The bijection from data to parameter space with the standard DEB model quantifies the supply-demand spectrum.
The standard Dynamic Energy Budget (DEB) model assumes that food is converted to reserve and a fraction κ of mobilised reserve of an individual is allocated to somatic maintenance plus growth, while the rest is allocated to maturity maintenance plus maturation (in embryos and juveniles) or reproduction (in adults). The add_my_pet collection of over 300 animal species from most larger phyla, and all chordate classes, shows that this model fits energy data very well. Nine parameters determine nine data points at abundant food: dry/wet weight ratio, age at birth, puberty, death, weight at birth, metamorphosis, puberty, ultimate weight and ultimate reproduction rate. We demonstrate that, given a few other parameters, these nine data points also determine the nine parameters uniquely that are independent of food availability: maturity at birth, metamorphosis and puberty, specific assimilation, somatic maintenance and costs for structure, allocation fraction of mobilised reserve to soma, energy conductance, and ageing acceleration. We provide an efficient algorithm for mapping between data and parameter space in both directions and found expressions for the boundaries of the parameter and data spaces. One of them quantifies the position of species in the supply-demand spectrum, which reflects the internalisation of energetic control. We link eco-physiological properties of species to their position in this spectrum and discuss it in the context of homeostasis. Invertebrates and ray-finned fish turn out to be close to the supply end of the spectrum, while other vertebrates, including cartilaginous fish, have stronger demand tendencies. We explain why birds and mammals up-regulate metabolism during reproduction. We study some properties of the bijection using elasticity coefficients. The properties have applications in parameter estimation and in the analysis of evolutionary constraints on parameter values; the relationship between DEB parameters and data has similarities to that between genotype and phenotype.


Differential Signaling Profiles of MC4R Mutations with Three Different Ligands.
The melanocortin 4 receptor (MC4R) is a key player in hypothalamic weight regulation and energy expenditure as part of the leptin-melanocortin pathway. Mutations in this G protein coupled receptor (GPCR) are the most common cause for monogenetic obesity, which appears to be mediated by changes in the anorectic action of MC4R via GS-dependent cyclic adenosine-monophosphate (cAMP) signaling as well as other signaling pathways. To study potential bias in the effects of MC4R mutations between the different signaling pathways, we investigated three major MC4R mutations: a GS loss-of-function (S127L) and a GS gain-of-function mutant (H158R), as well as the most common European single nucleotide polymorphism (V103I). We tested signaling of all four major G protein families plus extracellular regulated kinase (ERK) phosphorylation and β-arrestin2 recruitment, using the two endogenous agonists, α- and β-melanocyte stimulating hormone (MSH), along with a synthetic peptide agonist (NDP-α-MSH). The S127L mutation led to a full loss-of-function in all investigated pathways, whereas V103I and H158R were clearly biased towards the Gq/11 pathway when challenged with the endogenous ligands. These results show that MC4R mutations can cause vastly different changes in the various MC4R signaling pathways and highlight the importance of a comprehensive characterization of receptor mutations.


Hazards identified and the need for health risk assessment in the South African mining industry.
Although mining plays a prominent role in the economy of South Africa, it is associated with many chemical hazards. Exposure to dust from mining can lead to many pathological effects depending on mineralogical composition, size, shape and levels and duration of exposure. Mining and processing of minerals also result in occupational exposure to toxic substances such as platinum, chromium, vanadium, manganese, mercury, cyanide and diesel particulate. South Africa has set occupational exposure limits (OELs) for some hazards, but mine workers are still at a risk. Since the hazard posed by a mineral depends on its physiochemical properties, it is recommended that South Africa should not simply adopt OELs from other countries but rather set her own standards based on local toxicity studies. The limits should take into account the issue of mixtures to which workers could be exposed as well as the health status of the workers. The mining industry is also a source of contamination of the environment, due inter alia to the large areas of tailings dams and dumps left behind. Therefore, there is need to develop guidelines for safe land-uses of contaminated lands after mine closure.


Effect of sera from AChR-antibody negative myasthenia gravis patients on AChR and MuSK in cell cultures.
A proportion of patients with myasthenia gravis (MG) do not have antibodies to the acetylcholine receptor (AChR). Some of these patients have antibodies to muscle specific kinase (MuSK), whereas others have neither antibody (seronegative MG, SNMG). Both MuSK antibody positive MG (MuSK-MG) and SNMG are antibody-mediated diseases but how they cause neuromuscular junction failure is not clear. One possibility is that they reduce the clustering and expression of AChRs. We looked at the effects of MuSK-MG and SNMG sera/IgG on surface AChR distribution and expression, and AChR subunit and MuSK mRNA by quantitative RT-PCR, in TE671 and C2C12 myotubes. In TE671 cells MuSK-MG sera reduced AChR expression by about 20%, but had no effect on AChR subunit or MuSK mRNA expression. In C2C12 myotubes, MuSK-MG sera caused a reduction in the number of agrin-induced clusters, but the clusters became larger and there was no significant effect on total surface AChR numbers or AChR subunit or MuSK mRNA. By contrast, SNMG sera not only reduced AChR numbers by about 20% in TE671 cells, but modestly upregulated AChR gamma subunit expression in TE671 cells and both AChR gamma subunit and MuSK expression in C2C12 myotubes. Thus, although these results have, disappointingly, demonstrated little effect of MuSK antibodies on AChR expression, they do imply that SNMG antibodies act on AChR-associated pathways.


An integrative review of lateral line depigmentation in marine and freshwater fish.
To qualitatively review reports on lateral line depigmentation (LLD) in marine and freshwater fish. English-language publications concerning LLD published before March 1, 2020. Electronic searches of CAB abstracts, PubMed, and Web of Science databases and the proceedings of the International Association of Aquatic Animal Medicine were performed. Records were systematically screened and selected for inclusion in an integrative review. Bibliographies of records included in the review were examined to identify other records to be screened. Included records were qualitatively reviewed. Evidence level and quality were graded according to previously described criteria. Information pertinent to epidemiological factors, etiopathogenesis, clinical and histopathologic findings, treatment, and prevention of LLD was collected. 401 records were screened, and 24 unique publications (16 peer-reviewed articles, 1 textbook, and 7 abstracts) were included in the study; 12 (50%), 1 (4%), 6 (25%), and 5 (21%) were classified as evidence level I (experimental), II (quasi-experimental), III (nonexperimental), and V (clinical reports or clinician experience), respectively. Seventeen (71%) and 7 (29%) reports were classified as high quality and good quality, respectively. LLD should be considered a clinical observation indicative of a dermatologic response of fish to suboptimal conditions; LLD should continue to be adopted as the preferred term to describe the classic signs. Whereas gross findings are similar among species, histologic findings can vary. Evidence-based treatment of LLD for individual fish consists of source control (changing tanks or systems), topical treatment with 0.01% becaplermin gel, supportive care, and antimicrobial treatment when warranted. For schools of fish, treatment and prevention of LLD should be focused on improving suboptimal environmental and physiologic conditions.


Should Mandibular Symphyseal Distraction Osteogenesis be considered in OSA Surgery?
Surgical maxillary expansion for the treatment of obstructive sleep apnea (OSA) has become common place. To maximize airway improvement, over-expansion of the maxilla can occur, resulting in an excessively widened maxilla that creates a mismatch to the mandible. Therefore, mandibular symphyseal distraction osteogenesis (MSDO) to widen the mandible along with maxillary expansion is being increasingly advocated in OSA surgery. The authors discuss their 20-year experience with MSDO and surgical maxillary expansion. They also analyze the airway impact between Distraction Osteogenesis Maxillary Expansion (DOME) and Endoscopically-Assisted Surgical Expansion (EASE) based on currently available computational fluid dynamic (CFD) data, which has implications in whether MSDO needs to be considered. The goal of surgical maxillary expansion is to enlarge the nasal cavity and reduce the airway resistance. CFD data demonstrates that EASE results in a much greater reduction in airway resistance as compared to DOME. EASE achieved a 12-fold reduction in nasal airway resistance compared to 3-fold reduction by DOME; a 12-fold reduction of retropalatal airway resistance as compared to 3-fold reduction by DOME; a 10-fold reduction of oropharyngeal airway resistance as compared to a 3-fold reduction by DOME, and an 8-fold reduction of hypopharygeal airway resistance as compared to a 3-fold reduction by DOME. Because there is no physiologic basis or data that demonstrates mandibular widening improves OSA, an airway centric surgical expansion technique such as EASE can achieve a much greater airway impact without needing excessive maxillary widening, thus eliminating the necessity MSDO.


NEArender: an R package for functional interpretation of 'omics' data via network enrichment analysis.
The statistical evaluation of pathway enrichment, i.e. of gene profiles' confluence to the pathway level, allows exploring molecular landscapes using functionally annotated gene sets. However, pathway scores can also be used as predictive features in machine learning. That requires, firstly, increasing statistical power and biological relevance via a network enrichment analysis (NEA) and, secondly, a fast and convenient procedure for rendering the original data into a space of pathway scores. However, previous implementations of NEA involved multiple runs of network randomization and were therefore slow. Here, we present a new R package NEArender which can transform raw 'omics' features of experimental or clinical samples into matrices describing the same samples with many fewer NEA-based pathway scores. This is done via a parametric estimation of the null binomial distribution and is thus much faster and less biased than randomization procedures. Further, we compare estimates from these two alternative procedures and demonstrate that the summarization of individual genes to pathways increases the statistical power compared to both the default differential expression analysis on individual genes and the state-of-the-art gene set enrichment analysis. The package also contains functions for preparing input, modeling null distributions, and evaluating alternative versions of the global network. Beyond the state-of-the-art exploration of molecular data through pathway enrichment, score matrices produced by NEArender can be used in larger bioinformatics pipelines as input for phenotype modeling, predicting disease outcomes etc. This approach is often more sensitive and robust than using the original data. The package NEArender is complementary to the online NEA tool EviNet ( https://www.evinet.org ) and, unlike of the latter, enables high performance of computations off-line. The R package NEArender version 1.4 is available at CRAN repository https://cran.r-project.org/web/packages/NEArender/.


