Analysis of MADS-box genes revealed modified flowering gene network and diurnal expression in pineapple.
Pineapple is the most important crop with CAM photosynthesis, but its molecular biology is underexplored. MADS-box genes are crucial transcription factors involving in plant development and several biological processes. However, there is no systematic analysis of MADS-box family genes in pineapple (Ananas comosus). Forty-eight MADS-box genes were identified in the pineapple genome. Based on the phylogenetic studies, pineapple MADS-box genes can be divided into type I and type II MADS-box genes. Thirty-four pineapple genes were classified as type II MADS-box genes including 32 MIKC-type and 2 Mδ-type, while 14 type I MADS-box genes were further divided into Mα, Mβ and Mγ subgroups. A majority of pineapple MADS-box genes were randomly distributed across 19 chromosomes. RNA-seq expression patterns of MADS-box genes in four different tissues revealed that more genes were highly expressed in flowers, which was confirmed by our quantitative RT-PCR results. There is no FLC and CO orthologs in pineapple. The loss of FLC and CO orthologs in pineapple indicated that modified flowering genes network in this tropical plant compared with Arabidopsis. The expression patterns of MADS-box genes in photosynthetic and non-photosynthetic leaf tissues indicated the potential roles of some MADS-box genes in pineapple CAM photosynthesis. The 23% of pineapple MADS-box genes showed diurnal rhythm, indicating that these MADS-box genes are regulated by circadian clock. MADS-box genes identified in pineapple are closely related to flowering development. Some MADS-box genes are involved in CAM photosynthesis and regulated by the circadian clock. These findings will facilitate research on the development of unusual spiral inflorescences on pineapple fruit and CAM photosynthesis.


AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency.
A main function of white adipose tissue is to release fatty acids from stored triacylglycerol for other tissues to use as an energy source. Whereas endocrine regulation of lipolysis has been extensively studied, autocrine and paracrine regulation is not well understood. Here we describe the role of the newly identified major adipocyte phospholipase A(2), AdPLA (encoded by Pla2g16, also called HREV107), in the regulation of lipolysis and adiposity. AdPLA-null mice have a markedly higher rate of lipolysis owing to increased cyclic AMP levels arising from the marked reduction in the amount of adipose prostaglandin E(2) that binds the Galpha(i)-coupled receptor, EP3. AdPLA-null mice have markedly reduced adipose tissue mass and triglyceride content but normal adipogenesis. They also have higher energy expenditure with increased fatty acid oxidation within adipocytes. AdPLA-deficient ob/ob mice remain hyperphagic but lean, with increased energy expenditure, yet have ectopic triglyceride storage and insulin resistance. AdPLA is a major regulator of adipocyte lipolysis and is crucial for the development of obesity.


Imaging Mass Cytometry and Single-Cell Genomics Reveal Differential Depletion and Repletion of B-Cell Populations Following Ofatumumab Treatment in Cynomolgus Monkeys.
Ofatumumab is the first, fully human, anti-CD20 monoclonal antibody in Phase 3 development for multiple sclerosis (MS). The study focused on changes in lymphocyte subsets in blood and lymphoid tissues and on potential novel biomarkers as a result of anti-CD20 antibody action in Cynomolgus monkeys treated with human equivalent doses of subcutaneous (s.c.) ofatumumab on Days 0, 7, and 14. Axillary lymph nodes (LNs) and blood samples were collected at various time points until Day 90. Lymphocyte subsets were quantified by flow cytometry, while morphological and immune cell changes were assessed by imaging mass cytometry (IMC), immunohistochemistry (IHC), in situ hybridization (ISH), and transcriptome analyses using single-cell methodology. Ofatumumab treatment resulted in a potent and rapid reduction of B cells along with a simultaneous drop in CD20+ T cell counts. At Day 21, IHC revealed B-cell depletion in the perifollicular and interfollicular area of axillary LNs, while only the core of the germinal center was depleted of CD20+CD21+ cells. By Day 62, the perifollicular and interfollicular areas were abundantly infiltrated by CD21+ B cells and this distribution returned to the baseline cytoarchitecture by Day 90. By IMC CD20+CD3+CD8+ cells could be identified at the margin of the follicles, with a similar pattern of distribution at Day 21 and 90. Single-cell transcriptomics analysis showed that ofatumumab induced reversible changes in t-distributed stochastic neighbor embedding (t-SNE) defined B-cell subsets that may serve as biomarkers for drug action. In summary, low dose s.c. ofatumumab potently depletes both B cells and CD20+ T cells but apparently spares marginal zone (MZ) B cells in the spleen and LN. These findings add to our molecular and tissue-architectural understanding of ofatumumab treatment effects on B-cell subsets.


