinued due to (serious) adverse events (safety), and based on dose adjustment during the treatment period and/or nonadherence to randomized treatment (tolerability). All randomized subjects who took at least one dose of the study treatment or placebo were used for safety analyses. There was no significant difference between treatments in the number of subjects with (serious) adverse events, although there were slightly more patients with a serious adverse event in the PQ912 group compared to placebo. More subjects treated with PQ912 discontinued treatment due to adverse events, mostly related to gastrointestinal and skin/subcutaneous tissue disorders. PQ912 treatment resulted in a significant reduction in glutaminyl cyclase activity, which resulted in an average target occupancy of > 90%. A significant reduction of theta power in the EEG frequency analysis and a significant improvement in the One Back test of our Neuropsychological Test Battery was observed. The exploratory biomarker readouts, neurogranin for synaptic toxicity and YKL-40 as a marker of inflammation, appear to be sensitive enough to serve as efficacy markers in the next phase 2b study. The maximal tolerated dose of PQ912 has been identified and the results support future studies at still lower doses reaching > 50% target occupancy, a longer up-titration phase to potentially induce adaptation and longer treatment periods to confirm the early signals of efficacy as seen in this study. Clinicaltrials.gov, NCT 02389413 . Registered on 17 March 2015.


Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy.
Expansion of a CTG trinucleotide repeat in the 3' UTR of the gene DMPK at the DM1 locus on chromosome 19 causes myotonic dystrophy, a dominantly inherited disease characterized by skeletal muscle dystrophy and myotonia, cataracts and cardiac conduction defects. Targeted deletion of Dm15, the mouse orthologue of human DMPK, produced mice with a mild myopathy and cardiac conduction abnormalities, but without other features of myotonic dystrophy, such as myotonia and cataracts. We, and others, have demonstrated that repeat expansion decreases expression of the adjacent gene SIX5 (refs 7,8), which encodes a homeodomain transcription factor. To determine whether SIX5 deficiency contributes to the myotonic dystrophy phenotype, we disrupted mouse Six5 by replacing the first exon with a beta-galactosidase reporter. Six5-mutant mice showed reporter expression in multiple tissues, including the developing lens. Homozygous mutant mice had no apparent abnormalities of skeletal muscle function, but developed lenticular opacities at a higher rate than controls. Our results suggest that SIX5 deficiency contributes to the cataract phenotype in myotonic dystrophy, and that myotonic dystrophy represents a multigenic disorder.


Benefits of electroanatomic ablation of conventional cardiac arrhytmias: from fluoroscopy to zero X-ray mapping.
Electrophysiology procedures are traditionally performed under fluoroscopic guidance. Nowadays a growing interest in the radiation risk associated to these procedures has been cultivated, since radiation exposure has non-negligible stochastic and deterministic effects on health. A correlation between radiation exposure and lifetime malignancy effect is difficult to establish and the threshold of a completely safe exposure dose is unknown. Thus, electrophisiologists have become aware of the use of fluoroscopy and they have tried to use all the complementary imaging technologies available in order to reduce the radiological exposure. This review is aimed at evaluating the radiation exposure risk, both for the patients and the operators. We describe electroanatomical mapping systems and technologies, which allow the reduction of radiation exposure. We review the main literature based on different catheter ablation procedures with the use of the abovementioned technologies, specifically focusing on feasibility, safety, and radiation exposure. Finally, we highlight the necessity of increasing the radiological risk awareness among operators and cardiological scientific societies.