Enhanced Prophylactic and Therapeutic Effects of Polylysine-Modified Ara h 2 DNA Vaccine in a Mouse Model of Peanut Allergy.
The prevalence of food allergy has been increasing, but treatment is very limited. DNA vaccination has been recognized as a promising method for the treatment of allergic diseases; however, poor immunogenicity has hindered its application. BALB/c mice were intradermally injected with plasmid DNA encoding the peanut protein Ara h 2 (pAra h 2) or pAra h 2 pretreated with poly-L- lysine (PLL) before or after sensitization with Ara h 2 protein. Ara h 2-specific antibodies were measured by ELISA. CD207+ dendritic cells (DCs) and Treg cells in draining lymph nodes were analyzed by flow cytometry after DNA immunization, and cytokine production in splenocytes was also analyzed. In the prophylactic study, pretreatment with pAra h 2 or PLL-pAra h 2 resulted in lower levels of Ara h 2-specific IgG1, IgG2a, and IgE after sensitization with Ara h 2 protein, and mice in the PLL-pAra h 2 group had a significantly lower level of antibodies than those in the pAra h 2 group. In the treatment study, intradermal injection with pAra h 2 or PLL-pAra h 2 after Ara h 2 protein sensitization significantly decreased the level of Ara h 2-specific antibodies, and PLL- pAra h 2 had stronger effects than pAra h 2. There were increased numbers of CD207+ DCs and Treg cells in the mice receiving intradermal injection with PLL-pAra h 2, and splenocytes from PLL-pAra h 2-treated mice secreted increased levels of IFN-γ and IL-10. Modification of pAra h 2 with PLL improved its prophylactic and therapeutic effects in peanut-allergic mice.


Pollen and spores date origin of rift basins from Texas to nova scotia as early late triassic.
Palynological studies of the nonmarine Newark Supergroup of eastern North America and of rift basins in the northern Gulf of Mexico facilitate correlation with well-dated marine sections of Europe. New information emphasizes the chronological link between the Newark basins and a Gulf of Mexico basin and their common history in the rifting of North America from Pangea. Shales from the subsurface South Georgia Basin are shown to be of late Karnian age (early Late Triassic). The known time of earliest sedimentation in the Culpeper Basin is extended from Norian (late Late Triassic) to mid-Karnian, and the date of earliest sedimentation in the Richmond and Deep River basins is moved to at least earliest Karnian, perhaps Ladinian. The subsurface Eagle Mills Formation in Texas and Arkansas has been dated palynologically as mid- to late Karnian. The oldest parts of the Newark Supergroup, and the Eagle Mills Formation, mostly began deposition in precursor rift basins that formed in Ladinian to early Karnian time. In the southern Newark basins, sedimentation apparently ceased in late Karnian but continued in the northern basins well into the Jurassic, until genesis of the Atlantic ended basin sedimentation.


Structural characterization and immunomodulatory activity of a new heteropolysaccharide from Prunella vulgaris.
A new heteropolysaccharide, here called P1, was isolated from the fruit clusters of Prunella vulgaris using a hot water extraction method. Chemical and physical analyses indicated that P1 had a spherical conformation with an average molecular weight of 1750 kDa and consisted of arabinose (28.37%), xylose (54.67%), mannose (5.61%), glucose (5.46%), and galactose (5.89%). The main types of P1 linkages were proved to be (1→5)-linked α-L-Ara, (1→)-linked α-L-Ara, (1→3)-linked α-D-xyl, (1→3)-linked β-D-Gal, (1→3,6)-linked β-D-Gal, (1→3,6)-linked α-D-Man and (1→6)-linked α-D-Glc according to the periodate oxidation-Smith degradation and NMR analyses. P1 could significantly enhance the secretion of NO, TNF-α, and IL-6 in murine RAW 264.7 cells, involving the toll-like receptor 2 (TLR2), TLR4 and complement receptor 3 (CR3). Further studies showed that P1 exhibited stable immune activities in the pH range of 4.0-10.0 and below 121 °C. The results suggested that P1 could be used as a potent immunomodulatory agent in functional foods and pharmacological fields.


Modeling to link regional myocardial work, metabolism and blood flows.
Given the mono-functional, highly coordinated processes of cardiac excitation and contraction, the observations that regional myocardial blood flows, rMBF, are broadly heterogeneous has provoked much attention, but a clear explanation has not emerged. In isolated and in vivo heart studies the total coronary flow is found to be proportional to the rate-pressure product (systolic mean blood pressure times heart rate), a measure of external cardiac work. The same relationship might be expected on a local basis: more work requires more flow. The validity of this expectation has never been demonstrated experimentally. In this article we review the concepts linking cellular excitation and contractile work to cellular energetics and ATP demand, substrate utilization, oxygen demand, vasoregulation, and local blood flow. Mathematical models of these processes are now rather well developed. We propose that the construction of an integrated model encompassing the biophysics, biochemistry and physiology of cardiomyocyte contraction, then combined with a detailed three-dimensional structuring of the fiber bundle and sheet arrangements of the heart as a whole will frame an hypothesis that can be quantitatively evaluated to settle the prime issue: Does local work drive local flow in a predictable fashion that explains the heterogeneity? While in one sense one can feel content that work drives flow is irrefutable, the are no cardiac contractile models that demonstrate the required heterogeneity in local strain-stress-work; quite the contrary, cardiac contraction models have tended toward trying to show that work should be uniform. The object of this review is to argue that uniformity of work does not occur, and is impossible in any case, and that further experimentation and analysis are necessary to test the hypothesis.


A novel counter-selection method for markerless genetic modification in Synechocystis sp. PCC 6803.
The cyanobacterium Synechocystis sp. PCC 6803 is a photosynthetic organism capable of efficient harnessing of solar energy while capturing CO(2) from the environment. Methods to genetically alter its genomic DNA are essential for elucidating gene functions and are useful tools for metabolic engineering. In this study, a novel counter-selection method for the genetic alteration of Synechocystis was developed. This method utilizes the nickel inducible expression of mazF, a general protein synthesis inhibitor, as a counter-selection marker. Counter-selection is particularly useful because the engineered strain is free of any markers which make further genetic modification independent of available antibiotic resistance genes. The usability of this method was further demonstrated by altering genes at several loci in two variants of Synechocystis.


A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department.
We examined the preliminary feasibility, tolerability and efficacy of single-dose, intravenous (i.v.) ketamine in depressed emergency department (ED) patients with suicide ideation (SI). Fourteen depressed ED patients with SI received a single i.v. bolus of ketamine (0.2 mg/kg) over 1-2 min. Patients were monitored for 4 h, then re-contacted daily for 10 d. Treatment response and time to remission were evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS) and Kaplan-Meier survival analysis, respectively. Mean MADRS scores fell significantly from 40.4 (s.e.m.=1.8) at baseline to 11.5 (s.e.m.=2.2) at 240 min. Median time to MADRS score ≤10 was 80 min (interquartile range 0.67-24 h). SI scores (MADRS item 10) decreased significantly from 3.9 (s.e.m.=0.4) at baseline to 0.6 (s.e.m. =0.2) after 40 min post-administration; SI improvements were sustained over 10 d. These data provide preliminary, open-label support for the feasibility and efficacy of ketamine as a rapid-onset antidepressant in the ED.


Deep learning for healthcare: review, opportunities and challenges.
Gaining knowledge and actionable insights from complex, high-dimensional and heterogeneous biomedical data remains a key challenge in transforming health care. Various types of data have been emerging in modern biomedical research, including electronic health records, imaging, -omics, sensor data and text, which are complex, heterogeneous, poorly annotated and generally unstructured. Traditional data mining and statistical learning approaches typically need to first perform feature engineering to obtain effective and more robust features from those data, and then build prediction or clustering models on top of them. There are lots of challenges on both steps in a scenario of complicated data and lacking of sufficient domain knowledge. The latest advances in deep learning technologies provide new effective paradigms to obtain end-to-end learning models from complex data. In this article, we review the recent literature on applying deep learning technologies to advance the health care domain. Based on the analyzed work, we suggest that deep learning approaches could be the vehicle for translating big biomedical data into improved human health. However, we also note limitations and needs for improved methods development and applications, especially in terms of ease-of-understanding for domain experts and citizen scientists. We discuss such challenges and suggest developing holistic and meaningful interpretable architectures to bridge deep learning models and human interpretability.


[Development of an action scale to show the necessity of healthcare activities].
In order to promote high-quality healthcare activities, public health professionals such as public health nurses must improve their ability to systematically show health needs based on evidence and to lead decision making of superior officers and facility inhabitants for improved planning. This study developed and investigated its reliability and validity of an action scale to show the necessity of healthcare activities (SNH). The items in the SNH were originally selected based on previous studies and refined by researchers; they were subsequently adjusted after a pilot survey. The subjects were full-time public health nurses (PHNs) working at prefectural public health centers or randomly chosen municipal health centers. Questionnaires were distributed by mail. We explained the ethical considerations in writing and those who returned completed questionnaire forms were considered to have given their consent to participate in the study. The study plan was approved by the university Domestic Ethics Committee. Among 1,615 questionnaire recipients, 1,088 (67.4%) responded; of these, 1,035 (64.1%) responses were valid. Nineteen of 20 items were selected based on results of item analysis, and exploratory and confirmatory factor analyses showed that the SNH consisted of four factors: show existence of health needs, show evidence for the necessity of addressing health needs, show actual conditions requiring solution, and show priority for resolution. Cronbach's alpha, an SNH reliability coefficient, was 0.948, and individual factor scores were over 0.85, supporting the internal consistency of SNH. The correlation coefficient between SNH and the three other scales including related concepts was 0.6-0.8, with significant differences between scales, supporting the criterion-related validity of SNH. The score increased with increasing PHN experience and job seniority, which were used as the known-group, with significant differences between the lowest group and the top two groups. The results confirmed that SNH is a reliable and valid scale to show the necessity of healthcare activities.