Variations in outcomes by residential location for women with breast cancer: a systematic review.
To systematically assess the evidence for variations in outcomes at each step along the breast cancer continuum of care for Australian women by residential location. Systematic review. Systematic searches of peer-reviewed articles in English published from 1 January 1990 to 24 November 2017 using PubMed, EMBASE, CINAHL and Informit databases. Inclusion criteria were: population was adult female patients with breast cancer; Australian setting; outcome measure was survival, patient or tumour characteristics, screening rates or frequencies, clinical management, patterns of initial care or post-treatment follow-up with analysis by residential location or studies involving non-metropolitan women only. Included studies were critically appraised using a modified Newcastle-Ottawa Scale. Seventy-four quantitative studies met the inclusion criteria. Around 59% were considered high quality, 34% moderate and 7% low. No eligible studies examining treatment choices or post-treatment follow-up were identified. Non-metropolitan women consistently had poorer survival, with most of this differential being attributed to more advanced disease at diagnosis, treatment-related factors and socioeconomic disadvantage. Compared with metropolitan women, non-metropolitan women were more likely to live in disadvantaged areas and had differing clinical management and patterns of care. However, findings regarding geographical variations in tumour characteristics or diagnostic outcomes were inconsistent. A general pattern of poorer survival and variations in clinical management for Australian female patients with breast cancer from non-metropolitan areas was evident. However, the wide variability in data sources, measures, study quality, time periods and geographical classification made direct comparisons across studies challenging. The review highlighted the need to promote standardisation of geographical classifications and increased comparability of data systems. It also identified key gaps in the existing literature including a lack of studies on advanced breast cancer, geographical variations in treatment choices from the perspective of patients and post-treatment follow-up.


Sizing mitigation wetlands in agricultural watersheds.
In this study, we investigated use of microcosms to supplement field studies for establishing the size of wetlands required to mitigate nitrate pollution in agricultural watersheds. Wetlands investigated in this study were located in San Joaquin Valley (California, USA) and demonstrated mean nitrate-nitrogen mass removal efficiencies ranging between 10 and 34%. Mean areal nitrate removal rates (J) ranged from 142 to 380 mg-N m(-2) d(-1). First-order rate constants determined from field data had a high variance, with confidence intervals greater than 57% of mean values. Sediments and rooted plants from one site were placed in a flow-through microcosm and measurements of nitrate removal kinetics were made and compared with field results. The apparent half-saturation constant (K(m)) and maximum removal rate (J(max)) for nitrate-nitrogen were 43.8 mg/L and 4.11 g m(-2) d(-1) in the microcosm. The first-order rate constant from the microcosm (10.4 cm d(-1)) was in close agreement with the value for the field site (11.9 cm d(-1)) and had a confidence interval of less than 16%. Using this improved first-order rate constant, it was determined that between 1.3 and 3.6% of the land in the watershed should be managed as mitigation wetland, with the area required dependent on the level of nitrate reduction desired and how closely the wetland design approximates plug-flow.


Accuracy of diagnostic tests in multiple sclerosis--a systematic review.
New diagnostic criteria for multiple sclerosis (MS) have been recently proposed and further updates are upcoming. This systematic literature review summarizes diagnostic studies in suspected MS to clarify the value of diagnostic tests. We included studies of at least 40 patients followed up for 2 years. All studies are limited by the fact that no gold standard to validate diagnostic tests is available. A second relapse is used as a surrogate in relapsing-remitting MS, but long follow-up of at least 5 years is necessary to detect all cases. Many studies showed selection bias, partly because of the vague definition of a clinically isolated syndrome. Based on these limitations, sensitivity of magnetic resonance imaging (MRI) criteria was between 35% and 100%, and specificity was between 36% and 92%. Cerebrospinal fluid (CSF) oligoclonal banding showed sensitivities between 69% and 91% with specificities between 59% and 94%. Combination studies of MRI and CSF indicate enhanced sensitivity (56-100%) and specificity (53-96%). Studies on evoked potentials did not justify conclusions about their value. A combination of simplified MRI criteria with CSF might be the best approach for an early MS diagnosis. However, the value of a very early diagnosis stays questionable as patients' benefit of new diagnostic criteria has never been addressed.


Measurement of health status in diabetic patients. Diabetes impact measurement scales.
To develop an instrument to measure health status in adult insulin-dependent (type I) and non-insulin-dependent (type II) diabetic patients. Correlative study to examine psychometric properties of the questionnaire. Test-retest reliability, item-scale correlations, principal-components analysis, correlations with global clinical ratings, and correlations with clinical data extracted from medical records were examined at the diabetes clinics at the University of California, Davis, Medical Center. Patients were volunteer clinic patients able to complete the questionnaire. One hundred thirty patients completed a first administration of the questionnaire, and 52 completed a second administration. Test-retest reliability was satisfactory. Item-scale correlations showed that 40 of 44 questionnaire items were highly correlated with subscale and total scale scores. Principal-components analysis identified one major factor measured by the questionnaire. Cronbach's alpha, a measure of the scales' internal consistency, was of satisfactory magnitude. Global ratings of clinical status by patients and clinicians were highly correlated with scale scores. Correlations of scale scores with clinical data were generally of low magnitude but, where significant, were consistently in the direction hypothesized if the scale truly measures health status or disease impact. The Diabetes Impact Management Scales (DIMS) is an easily administered questionnaire with internal consistency and test-retest reliability. Preliminary correlative analyses support the validity of the instrument as a measure of health status in adult type I and type II diabetic patients. Further work will be necessary to firmly establish the validity of the DIMS and its usefulness in clinical outcomes research.


Newspaper Articles Related to the Not Criminally Responsible on Account of Mental Disorder (NCRMD) Designation: A Comparative Analysis.
The not criminally responsible on account of mental disorder (NCRMD) designation remains widely misunderstood by the public. Such misunderstandings may also be reflected in the media. As such, the aim of this study is to conduct a preliminary examination of the tone and content of recent Canadian newspaper articles where NCRMD is a major theme, comparing these to generic articles about mental illness. Articles about mental illness were gathered from major Canadian newspapers. These were then divided into two categories: 1) articles where NCRMD was a major theme and 2) articles where NCRMD was not a major theme. Articles were then coded for the presence or absence of 1) a negative tone, 2) stigmatising tone/content, 3) recovery/rehabilitation as a theme, and 4) shortage of resources/poor quality of care as a theme. The retrieval strategy resulted in 940 articles. Fourteen percent ( n = 131) of all articles had NCRMD as a major theme. In comparison to generic articles about mental illness, articles with NCRMD as a major theme were significantly more likely to have a negative tone ( P < 0.001) and stigmatising tone/content ( P < 0.001) and significantly less likely to have recovery/rehabilitation ( P < 0.001) or shortage of resources/poor quality of care as a theme ( P < 0.001). Articles with NCRMD as a theme were overwhelmingly negative and almost never focused on recovery or rehabilitation, in stark comparison to generic articles about mental illness.


Accuracy of the direct agglutination test for diagnosis of visceral leishmaniasis: a systematic review and meta-analysis.
Parasitological investigation of bone marrow, splenic or lymph node aspirations is the gold standard for the diagnosis of visceral leishmaniasis (VL). However, this invasive test requires skilled clinical and laboratory staff and adequate facilities, and sensitivity varies depending on the tissue used. The direct agglutination test (DAT) is a serological test that does not need specialised staff, with just minimal training required. While previous meta-analysis has shown DAT to have high sensitivity and specificity when using parasitology as the reference test for diagnosis, meta-analysis of DAT compared to other diagnostic techniques, such as PCR and ELISA, that are increasingly used in clinical and research settings, has not been done. We conducted a systematic review to determine the diagnostic performance of DAT compared to all available tests for the laboratory diagnosis of human VL. We searched electronic databases including Medline, Embase, Global Health, Scopus, WoS Science Citation Index, Wiley Cochrane Central Register of Controlled Trials, Africa-Wide Information, LILACS and WHO Global Index. Three independent reviewers screened reports and extracted data from eligible studies. A meta-analysis estimated the diagnostic sensitivity and specificity of DAT. Of 987 titles screened, 358 were selected for full data extraction and 78 were included in the analysis, reporting on 32,822 participants from 19 countries. Studies included were conducted between 1987-2020. Meta-analysis of studies using serum and DAT compared to any other test showed pooled sensitivity of 95% (95%CrI 90-98%) and pooled specificity of 95% (95%CrI 88-98%). Results were similar for freeze-dried DAT and liquid DAT when analysed separately. Sensitivity was lower for HIV-positive patients (90%, CrI 59-98%) and specificity was lower for symptomatic patients (70%, CrI 43-89%). When comparing different geographical regions, the lowest median sensitivity (89%, CrI 67-97%) was in Western Asia (five studies). This systematic review and meta-analysis demonstrates high estimated pooled sensitivity and specificity of DAT for diagnosis of VL, although sensitivity and specificity were lower for different patient groups and geographical locations. This review highlights the lack of standardisation of DAT methods and preparations, and the lack of data from some important geographical locations. Future well-reported studies could provide better evidence to inform test implementation for different patient populations and use cases. CRD42021240830.