GPNN: power studies and applications of a neural network method for detecting gene-gene interactions in studies of human disease.
The identification and characterization of genes that influence the risk of common, complex multifactorial disease primarily through interactions with other genes and environmental factors remains a statistical and computational challenge in genetic epidemiology. We have previously introduced a genetic programming optimized neural network (GPNN) as a method for optimizing the architecture of a neural network to improve the identification of gene combinations associated with disease risk. The goal of this study was to evaluate the power of GPNN for identifying high-order gene-gene interactions. We were also interested in applying GPNN to a real data analysis in Parkinson's disease. We show that GPNN has high power to detect even relatively small genetic effects (2-3% heritability) in simulated data models involving two and three locus interactions. The limits of detection were reached under conditions with very small heritability (<1%) or when interactions involved more than three loci. We tested GPNN on a real dataset comprised of Parkinson's disease cases and controls and found a two locus interaction between the DLST gene and sex. These results indicate that GPNN may be a useful pattern recognition approach for detecting gene-gene and gene-environment interactions.


Accommodative hysteresis. Fundamental asymmetry in decay rate after near and far focusing.
The resting level of accommodation, or dark focus (DF), was compared before and after subjects maintained 8-min of clear focus on targets either at the far point (FP) of accommodation or at an equivalent dioptric distance on the near side of the DF. Although both conditions showed significant shifts in tonic accommodation in the direction of their respective fixation targets, only after near fixation was the shift maintained in darkness for 24-min postfixation. After FP viewing the aftereffect decayed in darkness with a significant linear trend (P less than 0.05). Thus, maintaining focus on a near target is more likely to induce an enduring adaptive shift in tonic accommodation than is far-target viewing, for reasons associated with the systems controlling far and near accommodation, respectively. Additional analyses provided further evidence that the degree of separation of the target from the DF is a highly significant factor controlling individual differences in initial adaptation levels.


Influence of substituents on reductive dehalogenation of 3-chlorobenzoate analogs.
The biochemical effects of aryl substituents on the reductive dechlorination of 3-chlorobenzoate analogs were quantified with (i) a stable 3-chlorobenzoate-grown methanogenic sludge enrichment, (ii) Desulfomonile tiedjei DCB-1, isolated from this enrichment and able to catalyze the reductive dechlorination of 3-chlorobenzoate, and (iii) a defined 3-chlorobenzoate-degrading methanogenic consortium with D. tiedjei as the key dechlorinating organism. The addition of hydrogen stimulated the dechlorination rate in the consortium. The extent of this stimulation depended on the substituent. The data were evaluated with various sets of substituent constants compiled for the Hammett equation. None of the sets yielded a satisfactory correlation between experimental values and theoretical constants. This suggests that the microbially catalyzed reductive dechlorination of 3-chlorobenzoate cannot be described simply as either a nucleophilic or an electrophilic substitution reaction. Nevertheless, observations that the presence of a para-amino or -hydroxy group inhibited the rate of dechlorination suggest that the rate-limiting step in the reductive dechlorination of 3-chlorobenzoate is a nucleophilic attack on the negatively charged pi electron cloud around the benzene nucleus.


Mental health and HIV: research priorities related to the implementation and scale up of 'treat all' in sub-Saharan Africa.
World Health Organization (WHO) guidelines call for antiretroviral therapy (ART) for all people living with HIV (PLWH) regardless of CD4 cell count, a policy often referred to as 'treat all'. This article seeks to: (1) provide an overview of mental health research among PLWH in sub-Saharan Africa (SSA) and interventions or strategies to address comorbid mental illness among those living with HIV; and (2) describe key mental health-related recommendations to inform the successful implementation and scale up of 'treat all' policies in SSA. An initial set of mental health-related research recommendations was developed by a working group comprising investigators affiliated with the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. Recommendations were shared with those who attended the All-Africa IeDEA Meeting in Kigali, Rwanda in November 2017 and refined following the meeting. Recommendations reflect a need for epidemiological research to examine the prevalence, incidence, and impact of mental health multimorbidities on HIV treatment outcomes, intervention research to examine the extent to which improving the mental health of people living with HIV enhances HIV treatment outcomes, and implementation science research to evaluate promising models of integrated mental health and HIV care. Key research recommendations can advance understanding and treatment of mental illness among those living with HIV in sub-Saharan Africa and beyond.


The rapid size- and shape-controlled continuous hydrothermal synthesis of metal sulphide nanomaterials.
Continuous flow hydrothermal synthesis offers a cheap, green and highly scalable route for the preparation of inorganic nanomaterials which has predominantly been applied to metal oxide based materials. In this work we report the first continuous flow hydrothermal synthesis of metal sulphide nanomaterials. A wide range of binary metal sulphides, ZnS, CdS, PbS, CuS, Fe(1-x)S and Bi2S3, have been synthesised. By varying the reaction conditions two different mechanisms may be invoked; a growth dominated route which permits the formation of nanostructured sulphide materials, and a nucleation driven process which produces nanoparticles with temperature dependent size control. This offers a new and industrially viable route to a wide range of metal sulphide nanoparticles with facile size and shape control.


Long-term outcomes of disability benefits in US veterans with posttraumatic stress disorder.
Most studies examining the clinical impact of disability benefits have compared aid recipients with people who never applied for benefits. Such practices may bias findings against recipients because disability applicants tend to be much sicker than never-applicants. Furthermore, these studies ignore the outcomes of denied claimants. To examine long-term outcomes associated with receiving or not receiving Department of Veterans Affairs (VA) disability benefits for posttraumatic stress disorder (PTSD), the most common mental disorder for which veterans seek such benefits. Comparison of outcomes between successful and unsuccessful applicants for VA disability payments. Because we could not randomize the receipt of benefits, we used exact matching by propensity scores to control for potential baseline differences. We examined clinical outcomes approximately 10 years later. Stratified, nationally representative cohort of 3337 veterans who applied for VA PTSD disability benefits between January 1, 1994, and December 31, 1998. Assessment on validated survey measures of PTSD; work, role, social, and physical functioning; employment; and poverty. We compared outcomes with earlier scores. Homelessness and mortality were assessed using administrative data. Of still-living cohort members, 85.1% returned usable surveys. Symptoms of PTSD were elevated in both groups. After adjustment, awardees had more severe PTSD symptoms than denied claimants but were nonetheless more likely to have had a meaningful symptom reduction since their last assessment (-6.1 vs -4.4; SE, 0.1; P = .01). Both groups had meaningful improvements of similar magnitude in work, role, and social functioning (-0.15 vs -0.19; SE, 0.01; P = .94), but functioning remained poor nonetheless. Comparing awardees with denied claimants after adjustment, 13.2% vs 19.0% were employed (P = .11); 15.2% vs 44.8% reported poverty (P < .001); 12.0% vs 20.0% had been homeless (P = .02); and 10.4% vs 9.7% had died (P = .66). Regardless of claim outcome, veterans who apply for PTSD disability benefits are highly impaired. However, receiving PTSD benefits was associated with clinically meaningful reductions in PTSD symptoms and less poverty and homelessness.


Genetic variability of the grey wolf Canis lupus in the Caucasus in comparison with Europe and the Middle East: distinct or intermediary population?
Despite continuous historical distribution of the grey wolf (Canis lupus) throughout Eurasia, the species displays considerable morphological differentiation that resulted in delimitation of a number of subspecies. However, these morphological discontinuities are not always consistent with patterns of genetic differentiation. Here we assess genetic distinctiveness of grey wolves from the Caucasus (a region at the border between Europe and West Asia) that have been classified as a distinct subspecies C. l. cubanensis. We analysed their genetic variability based on mtDNA control region, microsatellite loci and genome-wide SNP genotypes (obtained for a subset of the samples), and found similar or higher levels of genetic diversity at all these types of loci as compared with other Eurasian populations. Although we found no evidence for a recent genetic bottleneck, genome-wide linkage disequilibrium patterns suggest a long-term demographic decline in the Caucasian population--a trend consistent with other Eurasian populations. Caucasian wolves share mtDNA haplotypes with both Eastern European and West Asian wolves, suggesting past or ongoing gene flow. Microsatellite data also suggest gene flow between the Caucasus and Eastern Europe. We found evidence for moderate admixture between the Caucasian wolves and domestic dogs, at a level comparable with other Eurasian populations. Taken together, our results show that Caucasian wolves are not genetically isolated from other Eurasian populations, share with them the same demographic trends, and are affected by similar conservation problems.


Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells.
Apoptosis is important in controlling hematopoietic stem cell (HSC) numbers. However, the specific BCL-2 family member(s) that regulate HSC homeostasis are not precisely defined. We tested myeloid leukemia-1 (MCL-1) as an attractive candidate that is highly expressed in HSCs and regulated by growth factor signals. Inducible deletion of Mcl-1 in mice resulted in ablation of bone marrow. This resulted in the loss of early bone marrow progenitor populations, including HSCs. Moreover, growth factors including stem cell factor increased transcription of the Mcl-1 gene and required MCL-1 to augment survival of purified bone marrow progenitors. Deletion of Mcl-1 in other tissues, including liver, did not impair survival. Thus, MCL-1 is a critical and specific regulator essential for ensuring the homeostasis of early hematopoietic progenitors.


Cinnamaldehyde/chemotherapeutic agents interaction and drug-metabolizing genes in colorectal cancer.
Cinnamaldehyde is an active monomer isolated from the stem bark of Cinnamomum cassia, a traditional oriental medicinal herb, which is known to possess marked antitumor effects in vitro and in vivo. The aim of the present study was to examine the potential advantages of using cinnamaldehyde in combination with chemotherapeutic agents commonly used in colorectal carcinoma (CRC) therapy, as well as to investigate the effect of cinnamaldehyde on chemotherapeutic-associated gene expression. The synergistic interaction of cinnamaldehyde and chemotherapeutic agents on human CRC HT-29 and LoVo cells was evaluated using the combination index (CI) method. The double staining with Annexin V conjugated to fluorescein-isothiocyanate and phosphatidylserine was employed for apoptosis detection. The expression of drug-metabolizing genes, including excision repair cross‑complementing 1 (ERCC1), orotate phosphoribosyltransferase (OPRT), thymidylate synthase (TS), breast cancer susceptibility gene 1 (BRCA1) and topoisomerase 1 (TOPO1), all in HT-29 and LoVo cells, with or without the addition of cinnamaldehyde, was examined by quantitative polymerase chain reaction (PCR). Cinnamaldehyde had a synergistic effect on the chemotherapeutic agents cytotoxicity in HT-29 and LoVo cells. In addition, cinnamaldehyde suppressed BRCA1, TOPO1, ERCC1 and TS mRNA expression, except for OPRT expression, which was markedly upregulated. Our findings indicate that cinnamaldehyde appears to be a promising candidate as an adjuvant in combination therapy with 5-fluorouracil (5-FU) and oxaliplatin (OXA), two chemotherapeutic agents used in CRC treatment. The possible mechanisms of its action may involve the regulation of drug‑metabolizing genes.