The Impact of Epicatechin on Human Cognition: The Role of Cerebral Blood Flow.
Epicatechin is a monomeric flavanol found in food sources such as tea, apples, berries and cocoa. A number of large-scale epidemiological studies have demonstrated an association between the consumption of these foods and cognitive function, as well as improved blood flow. The aim of this review is to summarise the evidence from intervention studies to clarify the effect of epicatechin on cognition and to consider the role of increased cerebral blood flow as a mechanism for any effects. The effects of epicatechin as consumed in cocoa are, therefore, reviewed here as this represents the only dietary source where it is purported to be the major active component. Our main findings are that a) the positive modulation of tasks that involve memory, executive function and processing speed in older adults; b) the cognitive benefits are more often shown in studies containing more than 50 mg epicatechin/day; and c) all studies with a duration of 28 days or longer in populations >50 years old demonstrate a cognitive improvement. However, as highlighted by this review, it is not currently possible to attribute effects solely to epicatechin without consideration of synergies. In order to overcome this issue, further studies examining the cognitive effects of epicatechin in isolation are required. The role of cerebral blood flow also requires further investigation through simultaneous measurement alongside cognitive function.


Right pneumonectomy for carcinoid tumor extending through the intermediate bronchus and the interlobar artery.
Uniportal video-assisted thoracic surgery (VATS) is the emerging technique in the modern thoracic surgery practice in Assiut University Hospitals in Egypt we try to keep up with the cutting edge of knowledge to deliver the best available service to our patient. So we invite Dr. Diego Gonzalez-Rivas the world pioneer surgeon in uniportal VATS approach to initiate a uniportal VATS program starting with a workshop with live surgery. The workshop was attended by 84 thoracic surgeons from all across Egypt with a high motivation for adopting the technique in the everyday practice. We believe that uniportal will be the first choice approach for thoracic surgeon in Egypt in the upcoming year.


Terahertz multilevel phase Fresnel lenses fabricated by laser patterning of silicon.
Multilevel phase Fresnel lenses (MPFLs) with a high numerical aperture for 0.58 THz frequencies were developed. The components based on a monocrystalline silicon wafer are prepared by patterning by a high-speed industrial-scale laser direct writing (LDW) system. Two consistent series of the terahertz-MPFLs with phase quantization levels varying between 2 and the continuous kinoform shape for the focal lengths of 5 and 10 mm were produced employing inherent flexibility of the LDW fabrication process. The focusing performance was studied at the optimal 0.58 THz frequency using a Gaussian beam profile and scanning 2D intensity distribution with a terahertz detector along the optical axis. The efficiency of the terahertz-MPFL was found to be dependent of the number of subzones. The position and orientation angles of the patterned plane of the silicon wafer were considered to reduce the effect of standing waves formation in the experiment.


Root Dentine Thickness and Concavity Depth in Mandibular Molars: A Cone Beam Computed Tomography Population Study.
The purposes of the present study were to evaluate dentine thickness and concavity depth below the furcation level of the mesial canals of the mandibular first and second molars, to examine differences between gender, age, and quadrant, and to prove if there is a relationship between root length and dentine thickness. Two hundred eleven mandibular first and second molars were included in this study. Samples were divided according to age, gender, quadrant, and root length. Measurements of dentine thickness from the external border of the root canal to the external root surface and concavity depth were recorded 1, 2, and 4 mm below the furcation level. Kruskal-Wallis and Wilcoxon rank sum tests were performed to estimate the influence of different variables, and a multiple regression analysis was performed to evaluate the influence of dentine thickness below the furcation level. First molars had a deeper concavity depth with significant differences in both 1 mm and 2 mm levels than second molars (P<0.05). According to concavity depth, there was no relationship with teeth length (P>0.05). The distal concavity was significantly deeper in the 1 and 2 mm levels (P<0.05). According to gender, the female group had a reduced dentine thickness in both mesiolingual and mesiobuccal canals in both 1 mm and 2 mm levels (P<0.05). Female patients have a reduced dentine thickness below the furcation level. In order to select the most appropriate instrumentation procedure in every specific case, clinicians must be aware of the dentine reduced thickness measurements to avoid procedural iatrogenic damage.