Pattern formation by interacting chemical fronts.
Experiments on a bistable chemical reaction in a continuously fed thin gel layer reveal a new type of spatiotemporal pattern, one in which fronts propagate at a constant speed until they reach a critical separation (typically 0.4 millimeter) and stop. The resulting asymptotic state is a highly irregular stationary pattern that contrasts with the regular patterns such as hexagons, squares, and stripes that have been observed in many nonequilibrium systems. The observed patterns are initiated by a finite amplitude perturbation rather than through spontaneous symmetry breaking.


Composition of the Earth.
New estimates of solar composition, compared to earlier measurements, are enriched in Fe and Ca relative to Mg, Al, and Si. The Fe/Si and Ca/Al atomic ratios are 30 to 40 percent higher than chondritic values. These changes necessitate a revision in the cosmic abundances and in the composition of the nebula from which the planets accreted (which have been based on chondritic values). These new values imply that the mantle could contain about 15 weight percent FeO and more CaMgSi(2)O(6) than has been supposed. Geophysical data are consistent with a dense, FeO-rich lower mantle and a CaMgSi(2)O(6) (diopside)-rich transition region. FeO contents of 13 to 18 weight percent appear to be typical of the mantles of bodies in the inner solar system. The oldest komatiites (high-temperature MgO-rich magmas) have a similar chemistry to the derived mantle. These results favor a chemically zoned mantle.


Cardiac evaluation in adults with dengue virus infection by serial echocardiography.
Dengue virus infection (DVI) is a major health problem in many parts of the world. Its manifestations range from asymptomatic infections to severe disease. Although cardiac involvement has been reported in DVI, its incidence has not yet been well established. From July 2016 to January 2018, patients hospitalized at the Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Thailand, with dengue virus infection confirmed by positive NS1 or positive dengue immunoglobulin M findings, participated in the study. We characterized the incidence and change in cardiac function by serial echocardiography and levels of troponin-T and creatine kinase-myocardial band (CK-MB) on the day of admission, the day of defervescence, the first day of hypotension (if any), and at 2 week follow-up. Of the 81 patients evaluated, 6 (7.41%) exhibited elevated biomarker levels. There was no difference in clinical presentation amongst dengue fever, dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS), except for the amount of bleeding. Cardiac involvement was found in 22.2% of patients: 3 (3.70%) had left ventricular systolic dysfunction, 3 (3.70%) had transient diastolic dysfunction, 6 (7.41%) had increased levels of at least one cardiac biomarker (troponin-T or CK-MB), and 6 (7.41%) had small pericardial effusion. Myocarditis was suspected in only two patients (with DHF); thus, myocarditis was uncommon in patients with dengue virus infection. Three patients developed DSS during admission and were transferred to the intensive care unit. Cardiac involvement in adults with dengue infection was common, ranging from elevated cardiac biomarker to myocarditis. Abnormalities in cardiac function had resolved spontaneously by the day of follow-up, without specific treatment. We found that DHF was a significant risk factor for cardiac involvement. Echocardiography is the investigation of choice for evaluating the haemodynamic status of patients with DVI, especially in severe dengue.


Chromosome size-dependent control of meiotic recombination.
Smaller chromosomes have higher rates of meiotic reciprocal recombination (centimorgans per kilobase pair) than larger chromosomes. This report demonstrates that decreasing the size of Saccharomyces cerevisiae chromosomal DNA molecules increases rates of meiotic recombination and increasing chromosome size decreases recombination rates. These results indicate that chromosome size directly affects meiotic reciprocal recombination.


Adrenocortical regulation, eating in the absence of hunger and BMI in young children.
The purpose of this study was to examine relations among adrenocortical regulation, eating in the absence of hunger, and body mass index (BMI) in children ages 5-9years (N=43). Saliva was collected before and after the Trier Social Stress Test for Children (TSST-C), and was later assayed for cortisol. Area under the curve with respect to increase (AUCi) was used as a measure of changes in cortisol release from baseline to 60min post-TSST-C. Age- and sex-specific BMI scores were calculated from measured height and weight, and eating in the absence of hunger was assessed using weighed food intake during a behavioral procedure. We also included a measure of parents' report of child impulsivity, as well as family demographic information. Participants were stratified by age into younger (5-7years) and older (8-9years) groups. In younger children, parents' reports of child impulsivity were significantly and positively associated with BMI; cortisol AUCi was not associated with BMI or eating in the absence of hunger. In older children, however, greater stress-related cortisol AUCi was related to higher BMI scores and greater energy intake in the absence of hunger. The results suggest that cortisol AUCi in response to psychosocial stress may be linked to problems with energy balance in children, with some variation by age.


Workshop to identify critical windows of exposure for children's health: reproductive health in children and adolescents work group summary.
This work group report addresses the central question: What are the critical windows during development (preconception through puberty) when exposure to xenobiotics may have the greatest adverse impact on subsequent reproductive health? The reproductive system develops in stages, with sex-specific organogenesis occurring prenatally and further maturational events occurring in the perinatal period and at puberty. Complex endocrine signals as well as other regulatory factors (genetics, growth factors) are involved at all stages. Evidence from animal models and human studies indicates that many specific events can be perturbed by a variety of toxicants, with endocrine-mediated mechanisms being the more widely studied. Prioritized research needs include basic studies on the cellular-molecular and endocrine regulation of sexual differentiation and development; increased efforts regarding potential adverse effects on development in females, including breast development; expanded animal studies on different classes of chemicals, comparing responses during development (prenatal and postnatal) with responses in adults; and, more extensive explorations regarding the reproductive biology and toxicology of puberty in humans.


Coherent atomic motions in a nanostructure studied by femtosecond X-ray diffraction.
Reversible structural changes of a nanostructure were measured nondestructively with subpicometer spatial and subpicosecond temporal resolution via x-ray diffraction (XRD). The spatially periodic femtosecond excitation of a gallium arsenide/aluminum gallium arsenide superlattice results in coherent lattice motions with a 3.5-picosecond period, which was directly monitored by femtosecond x-ray pulses at a 1-kilohertz repetition rate. Small changes (DeltaR/R = 0.01) of weak Bragg reflexes (R = 0.005) were detected. The phase and amplitude of the oscillatory XRD signal around a new equilibrium demonstrate that displacive excitation of the zone-folded acoustic phonons is the dominant mechanism for strong excitation.


Twenty years of SHIELD: decreasing incidence of occupational asthma in the West Midlands, UK?
Since 2000 a decline in the incidence of occupational asthma (OA) has been reported in the UK and Europe. We aimed to describe and account for trends in the incidence of OA in the West Midlands, UK using annual notification data from the SHIELD voluntary surveillance scheme over the period 1991-2011. All notifications to the SHIELD database between January 1991 and December 2011 were identified, along with patients' demographic data, occupations, causative agents and confirmatory tests. Annual notifications were scaled to give an annual count per million workers, giving a measure of incidence, and also standardised against those of bakers' asthma. Non-parametric analyses were undertaken between annual incidence and time (years) for common causative agents using (1) a negative binomial regression univariate model and (2) a logistic regression model calculating annual reporting ORs. A step-change analysis was used to examine time points at which there were marked reductions in incidence. A decrease in annual incidence of OA was observed over the study period (incident rate ratio=0.945; 95% CI 0.933 to 0.957; p<0.0001), an effect that was lost after standardising for bakers' asthma. Decreases in incidence were seen for most common causative agents, with only cleaning product-related OA increasing over 21 years. Marked fall in incidence was seen in 2004 for isocyanates, and in 1995 for latex. Most notifications came from a regional specialist occupational lung disease unit, with notifications from other sites falling from 16 cases/million workers/annum in 1995 to 0 in 2004. Reporter fatigue and increasing under-recognition of OA are both factors which contribute to the apparent fall in incidence of OA in the West Midlands. There is a future need for interventions that enable health professionals to identify potential cases of OA in the workplace and in healthcare settings.


Integration of differing chromaticities in early and midlevel spatial vision.
Using Glass patterns composed of isoluminant dots we have investigated the segregation and integration of chromatic information by the visual system. By measuring pattern detection when the chromaticities of the two elements forming a dot pair are varied (intradipole variation), we characterize integration at an early level of spatial processing. By measuring pattern detection for dot pairs where the within-pair chromaticity is the same but the among-pair chromaticities are varied (interdipole variation) we characterize integration and segregation for a more global, midlevel, spatial processing mechanism. Using isoluminant patterns in which all dots have the same chromaticity, we find that (i) detection thresholds are similar to those for luminance-defined dots, and (ii) an equivalent-contrast metric approximately equates thresholds for various chromaticities, including those along both the cardinal and the intermediate axes of an opponent-color space. When intradipole chromaticity is varied we observe that (i) the ability of visual mechanisms to extract oriented dot pairs decreases with increasing chromaticity differences, and (ii) average bandwidths are similar for cardinal and intermediate directions. For pattern detection with interdipole chromatic variation the visual system does not segregate noise dot pairs from correlated dot pairs on the basis of chromatic differences alone, and appears to integrate oriented dot pairs of differing chromaticities in forming a global percept, even for large color differences. Isoluminant Glass patterns with translational and concentric correlations give similar results. The results are compared with those obtained for contrast variation in luminance-defined Glass Patterns and are discussed in terms of current multistage models of color processing by the visual system.


Institutional review of compliance with NCCN guidelines for breast cancer: lessons learned from real-time multidimensional synoptic reporting.
Variations exist in compliance with NCCN Guidelines. Prior reports of adherence to NCCN Guidelines contain limitations because of lack of contemporary review and incomplete listing of reasons for noncompliance. To assess institutional compliance and assist national quality improvement strategies through identifying valid reasons for noncompliance. Compliance with NCCN Guidelines was recorded prospectively using electronic synoptic templates for patients with newly diagnosed breast cancer treated at a single institution between January 2010 and December 2011. Compliance with NCCN Guidelines was recorded. The accuracy of real-time synoptic auditing methods compared with retrospective chart review and reasons for noncompliance was assessed. SAS 9.3 software was used for data analysis. Compliance with NCCN Guidelines among 395 patients was 94% for initial staging evaluation, 97% for surgery, 91% for chemotherapy, 89% for hormone therapy, 91% for radiation therapy, 85% for follow-up, and 100% for determination of estrogen receptor/progesterone receptor and HER2 status. Age, comorbidities, and stage influenced guideline compliance. The most common reasons for noncompliance were patient refusal, patient choice after shared decision-making, and overuse of testing. Synoptic templated reporting was accurate in 97% patients. High compliance with NCCN Guidelines was demonstrated. Reasons for noncompliance were identifiable. Compliance and nonadherence can be evaluated quickly with electronic synoptic reporting. This allows real-time action plans to address quality concerns and aids national risk adjustment for comparison and benchmarking.


Zoledronic acid effectively prevents aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z-FAST study 36-month follow-up results.
Postmenopausal women with breast cancer receiving adjuvant aromatase inhibitors (AIs) are at risk for accelerated bone loss and subsequent fractures. The ongoing Zometa-Femara Adjuvant Synergy Trial (Z-FAST) is evaluating the efficacy and safety of zoledronic acid in preventing such bone loss. In this multicenter study, postmenopausal women with early hormone receptor-positive breast cancer receiving adjuvant letrozole were randomized to receive up-front or delayed-start zoledronic acid (ZA; 4 mg intravenously every 6 months) for 5 years. Delayed-start ZA was administered if the lumbar spine (LS) or total hip (TH) T score fell below -2.0 or a nontraumatic fracture occurred. The primary endpoint was to compare the change from baseline in LS bone mineral density (BMD) between groups at month 12; secondary endpoints, measured at other predetermined timepoints, included comparing changes in TH BMD, LS BMD, and markers of bone turnover, fracture incidence, and time to disease recurrence. Herein, we report the results of the 36-month interim analysis. Overall, 301 patients were randomized to each group. At month 36, the absolute difference in mean LS and TH BMDs between the up-front and delayed groups was 6.7% and 5.2%, respectively (P < .0001 for both). Although this study was not designed to show antifracture efficacy, the incidence of fractures was slightly higher in the delayed group (up-front, 17 [5.7%] vs. delayed, 19 [6.3%]) but not statistically significant (P = .8638). Pyrexia (27 [9%] vs. 6 [2%]; P = .0002) and bone pain (39 [13%] vs. 20 [6.7%]; P = .01) were more common in up-front patients; cough (13 [4.3%] vs. 27 [9%]; P = .03) was more common in delayed patients. No severe renal dysfunction or confirmed cases of osteonecrosis of the jaw were reported. Disease recurrence was reported in 9 up-front (3.0%) and 16 delayed (5.3%) patients (Kaplan-Meier analysis, P = .127), with an absolute decrease of 2.3%. Up-front ZA more effectively prevents AI-associated bone loss in postmenopausal women with early breast cancer than delaying therapy until substantial bone loss or fracture occurs.


Association of single-stranded transferred DNA from Agrobacterium tumefaciens with tobacco cells.
During the inception of crown gall tumorigenesis, the transferred DNA (T-DNA) is processed from the Ti (tumor inducing) plasmid of Agrobacterium tumefaciens and is transferred to plant cells. T-DNA processing and transfer require the induction of vir (virulence) genes by phenolic compounds secreted by wounded plant cells. After vir gene induction, both single-stranded (T-strands) and double-stranded forms of processed T-DNA accumulate in the bacteria. Although current models favor the transfer of T-strands to plants, there has yet been no experimental evidence to show this. In this paper, we show that T-strands disappear from acetosyringone-induced A. tumefaciens within 30 min of bacterial cocultivation with tobacco protoplasts. PCR analysis of T-DNA associated with protoplasts indicates that single-stranded, but not double-stranded, T-DNA can be detected in the plant cells within 30 min of bacterial cocultivation. Control experiments show that this T-DNA does not originate from lysed contaminating bacterial cells. T-DNA transfer depends on a functional bacterial virB operon. Protoplast infections using an A. tumefaciens virE mutant result in a low level of accumulation of T-strands in the plant cells.


Treatment-resistant depression in adolescents: is the addition of cognitive behavioral therapy of benefit?
Many young people with major depression fail first-line treatments. Treatment-resistant depression has various definitions in the literature but typically assumes nonresponse to medication. In young people, cognitive behavioral therapy (CBT) is the recommended first-line intervention, thus the definition of treatment resistance should be expanded. Therefore, our aim was to synthesize the existing evidence of any interventions for treatment-resistant depression, broadly defined, in children and adolescents and to investigate the effectiveness of CBT in this context. We used Cochrane Collaboration methodology, with electronic searches of Medline, PsycINFO, Embase, and the Cochrane Depression Anxiety and Neurosis Group trials registers. Only randomized controlled trials were included, and were assessed for risk of bias. Meta- analysis was undertaken where possible and appropriate. Of 953 articles retrieved, four trials were eligible for inclusion. For one study, only the trial registration document was available, because the study was never completed. All other studies were well conducted with a low risk of bias, although one study had a high dropout rate. Two studies assessed the effect of adding CBT to medication. While an assertive trial of antidepressants does appear to lead to benefit, when compared with placebo, there was no significant advantage, in either study, or in a meta-analysis of data from these trials, that clearly demonstrated an additional benefit of CBT. The third trial showed little advantage of a tricyclic antidepressant over placebo in the context of an inpatient admission. Few randomized controlled trials have investigated interventions for treatment-resistant depression in young people, and results from these show modest benefit from antidepressants with no additional benefit over medication from CBT. Overall, there is a lack of evidence about effective interventions to treat young people who have failed to respond to evidence-based interventions for depression. Research in this area is urgently required.


Metabolomics reveal alterations in arachidonic acid metabolism in Schistosoma mekongi after exposure to praziquantel.
Mekong schistosomiasis is a parasitic disease caused by the blood-dwelling fluke Schistosoma mekongi. This disease contributes to human morbidity and mortality in the Mekong region, posing a public health threat to people in the area. Currently, praziquantel (PZQ) is the drug of choice for the treatment of Mekong schistosomiasis. However, the molecular mechanisms of PZQ action remain unclear, and Schistosoma PZQ resistance has been reported occasionally. Through this research, we aimed to use a metabolomic approach to identify the potentially altered metabolic pathways in S. mekongi associated with PZQ treatment. Adult stage S. mekongi were treated with 0, 20, 40, or 100 μg/mL PZQ in vitro. After an hour of exposure to PZQ, schistosome metabolites were extracted and studied with mass spectrometry. The metabolomic data for the treatment groups were analyzed with the XCMS online platform and compared with data for the no treatment group. After low, medium (IC50), and high doses of PZQ, we found changes in 1,007 metabolites, of which phosphatidylserine and anandamide were the major differential metabolites by multivariate and pairwise analysis. In the pathway analysis, arachidonic acid metabolism was found to be altered following PZQ treatment, indicating that this pathway may be affected by the drug and potentially considered as a novel target for anti-schistosomiasis drug development. Our findings suggest that arachidonic acid metabolism is a possible target in the parasiticidal effects of PZQ against S. mekongi. Identifying potential targets of the effective drug PZQ provides an interesting viewpoint for the discovery and development of new agents that could enhance the prevention and treatment of schistosomiasis.


Perceptions of self-determination and quality of life among Swedish home care recipients - a cross-sectional study.
It is acknowledged that preservation of self-determination is very important in order for older adults to experience good quality of life, but to what degree and in what areas people receiving help from home care service experience self-determination is unknown. Few studies have examined the perception of self-determination in relation to quality of life among older adults living at home with help from home care services. Thus, the aim of this study was to explore perceptions of self-determination among older adults living at home with the support of home care services, and to test whether older adults who perceive a higher degree of self-determination also feel they have a better quality of life. This cross-sectional study was conducted in one municipality in northern Sweden. A total of 134 older adults (≥ 65 years) were included. Data were collected by means of a survey including questionnaires about background characteristics, self-determination, and health-related quality of life. Descriptive statistics regarding background characteristics for groups with high and low self-determination respectively were presented and the differences between the groups were analyzed using the Chi-square test and the Mann-Whitney U test. Our main finding shows that the majority of older adults with support from home care services experience self-determination in the dimensions use of time, and self-care. However, a wide variation was found in self-reported self-determination in all dimensions. Results also show that the group with higher self-reported self-determination also reported a greater degree of experienced quality of life in comparison with the group with lower self-reported self-determination. In line with earlier research, our results found a positive relation between self-determination and quality of life. The results are relevant for the care of older adults and indicate a need of further research. The results presented in this paper could serve as a guide when planning for improved self-determination among older adults in home care service. NCT02846246 .


An orthotopic murine model of human prostate cancer metastasis.
Our laboratory has developed a novel orthotopic implantation model of human prostate cancer (PCa). As PCa death is not due to the primary tumor, but rather the formation of distinct metastasis, the ability to effectively model this progression pre-clinically is of high value. In this model, cells are directly implanted into the ventral lobe of the prostate in Balb/c athymic mice, and allowed to progress for 4-6 weeks. At experiment termination, several distinct endpoints can be measured, such as size and molecular characterization of the primary tumor, the presence and quantification of circulating tumor cells in the blood and bone marrow, and formation of metastasis to the lung. In addition to a variety of endpoints, this model provides a picture of a cells ability to invade and escape the primary organ, enter and survive in the circulatory system, and implant and grow in a secondary site. This model has been used effectively to measure metastatic response to both changes in protein expression as well as to response to small molecule therapeutics, in a short turnaround time.