Acute effect of calcium citrate on serum calcium and cardiovascular function.
Calcium supplements have been associated with an increased risk of cardiovascular events. However, the validity of these findings has been questioned. A major concern is that the mechanism underlying an increase in cardiovascular events has not been demonstrated. Calcium initiates cardiac and vascular contraction following influx of calcium into cardiac and smooth muscle from extracellular fluid. We have investigated whether the acute rise in serum calcium following calcium supplement administration is associated with adverse changes in cardiovascular function. In an open interventional study, we recruited 25 volunteers (16 female, age 60.3 ± 6.5 years, body mass index 25.7 ± 2.7 kg/m2) from the community who were not taking calcium supplements. Participants were studied before and 3 hours after a single oral dose of 1000 mg calcium citrate. We assessed well-validated markers of arterial stiffness (pulse wave velocity [PWV]), arterial wave reflection (augmentation index [AIx]), and myocardial perfusion (subendocardial viability ratio [SEVR]) by pulse wave analysis and endothelial function (reactive hyperemia index [RHI]) by peripheral arterial tonometry. Total and ionized serum calcium were acutely increased by 0.10 ± 0.07 and 0.06 ± 0.03 mmol/L, respectively, 3 hours after calcium citrate administration (p < 0.0001 for both comparisons). Following administration of calcium citrate there was a fall in AIx from a median of 29.7% (23.8% to 34.0%) to 26.4% (22.7% to 34.0%, p = 0.03) and an increase in SEVR from 163% (148% to 174%) to 170% (149% to 185%, p = 0.007). PWV and RHI were not significantly altered. The change in total calcium was negatively correlated with the change in AIx (r = -0.48, p = 0.02). In summary, the acute increase in serum calcium following calcium supplement administration is associated with reduced arterial wave reflection and a marker of increased myocardial perfusion. If maintained long-term, these changes would be expected to reduce cardiovascular risk. Acute serum calcium-mediated changes in these parameters of cardiovascular function are unlikely to underlie an association between calcium supplementation and cardiovascular events.


Detection of chemical exchange in methyl groups of macromolecules.
The zero- and double-quantum methyl TROSY Hahn-echo and the methyl 1H-1H dipole-dipole cross-correlation nuclear magnetic resonance experiments enable estimation of multiple quantum chemical exchange broadening in methyl groups in proteins. The two relaxation rate constants are established to be linearly dependent using molecular dynamics simulations and empirical analysis of experimental data. This relationship allows chemical exchange broadening to be recognized as an increase in the Hahn-echo relaxation rate constant. The approach is illustrated by analyzing relaxation data collected at three temperatures for E. coli ribonuclease HI and by analyzing relaxation data collected for different cofactor and substrate complexes of E. coli AlkB.


Tumor engraftment in nude mice and enrichment in stroma- related gene pathways predict poor survival and resistance to gemcitabine in patients with pancreatic cancer.
The goal of this study was to evaluate prospectively the engraftment rate, factors influencing engraftment, and predictability of clinical outcome of low-passage xenografts from patients with resectable pancreatic ductal adenocarcinoma (PDA) and to establish a bank of PDA xenografts. Patients with resectable PDA scheduled for resection at the Johns Hopkins Hospital were eligible. Representative pieces of tumor were implanted in nude mice. The status of the SMAD4 gene and content of tumor-generating cells were determined by immunohistochemistry. Gene expression was carried out by using a U133 Plus 2.0 array. Patients were followed for progression and survival. A total of 94 patients with PDA were resected, 69 tumors implanted in nude mice, and 42 (61%) engrafted. Engrafted carcinomas were more often SMAD4 mutant, and had a metastatic gene expression signature and worse prognosis. Tumors from patients resistant to gemcitabine were enriched in stroma-related gene pathways. Tumors sensitive to gemcitabine were enriched in cell cycle and pyrimidine gene pathways. The time to progression for patients who received treatment with gemcitabine for metastatic disease (n = 7) was double in patients with xenografts sensitive to gemcitabine. A successful xenograft was generated in 61% of patients attempted, generating a pool of 42 PDA xenografts with significant biological information and annotated clinical data. Patients with PDA and SMAD4 inactivation have a better engraftment rate. Engraftment is a poor prognosis factor, and engrafted tumors have a metastatic gene expression signature. Tumors from gemcitabine-resistant patients were enriched in stromal pathways.


X-ray micro-modulated luminescence tomography (XMLT).
Imaging depth of optical microscopy has been fundamentally limited to millimeter or sub-millimeter due to strong scattering of light in a biological sample. X-ray microscopy can resolve spatial details of few microns deep inside a sample but contrast resolution is inadequate to depict heterogeneous features at cellular or sub-cellular levels. To enhance and enrich biological contrast at large imaging depth, various nanoparticles are introduced and become essential to basic research and molecular medicine. Nanoparticles can be functionalized as imaging probes, similar to fluorescent and bioluminescent proteins. LiGa(5)O(8):Cr(3+) nanoparticles were recently synthesized to facilitate luminescence energy storage with x-ray pre-excitation and subsequently stimulated luminescence emission by visible/near-infrared (NIR) light. In this paper, we propose an x-ray micro-modulated luminescence tomography (XMLT, or MLT to be more general) approach to quantify a nanophosphor distribution in a thick biological sample with high resolution. Our numerical simulation studies demonstrate the feasibility of the proposed approach.