Renoprotective Effect of Humic Acid on Renal Ischemia-Reperfusion Injury: An Experimental Study in Rats.
Humic acid is an antioxidant molecule used in agriculture and livestock breeding, as well as in medicine. Our aim was to investigate the potential renoprotective effects of humic acid in a renal ischemia reperfusion model. Twenty-one rats were randomly divided into three equal groups. Intraperitoneal serum or humic acid was injected at 1, 12, and 24 h. Non-ischemic group I was evaluated as sham. The left renal artery was clamped in serum (group II) and intraperitoneal humic acid (group III) to subject to left renal ischemic reperfusion procedure. Ischemia and reperfusion time was 60 min for each. Total antioxidant status, total oxidative status, oxidative stress index, and ischemia-modified albumin levels were analyzed biochemically from the serum samples. Kidneys were evaluated histopatologically and immunohistochemically. Biochemical results showed that total oxidative status, ischemia-modified albumin, and oxidative stress index levels were significantly decreased, but total antioxidant status was increased in the humic acid group (III) compared with the ischemia group (II) On histopathological examination, renal tubular dilatation, tubular cell damage and necrosis, dilatation of Bowman's capsule, hyaline casts, and tubular cell spillage were decreased in the humic acid group (III) compared with the ischemia group (II). Immunohistochemical results showed that apoptosis was deteriorated in group III. Renal ischemia reperfusion injury was attenuated by humic acid administration. These observations indicate that humic acid may have a potential therapeutic effect on renal ischemia reperfusion injury by preventing oxidative stress.


A novel pedicle channel classification describing osseous anatomy: how many thoracic scoliotic pedicles have cancellous channels?
Prospective clinical series. To determine how many thoracic scoliotic pedicles have cancellous versus cortical versus absent channels. Although morphologic evaluations of thoracic pedicles have been well reported, the results do not practically reflect clinical findings during actual pedicle screw placement. We propose a novel pedicle channel classification describing the osseous anatomy encountered during pedicle probe insertion. We noted 4 pedicle types in 53 consecutive scoliosis patients. Type A: pedicle probe smoothly inserted without difficulty; the morphology is described as a "Large Cancellous Channel." Type B: pedicle probe inserted snugly with increased force; described as a "Small Cancellous Channel." Type C: pedicle probe cannot be manually pushed but must be tapped with a mallet down the pedicle into the body; described as a "Cortical Channel." Type D: pedicle probe cannot locate a channel thus necessitating a "juxtapedicular" screw position; described as a "Slit/Absent Channel." The average age at time of surgery was 23.4 ± 16.7 years. Diagnoses included idiopathic scoliosis (n = 38) and syndromic scoliosis (n = 15). The average main thoracic Cobb angle was 73° ± 26°. Evaluation of pedicle morphology of the 4 types was also performed in 21 consecutive cases of adolescent idiopathic scoliosis using preoperative computed tomography images. A total of 1021 pedicles with screws placed were evaluated. The average percent per type was as follows: 61.0% type A; 29.2% type B, 6.8% type C, and 3.0% type D. On the convexity, 98.2% of pedicles were type A or B versus 81.5% on the concavity (P < 0.05). There were significant differences between adolescent versus adult idiopathic scoliosis (P = 0.007), and syndromic scoliosis versus adult idiopathic scoliosis (P = 0.017) regarding pedicle morphologic proportions. There was a significant tendency toward a decrease in the proportion of type A pedicles, an increase in the proportion of type B pedicles as the Cobb angle increased (P < 0.0001). Evaluation based on 312 thoracic pedicles in 21 consecutive adolescent idiopathic scoliosis patients using preoperative computed tomography axial images confirmed assumptions of the 4 pedicle types. We propose a classification for pedicle channels describing the osseous anatomy encountered during pedicle probe insertion. Based on the classification, surprisingly, we found during surgery that 90% of thoracic pedicles had a cancellous channel, whereas 7% had a cortical channel and only 3% had an absent channel.


Variations in normal color vision. IV. Binary hues and hue scaling.
We used hue cancellation and focal naming to compare individual differences in stimuli selected for unique hues (e.g., pure blue or green) and binary hues (e.g., blue-green). Standard models assume that binary hues depend on the component responses of red-green and blue-yellow processes. However, variance was comparable for unique and binary hues, and settings across categories showed little correlation. Thus, the choices for the binary mixtures are poorly predicted by the unique hue settings. Hue scaling was used to compare individual differences both within and between categories. Ratings for distant stimuli were again independent, while neighboring stimuli covaried and revealed clusters near the poles of the LvsM and SvsLM cardinal axes. While individual differences were large, mean focal choices for red, blue-green, yellow-green, and (to a lesser extent) purple fall near the cardinal axes, such that the cardinal axes roughly delineate the boundaries for blue vs. green and yellow vs. green categories. This suggests a weak tie between the cone-opponent axes and the structure of color appearance.


Parent training for preschool ADHD: a randomized controlled trial of specialized and generic programs.
The 'New Forest Parenting Package' (NFPP), an 8-week home-based intervention for parents of preschoolers with attention-deficit/hyperactivity disorder (ADHD), fosters constructive parenting to target ADHD-related dysfunctions in attention and impulse control. Although NFPP has improved parent and laboratory measures of ADHD in community samples of children with ADHD-like problems, its efficacy in a clinical sample, and relative to an active treatment comparator, is unknown. The aims are to evaluate the short- and long-term efficacy and generalization effects of NFPP compared to an established clinic-based parenting intervention for treating noncompliant behavior ['Helping the Noncompliant Child' (HNC)] in young children with ADHD. A randomized controlled trial with three parallel arms was the design for this study. A total of 164 3-4-year-olds, 73.8% male, meeting DSM-IV ADHD diagnostic criteria were randomized to NFPP (N = 67), HNC (N = 63), or wait-list control (WL, N = 34). All participants were assessed at post-treatment. NFPP and HNC participants were assessed at follow-up in the next school year. Primary outcomes were ADHD ratings by teachers blind to and uninvolved in treatment, and by parents. Secondary ADHD outcomes included clinician assessments, and laboratory measures of on-task behavior and delay of gratification. Other outcomes included parent and teacher ratings of oppositional behavior, and parenting measures. (Trial name: Home-Based Parent Training in ADHD Preschoolers; Registry: ClinicalTrials.gov Identifier: NCT01320098; URL: http://www/clinicaltrials.gov/ct2/show/NCT01320098). In both treatment groups, children's ADHD and ODD behaviors, as well as aspects of parenting, were rated improved by parents at the end of treatment compared to controls. Most of these gains in the children's behavior and in some parenting practices were sustained at follow-up. However, these parent-reported improvements were not corroborated by teacher ratings or objective observations. NFPP was not significantly better, and on a few outcomes significantly less effective, than HNC. The results do not support the claim that NFPP addresses putative dysfunctions underlying ADHD, bringing about generalized change in ADHD, and its underpinning self-regulatory processes. The findings support documented difficulties in achieving generalization across nontargeted settings, and the importance of using blinded measures to provide meaningful assessments of treatment effects.


The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS.
The immediate or innate immune response is the first line of defense against diverse microbial pathogens and requires the expression of recently discovered toll-like receptors (TLRs). TLR4 serves as a specific receptor for lipopolysaccharide (LPS) and is localized on the surface of a subset of mammalian cells. Although innate immunity is a necessary host defense against microbial pathogens, the consequences of its activation in the CNS can be deleterious, as we show here in a developing neural model. We examined the major non-neuronal cell types in the CNS for expression of TLR4 and found that microglia expressed high levels, whereas astrocytes and oligodendrocytes expressed none. Consistent with TLR4 expression solely in microglia, we show that microglia are the only CNS glial cells that bind fluorescently tagged lipopolysaccharide. Lipopolysaccharide led to extensive oligodendrocyte death in culture only under conditions in which microglia were present. To determine whether TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte death in mixed glial cultures, we studied cultures generated from mice bearing a loss-of-function mutation in the tlr4 gene. Lipopolysaccharide failed to induce oligodendrocyte death in such cultures, in contrast to the death induced in cultures from wild-type mice. Finally, stereotactic intracerebral injection of lipopolysaccharide into the developing pericallosal white matter of immature rodents resulted in loss of oligodendrocytes and hypomyelination and periventricular cysts. Our data provide a general mechanistic link between (1) lipopolysaccharide and similar microbial molecular motifs and (2) injury to oligodendrocytes and myelin as occurs in periventricular leukomalacia and multiple sclerosis.


Spontaneous intracranial hypotension syndrome accompanied by bilateral hearing loss and venous engorgement in the internal acoustic canal and positional change of audiography.
Hearing loss, tinnitus, and vertigo are very common complaints in otolaryngology practice. Here, we describe spontaneous intracranial hypotension (SIH) as a curable reason of hearing loss, tinnitus, and vertigo. A 29-year-old woman presented to the emergency room with nausea, dizziness, vertigo, instability, hearing loss, tinnitus, and neck and back pain. Cranial computed tomography, magnetic resonance imaging (MRI), and lumbar puncture were performed. The patient stated that the hearing loss and tinnitus became worse after effort or standing for prolonged times. Therefore, we performed audiogram in sitting and standing positions. The tinnitus severity index was used to evaluate tinnitus. Lumbar puncture revealed no cerebrospinal fluid, and cerebrospinal fluid could be obtained by aspiration. Cranial MRI showed dural thickness and venous engorgement in the internal acoustic canals bilaterally. Audiography showed worse hearing capacity in standing position than in sitting position and revealed especially low-frequency hearing loss bilaterally. The patient's tinnitus severity index was 48 of 60. The patient was diagnosed as having SIH and treated with autologous blood punch. Cranial MRI and audiogram were normal after the treatment. The patient had no tinnitus after the treatment. Spontaneous intracranial hypotension, which may cause Ménière syndrome-like symptoms, is a curable reason of hearing loss, tinnitus, and vertigo. In addition, the fluctuation of the hearing loss with positional changes supports the use of positional audiometry when evaluating hearing loss-related SIH. Venous engorgement in the internal acoustic canal may be related to the symptoms.


Geographic variation in one-year recurrent ischemic stroke rates for elderly Medicare beneficiaries in the USA.
While geographic disparities in stroke mortality are well documented, there are no data describing geographic variation in recurrent stroke. Accordingly, we evaluated geographic variations in 1-year recurrent ischemic stroke rates in the USA with adjustment for patient characteristics. One-year recurrent stroke rates for ischemic stroke (International Classification of Diseases, 9th Revision codes 433, 434 and 436) following hospital discharge were calculated by county for all fee-for-service Medicare beneficiaries from 2000 to 2002. The rates were standardized and smoothed using a bayesian conditional autoregressive model that was risk-standardized for patients' age, gender, race/ethnicity, prior hospitalizations, Deyo comorbidity score, acute myocardial infarction, congestive heart failure, diabetes, hypertension, dementia, cancer, chronic obstructive pulmonary disease and obesity. The overall 1-year recurrent stroke rate was 9.4% among 895,916 ischemic stroke patients (mean age: 78 years; 56.6% women; 86.6% White, 9.7% Black and 1.2% Latino/Hispanic). The rates varied by geographic region and were highest in the South and in parts of the West and Midwest. Regional variation was present for all racial/ethnic subgroups and persisted after adjustment for individual patient characteristics. Almost 1 in 10 hospitalized ischemic stroke patients was readmitted for an ischemic stroke within 1 year. There was heterogeneity in recurrence patterns by geographic region. Further work is needed to understand the reasons for this regional variability.


FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis.
Although the link between inflammation and cancer initiation is well established, its role in metastatic diseases, the primary cause of cancer deaths, has been poorly explored. Our previous studies identified a population of metastasis-associated macrophages (MAMs) recruited to the lung that promote tumor cell seeding and growth. Here we show that FMS-like tyrosine kinase 1 (Flt1, also known as VEGFR1) labels a subset of macrophages in human breast cancers that are significantly enriched in metastatic sites. In mouse models of breast cancer pulmonary metastasis, MAMs uniquely express FLT1. Using several genetic models, we show that macrophage FLT1 signaling is critical for metastasis. FLT1 inhibition does not affect MAM recruitment to metastatic lesions but regulates a set of inflammatory response genes, including colony-stimulating factor 1 (CSF1), a central regulator of macrophage biology. Using a gain-of-function approach, we show that CSF1-mediated autocrine signaling in MAMs is downstream of FLT1 and can restore the tumor-promoting activity of FLT1-inhibited MAMs. Thus, CSF1 is epistatic to FLT1, establishing a link between FLT1 and inflammatory responses within breast tumor metastases. Importantly, FLT1 inhibition reduces tumor metastatic efficiency even after initial seeding, suggesting that these pathways represent therapeutic targets in metastatic disease.


A feasibility study of a culturally tailored diabetes intervention for Mexican Americans.
Latinos, the fastest growing minority group in the United States, are among the hardest hit by diabetes. Among Latinos, Mexican Americans have the highest rate (23.9%) of diabetes. Good self-management can improve glycemic control and decrease diabetes complications but can be challenging to achieve. The purpose of this study was to test the feasibility and examine the effects of a culturally tailored intervention for Mexican Americans with type 2 diabetes on outcomes of self-management. The study used a pretest/posttest control group design with 10 participants in each group (N = 17). Feasibility and acceptability of the tailored diabetes self-management program was assessed by examining ease of recruitment and retention rates. The behavioral outcomes of self-efficacy, diabetes knowledge and self-care measures, and the biologic outcomes of weight, body mass index, HbA1C, and blood glucose were used to examine intervention effectiveness. Successful recruitment of participants came from personal referrals from providers or the promotora. Retention rates were 100% for the intervention group and 80% for the control group. Findings suggest that the intervention had a positive clinical and statistical effect on diabetes knowledge, weight, and body mass index. Improvements were also noted in self-efficacy scores, blood glucose, and HbA1C, but these changes did not reach statistical significance. A culturally tailored diabetes self-management program may result in improved outcomes for Mexican Americans with type 2 diabetes.


Nonparametric estimation of the survival distribution under covariate-induced dependent truncation.
There is often delayed entry into observational studies, which results in left truncation. In the estimation of the distribution of time-to-event from left-truncated data, standard survival analysis methods require quasi-independence between the truncation time and event time. Incorrectly assuming quasi-independence may lead to biased estimation. We address the problem of estimation of the survival distribution when dependence between the event time and its left truncation time is induced by shared covariates. We introduce propensity scores for truncated data and propose two inverse probability weighting methods that adjust for both truncation and dependence, if all of the shared covariates are measured. The proposed methods additionally allow for right censoring. We evaluate the proposed methods in simulations, conduct sensitivity analyses, and provide guidelines for use in practice. We illustrate our approach in application to data from a central nervous system lymphoma study. The proposed methods are implemented in the R package, depLT.


Knowing where and getting there: a human navigation network.
The neural basis of navigation by humans was investigated with functional neuroimaging of brain activity during navigation in a familiar, yet complex virtual reality town. Activation of the right hippocampus was strongly associated with knowing accurately where places were located and navigating accurately between them. Getting to those places quickly was strongly associated with activation of the right caudate nucleus. These two right-side brain structures function in the context of associated activity in right inferior parietal and bilateral medial parietal regions that support egocentric movement through the virtual town, and activity in other left-side regions (hippocampus, frontal cortex) probably involved in nonspatial aspects of navigation. These findings outline a network of brain areas that support navigation in humans and link the functions of these regions to physiological observations in other mammals.


Inferring gene function and network organization in Drosophila signaling by combined analysis of pleiotropy and epistasis.
High-throughput genetic interaction screens have enabled functional genomics on a network scale. Groups of cofunctional genes commonly exhibit similar interaction patterns across a large network, leading to novel functional inferences for a minority of previously uncharacterized genes within a group. However, such analyses are often unsuited to cases with a few relevant gene variants or sparse annotation. Here we describe an alternative analysis of cell growth signaling using a computational strategy that integrates patterns of pleiotropy and epistasis to infer how gene knockdowns enhance or suppress the effects of other knockdowns. We analyzed the interaction network for RNAi knockdowns of a set of 93 incompletely annotated genes in a Drosophila melanogaster model of cellular signaling. We inferred novel functional relationships between genes by modeling genetic interactions in terms of knockdown-to-knockdown influences. The method simultaneously analyzes the effects of partially pleiotropic genes on multiple quantitative phenotypes to infer a consistent model of each genetic interaction. From these models we proposed novel candidate Ras inhibitors and their Ras signaling interaction partners, and each of these hypotheses can be inferred independent of network-wide patterns. At the same time, the network-scale interaction patterns consistently mapped pathway organization. The analysis therefore assigns functional relevance to individual genetic interactions while also revealing global genetic architecture.


Women's perceptions and experiences of fetal macrosomia.
to explore women's perceptions and experiences of pregnancy and childbirth following birth of a macrosomic infant (birth weight ≥4000g). a qualitative design utilising interviews conducted 13-19 weeks post partum in women's homes. The study was conducted in one Health and Social Care Trust in Northern Ireland between January and September 2010. Participants were identified from a larger cohort of women recruited to a prospective study exploring the impact of physical activity and nutrition on macrosomia. Eleven women who delivered macrosomic infants participated in this phase of the study. four overarching themes emerged: preparation for delivery; physical and emotional impact of macrosomia; professional relations and perceptions of macrosomia. Findings highlighted the importance of communication with health professionals in relation to both prediction of macrosomia and decision making about childbirth, and offers further understanding into the physical and emotional impact of having a macrosomic infant on women. Furthermore, there was evidence that beliefs and perceptions relating to macrosomia may influence birth experiences and uptake of health promotion messages. this study provides important insight into women's experiences of macrosomia throughout the perinatal period and how they were influenced by previous birth experiences, professional relations and personal perceptions and beliefs about macrosomia. Pregnant women at risk of having a macrosomic infant may require extra support throughout the antenatal period continuing into the postnatal period. Support needs to be tailored to the woman's information needs, with time allocated to explore previous birth experiences, beliefs about macrosomia and options for childbirth.


Modeling the ice-age climate.
Using the boundary conditions of seasurface temperature, ice sheet topography, and surface albedo assembled by CLIMAP for 18,000 B.P., the global ice-age July climate has been simulated with a two-level dynamical atmospheric model. Compared with the simulation for present July climate, the ice age is substantially cooler and drier over the unglaciated continental areas, with the maximum zonal westerlies in the Northern Hemisphere displaced southward in the vicinity of the ice sheets. The simulated changes of surface air temperature agree reasonably well with the estimates available from the analysis of fossil pollen and periglacial data, and are consistent with the simulated changes of other climatic variables. These results are generally supported by independent investigations with simpler models. In spite of this qualified success, further analysis of both simulated and verification data is needed to establish the details of ice-age climate, especially the precipitation regimes, and to document the role of eddy fluxes in maintaining the heat, momentum, and moisture balances of the ice-age general circulation. New paleoclimatic data bases for both July and January of 18,000 B.P. are being assembled by CLIMAP and will be used in new simulations of the seasonal ice-age climate.


Inverse scattering transform analysis of rogue waves using local periodization procedure.
The nonlinear Schrödinger equation (NLSE) stands out as the dispersive nonlinear partial differential equation that plays a prominent role in the modeling and understanding of the wave phenomena relevant to many fields of nonlinear physics. The question of random input problems in the one-dimensional and integrable NLSE enters within the framework of integrable turbulence, and the specific question of the formation of rogue waves (RWs) has been recently extensively studied in this context. The determination of exact analytic solutions of the focusing 1D-NLSE prototyping RW events of statistical relevance is now considered as the problem of central importance. Here we address this question from the perspective of the inverse scattering transform (IST) method that relies on the integrable nature of the wave equation. We develop a conceptually new approach to the RW classification in which appropriate, locally coherent structures are specifically isolated from a globally incoherent wave train to be subsequently analyzed by implementing a numerical IST procedure relying on a spatial periodization of the object under consideration. Using this approach we extend the existing classifications of the prototypes of RWs from standard breathers and their collisions to more general nonlinear modes characterized by their nonlinear spectra.