Healthcare for persons with intellectual and developmental disability in the community.
While there has been impressive progress in creating and improving community healthcare delivery systems that support people with intellectual and developmental disabilities (IDD), there is much more that can and should be done. This paper offers a review of healthcare delivery concepts on which new models are being developed, while also establishing an historical context. We review the need for creating fully integrated models of healthcare, and at the same time offer practical considerations that range from specific healthcare delivery system components to the need to expand our approach to training healthcare providers. The models and delivery systems, and the areas of needed focus in their development are reviewed to set a starting point for more and greater work going forward. Today, we celebrate longer life spans of people with IDD, increased attention to the benefits of healthcare that is responsive to their needs, and the development of important healthcare delivery systems that are customized to their needs. We also know that the growing body of research on health status offers incentive to continue developing healthcare structures for people with IDD by training healthcare providers about the needs of people with IDD, by establishing systems of care that integrate acute healthcare with long-term services and support, by developing IDD medicine as a specialty, and by building health promotion and wellness resources to provide people with IDD a set of preventative health supports.


Ecological adaptation of diverse honey bee (Apis mellifera) populations.
Honey bees are complex eusocial insects that provide a critical contribution to human agricultural food production. Their natural migration has selected for traits that increase fitness within geographical areas, but in parallel their domestication has selected for traits that enhance productivity and survival under local conditions. Elucidating the biochemical mechanisms of these local adaptive processes is a key goal of evolutionary biology. Proteomics provides tools unique among the major 'omics disciplines for identifying the mechanisms employed by an organism in adapting to environmental challenges. Through proteome profiling of adult honey bee midgut from geographically dispersed, domesticated populations combined with multiple parallel statistical treatments, the data presented here suggest some of the major cellular processes involved in adapting to different climates. These findings provide insight into the molecular underpinnings that may confer an advantage to honey bee populations. Significantly, the major energy-producing pathways of the mitochondria, the organelle most closely involved in heat production, were consistently higher in bees that had adapted to colder climates. In opposition, up-regulation of protein metabolism capacity, from biosynthesis to degradation, had been selected for in bees from warmer climates. Overall, our results present a proteomic interpretation of expression polymorphisms between honey bee ecotypes and provide insight into molecular aspects of local adaptation or selection with consequences for honey bee management and breeding. The implications of our findings extend beyond apiculture as they underscore the need to consider the interdependence of animal populations and their agro-ecological context.


Surge capacity logistics: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement.
Successful management of a pandemic or disaster requires implementation of preexisting plans to minimize loss of life and maintain control. Managing the expected surges in intensive care capacity requires strategic planning from a systems perspective and includes focused intensive care abilities and requirements as well as all individuals and organizations involved in hospital and regional planning. The suggestions in this article are important for all involved in a large-scale disaster or pandemic, including front-line clinicians, hospital administrators, and public health or government officials. Specifically, this article focuses on surge logistics-those elements that provide the capability to deliver mass critical care. The Surge Capacity topic panel developed 23 key questions focused on the following domains: systems issues; equipment, supplies, and pharmaceuticals; staffing; and informatics. Literature searches were conducted to identify studies upon which evidence-based recommendations could be made. The results were reviewed for relevance to the topic, and the articles were screened by two topic editors for placement within one of the surge domains noted previously. Most reports were small scale, were observational, or used flawed modeling; hence, the level of evidence on which to base recommendations was poor and did not permit the development of evidence-based recommendations. The Surge Capacity topic panel subsequently followed the American College of Chest Physicians (CHEST) Guidelines Oversight Committee's methodology to develop suggestion based on expert opinion using a modified Delphi process. This article presents 22 suggestions pertaining to surge capacity mass critical care, including requirements for equipment, supplies, and pharmaceuticals; staff preparation and organization; methods of mitigating overwhelming patient loads; the role of deployable critical care services; and the use of transportation assets to support the surge response. Critical care response to a disaster relies on careful planning for staff and resource augmentation and involves many agencies. Maximizing the use of regional resources, including staff, equipment, and supplies, extends critical care capabilities. Regional coalitions should be established to facilitate agreements, outline operational plans, and coordinate hospital efforts to achieve predetermined goals. Specialized physician oversight is necessary and if not available on site, may be provided through remote consultation. Triage by experienced providers, reverse triage, and service deescalation may be used to minimize ICU resource consumption. During a temporary loss of infrastructure or overwhelmed hospital resources, deployable critical care services should be considered.


X-ray phase, absorption and scatter retrieval using two or more phase contrast images.
We have developed two phase-retrieval techniques for analyser-based phase contrast imaging that provide information about an object's X-ray absorption, refraction and scattering properties. The first requires rocking curves to be measured with and without the sample and improves upon existing techniques by accurately fitting the curves with Pearson type VII functions. The second employs an iterative approach using two simultaneously recorded images by exploiting the Laue crystal geometry. This technique provides a substantial reduction in X-ray dose and enables quantitative phase retrieval to be performed on images of moving objects.


Interpretation of the molecular mechanism of the electroporation induced by symmetrical bipolar picosecond pulse trains.
Picosecond pulse trains (psPTs) are emerging as a new characteristic diagnostic and therapeutic tool in biomedical fields. To specifically determine the stimulus provided to cells, in this article, we use a molecular dynamics (MD) model to show the molecular mechanisms of electroporation induced by symmetrical bipolar psPTs and predict a bipolar cancellation for the studied picosecond pulses. Electric field conditions that do not cause electroporation reveal that the interfacial water molecules continuously flip and redirect as the applied bipolar psPT reverses, and the molecules cannot keep moving in one direction or leave the lipid-water interface. Based on our simulation results, we determine the threshold for electroporation with symmetrical bipolar psPTs. For a fixed electric field intensity, a lower repetition frequency leads to more rapid electroporation. For a fixed repetition frequency, a higher electric field intensity leads to more rapid electroporation. We found that the water dipole relaxation time decreases as the electric field magnitude increases. Additionally, the influences of the symmetrical bipolar psPT intensity and frequency on the pore formation time are presented. Discrete nanoscale pores can form with the applied psPT at terahertz (THz) repetition frequency. When the psPT amplitude increases or the frequency decreases, the number of water bridges will increase. Moreover, for the first time, the molecular mechanism of bipolar cancellation for the studied picosecond pulse is discussed preliminarily. Our results indicate that the influence of the unipolar picosecond pulse on the interfacial water dipoles will accumulate in one direction, but the bipolar picosecond pulse does not cause this effect.


Anatomy, ontogeny, and evolution of the archosaurian respiratory system: A case study on Alligator mississippiensis and Struthio camelus.
The avian lung is highly specialized and is both functionally and morphologically distinct from that of their closest extant relatives, the crocodilians. It is highly partitioned, with a unidirectionally ventilated and immobilized gas-exchanging lung, and functionally decoupled, compliant, poorly vascularized ventilatory air-sacs. To understand the evolutionary history of the archosaurian respiratory system, it is essential to determine which anatomical characteristics are shared between birds and crocodilians and the role these shared traits play in their respective respiratory biology. To begin to address this larger question, we examined the anatomy of the lung and bronchial tree of 10 American alligators (Alligator mississippiensis) and 11 ostriches (Struthio camelus) across an ontogenetic series using traditional and micro-computed tomography (µCT), three-dimensional (3D) digital models, and morphometry. Intraspecific variation and left to right asymmetry were present in certain aspects of the bronchial tree of both taxa but was particularly evident in the cardiac (medial) region of the lungs of alligators and the caudal aspect of the bronchial tree in both species. The cross-sectional area of the primary bronchus at the level of the major secondary airways and cross-sectional area of ostia scaled either isometrically or negatively allometrically in alligators and isometrically or positively allometrically in ostriches with respect to body mass. Of 15 lung metrics, five were significantly different between the alligator and ostrich, suggesting that these aspects of the lung are more interspecifically plastic in archosaurs. One metric, the distances between the carina and each of the major secondary airways, had minimal intraspecific or ontogenetic variation in both alligators and ostriches, and thus may be a conserved trait in both taxa. In contrast to previous descriptions, the 3D digital models and CT scan data demonstrate that the pulmonary diverticula pneumatize the axial skeleton of the ostrich directly from the gas-exchanging pulmonary tissues instead of the air sacs. Global and specific comparisons between the bronchial topography of the alligator and ostrich reveal multiple possible homologies, suggesting that certain structural aspects of the bronchial tree are likely conserved across Archosauria, and may have been present in the ancestral archosaurian lung.


True polar wander as a mechanism for second-order sea-level variations
Long-term wander of the rotation pole can be a significant contributor to second-order (time scales of approximately 100 million years) sea-level variations. Numerical predictions based on realistic viscoelastic Earth models and paleomagnetically constrained polar motion yield global-scale, differential sea-level trends that can be as large as approximately 200 meters. From the results presented here, it is argued that the well-documented, second-order, Cretaceous-Tertiary sea-level cycle should be reinterpreted as some combination of a eustatic and a regionally varying rotational signal.