Everyday music listening and affect regulation: the role of MP3 players.
The use of digital portable music devices such as MP3 players has rapidly increased during the last decade, and the sheer availability of music offered by such players raises questions about their impact on listeners' mental and physical health and well-being. This article explores MP3 player use as an everyday tactic for affect regulation, here understood as an individual's efforts to maintain or change the intensity or duration of a given affect. The ability to understand and regulate affects has significant health implications, and among the tactics relevant to such regulation, engagement with music has proven to be particularly successful. The material presented in this article is based on a qualitative interview study focused on MP3 player use as a medium for musical self-care. Because MP3 users can listen to whatever they want, whenever they want, and target their music in the interests of managing and regulating moods and emotions, the MP3 player represents a valuable and convenient technology of affect regulation.


Reaction dynamics of the UV-B photosensor UVR8.
UVR8 is a recently discovered ultraviolet-B (UV-B) photoreceptor protein identified in plants and algae. In the dark state, UVR8 exists as a homodimer, whereas UV-B irradiation induces UVR8 monomerization and initiation of signaling. Although the biological functions of UVR8 have been studied, the fundamental reaction mechanism and associated kinetics have not yet been fully elucidated. Here, we used the transient grating method to determine the reaction dynamics of UVR8 monomerization based on its diffusion coefficient. We found that the UVR8 photodissociation reaction proceeds in three stages: (i) photoexcitation of cross-dimer tryptophan (Trp) pyramids; (ii) an initial conformational change with a time constant of 50 ms; and (iii) dimer dissociation with a time constant of 200 ms. We identified W285 as the key Trp residue responsible for initiating this photoreaction. Although the C-terminus of UVR8 is essential for biological interactions and signaling via downstream components such as COP1, no obvious differences were detected between the photoreactions of wild-type UVR8 (amino acids 1-440) and a mutant lacking the C-terminus (amino acids 1-383). This similarity indicates that the conformational change associated with stage ii cannot primarily be attributed to this region. A UV-B-driven conformational change with a time constant of 50 ms was also detected in the monomeric mutants of UVR8. Dimer recovery following monomerization, as measured by circular dichroism spectroscopy, was decreased under oxygen-purged conditions, suggesting that redox reactivity is a key factor contributing to the UVR8 oligomeric state.


A late miocene accipitrid (Aves: Accipitriformes) from Nebraska and its implications for the divergence of old world vultures.
Old World vultures are likely polyphyletic, representing two subfamilies, the Aegypiinae and Gypaetinae, and some genera of the latter may be of independent origin. Evidence concerning the origin, as well as the timing of the divergence of each subfamily and even genera of the Gypaetinae has been elusive. Compared with the Old World, the New World has an unexpectedly diverse and rich fossil component of Old World vultures. Here we describe a new accipitriform bird, Anchigyps voorhiesi gen. et sp. nov., from the Ash Hollow Formation (Upper Clarendonian, Late Miocene) of Nebraska. It represents a form close in morphology to the Old World vultures. Characteristics of its wing bones suggest it was less specialized for soaring than modern vultures. It was likely an opportunistic predator or scavenger having a grasping foot and a mandible morphologically similar to modern carrion-feeding birds. The new fossil reported here is intermediate in morphology between the bulk of accipitrids and the Old World gypaetine vultures, representing a basal lineage of Accipitridae trending towards the vulturine habit, and of its Late Miocene age suggests the divergence of true gypaetine vultures, may have occurred during or slightly before the Miocene.


Constant denaturant gel electrophoresis (CDGE) in BRCA1 mutation screening.
Screening for mutations in the breast and ovarian cancer susceptibility gene, BRCA1, is complicated by the wide spectrum of mutations found in this large gene. In the present study a constant denaturant gel electrophoresis (CDGE) mutation screening strategy was established for approximately 80% of the genomic coding sequence (exons 2, 11, 13-16, 20, 24). This strategy was applied to screen genomic DNA from 50 familial breast and/or ovarian cancer patients who had previously been examined for BRCA1 mutations by SSCP. A total of 14 carriers of 12 distinct disease-associated mutations and 7 carriers of 6 distinct rare substitutions leading to amino acid substitutions were identified. The SSCP failed to detect 40% of the different deletions/insertions (4/10) and 75% (6/8) of the different base substitutions leading to terminating codons or rare amino acid changes. SSCP did, however, identify one rare base substitution that could not be detected in the CDGE screening. To evaluate the CDGE mutation screening strategy further, 25 unrelated patients from Norwegian breast and/or ovarian cancer families were examined for BRCA1 mutations using a combined genomic DNA/cDNA approach covering the entire coding sequence of the gene. A total of six mutation carriers were detected, all of whom had cases of ovarian cancer in their families. Three patients from independent families carried an 1135insA mutation in exon 11, two others had a Gly484ter and an 1675delA mutation, respectively, and the sixth carried a splice mutation (5194-2 a-->c) causing deletion of exon 18. CDGE may become an efficient tool in diagnostic and population based screening for BRCA1 mutations.


Computational methods for 16S metabarcoding studies using Nanopore sequencing data.
Assessment of bacterial diversity through sequencing of 16S ribosomal RNA (16S rRNA) genes has been an approach widely used in environmental microbiology, particularly since the advent of high-throughput sequencing technologies. An additional innovation introduced by these technologies was the need of developing new strategies to manage and investigate the massive amount of sequencing data generated. This situation stimulated the rapid expansion of the field of bioinformatics with the release of new tools to be applied to the downstream analysis and interpretation of sequencing data mainly generated using Illumina technology. In recent years, a third generation of sequencing technologies has been developed and have been applied in parallel and complementarily to the former sequencing strategies. In particular, Oxford Nanopore Technologies (ONT) introduced nanopore sequencing which has become very popular among molecular ecologists. Nanopore technology offers a low price, portability and fast sequencing throughput. This powerful technology has been recently tested for 16S rRNA analyses showing promising results. However, compared with previous technologies, there is a scarcity of bioinformatic tools and protocols designed specifically for the analysis of Nanopore 16S sequences. Due its notable characteristics, researchers have recently started performing assessments regarding the suitability MinION on 16S rRNA sequencing studies, and have obtained remarkable results. Here we present a review of the state-of-the-art of MinION technology applied to microbiome studies, the current possible application and main challenges for its use on 16S rRNA metabarcoding.


Randomized phase II trial of All-trans-retinoic acid with chemotherapy based on paclitaxel and cisplatin as first-line treatment in patients with advanced non-small-cell lung cancer.
This randomized phase II trial evaluated whether the combination of cisplatin and paclitaxel (PC) plus all-trans retinoic acid (ATRA) increases response rate (RR) and progression-free survival (PFS) in patients with advanced non-small-cell lung cancer (NSCLC) with an acceptable toxicity profile and its association with the expression of retinoic acid receptor beta 2 (RAR-beta2) as a response biomarker. Patients with stages IIIB with pleural effusion and IV NSCLC were included to receive PC, and randomly assigned to receive ATRA 20 mg/m(2)/d (RA/PC) or placebo (P/PC) 1 week before treatment until two cycles were completed. RAR-beta2 expression was analyzed in tumor and adjacent lung tissue. One hundred seven patients were included, 55 in the P/PC group and 52 in the RA/PC group. RR for RA/PC was 55.8% (95% CI, 46.6% to 64.9%) and for P/PC, 25.4% (95% CI, 21.3 to 29.5%; P = .001). The RA/PC group had a longer median PFS (8.9 v 6.0 months; P = .008). Multivariate analysis of PFS showed significant differences for the RA/PC group (hazard ratio, 0.62; 95% CI, 0.4 to 0.95). No significant differences in toxicity grade 3/4 were found between groups, except for hypertriglyceridemia (10% v 0%) in RA/PC (P = .05). Immunohistochemistry and reverse-transcriptase polymerase chain reaction assays showed expression of RAR-beta2 in normal tissues of all tumor samples, but only 10% of samples in the tumor tissue. Adding ATRA to chemotherapy could increase RR and PFS in patients with advanced NSCLC with an acceptable toxicity profile. A phase III clinical trial is warranted to confirm these findings.


A compact nonlinear fiber-based optical autocorrelation peak discriminator.
We experimentally demonstrate a nonlinear fiber-based optical autocorrelation peak discriminator. The approach exploits four-wave mixing in a 37-cm highly-nonlinear bismuth-oxide fiber that provides a passive and compact means for rejecting cross-correlation peaks. The autocorrelation peak discriminator plays an important role in improving the detection of optical CDMA signals. Eye diagrams and bit-error rates are measured at different power ratios. Significant receiver sensitivity improvements are obtained and error-floors are removed. The experimental results show that the autocorrelation peak discriminator works well even when the amplitudes of individual cross-correlation peaks are higher than that of the autocorrelation peak.


dachsous and frizzled contribute separately to planar polarity in the Drosophila ventral epidermis.
Cells that comprise tissues often need to coordinate cytoskeletal events to execute morphogenesis properly. For epithelial tissues, some of that coordination is accomplished by polarization of the cells within the plane of the epithelium. Two groups of genes--the Dachsous (Ds) and Frizzled (Fz) systems--play key roles in the establishment and maintenance of such polarity. There has been great progress in uncovering the how these genes work together to produce planar polarity, yet fundamental questions remain unanswered. Here, we study the Drosophila larval ventral epidermis to begin to address several of these questions. We show that ds and fz contribute independently to polarity and that they do so over spatially distinct domains. Furthermore, we find that the requirement for the Ds system changes as field size increases. Lastly, we find that Ds and its putative receptor Fat (Ft) are enriched in distinct patterns in the epithelium during embryonic development.