Platelet function defects in adolescents with heavy menstrual bleeding.
Platelet function defects (PFD) are reported to occur frequently in adult women with heavy menstrual bleeding (HMB). Few studies on adolescent HMB report varying incidence rates (2-44%) for PFD. We reviewed our institutional experience in detecting and managing PFD in adolescent HMB. Postmenarchial girls and adolescents with HMB seen at our institution undergo a comprehensive bleeding disorder work-up by paediatric haematology and paediatric gynaecology providers. Whole blood platelet aggregometry (WBPA) is performed as a second tier test after excluding thrombocytopaenia, coagulation factor deficiencies and Von Willebrand disease (VWD). We retrospectively reviewed the medical records of adolescents with HMB seen between June 2009 and November 2010, as approved by the Institutional Review Board. Patient demographics, clinical features, laboratory results, therapy details and patient outcome information were analysed. Overall, 114 postmenarchial girls and adolescents with HMB were evaluated; 68 patients (59%) had WBPA study performed. Nineteen patients (28%) had at least one aggregation or secretion defect; 12 (18%) had two or more such defects. Treatment included hormonal therapy (13/19; 68%), antifibrinolytic agents (8/19; 42%) and intra-nasal DDAVP (3/19; 16%). Thirteen patients (81%) had improved outcome (median follow-up--15.6 months; range of 1-66 months). In this study, PFD were identified in nearly one-third of girls with HMB, with the majority of these having two or more defects as identified by WBPA. Further prospective studies are needed to better define the prevalence and address appropriate management of HMB and other bleeding complications of PFD in adolescents.


Diversity and Distribution of Prokaryotes within a Shallow-Water Pockmark Field.
Pockmarks are crater-like depression on the seafloor associated with hydrocarbon ascent through muddy sediments in continental shelves around the world. In this study, we examine the diversity and distribution of benthic microbial communities at shallow-water pockmarks adjacent to the Middle Adriatic Ridge. We integrate microbial diversity data with characterization of local hydrocarbons concentrations and sediment geochemistry. Our results suggest these pockmarks are enriched in sedimentary hydrocarbons, and host a microbial community dominated by Bacteria, even in deeper sediment layers. Pockmark sediments showed higher prokaryotic abundance and biomass than surrounding sediments, potentially due to the increased availability of organic matter and higher concentrations of hydrocarbons linked to pockmark activity. Prokaryotic diversity analyses showed that the microbial communities of these shallow-water pockmarks are unique, and comprised phylotypes associated with the cycling of sulfur and nitrate compounds, as well as numerous know hydrocarbon degraders. Altogether, this study suggests that shallow-water pockmark habitats enhance the diversity of the benthic prokaryotic biosphere by providing specialized environmental niches.


A Bayesian method for comparing and combining binary classifiers in the absence of a gold standard.
Many problems in bioinformatics involve classification based on features such as sequence, structure or morphology. Given multiple classifiers, two crucial questions arise: how does their performance compare, and how can they best be combined to produce a better classifier? A classifier can be evaluated in terms of sensitivity and specificity using benchmark, or gold standard, data, that is, data for which the true classification is known. However, a gold standard is not always available. Here we demonstrate that a Bayesian model for comparing medical diagnostics without a gold standard can be successfully applied in the bioinformatics domain, to genomic scale data sets. We present a new implementation, which unlike previous implementations is applicable to any number of classifiers. We apply this model, for the first time, to the problem of finding the globally optimal logical combination of classifiers. We compared three classifiers of protein subcellular localisation, and evaluated our estimates of sensitivity and specificity against estimates obtained using a gold standard. The method overestimated sensitivity and specificity with only a small discrepancy, and correctly ranked the classifiers. Diagnostic tests for swine flu were then compared on a small data set. Lastly, classifiers for a genome-wide association study of macular degeneration with 541094 SNPs were analysed. In all cases, run times were feasible, and results precise. The optimal logical combination of classifiers was also determined for all three data sets. Code and data are available from http://bioinformatics.monash.edu.au/downloads/. The examples demonstrate the methods are suitable for both small and large data sets, applicable to the wide range of bioinformatics classification problems, and robust to dependence between classifiers. In all three test cases, the globally optimal logical combination of the classifiers was found to be their union, according to three out of four ranking criteria. We propose as a general rule of thumb that the union of classifiers will be close to optimal.


A role for silent synapses in the development of the pathway from layer 2/3 to 5 pyramidal cells in the neocortex.
The integration of neurons within the developing cerebral cortex is a prolonged process dependent on a combination of molecular and physiological cues. To examine the latter we used laser scanning photostimulation (LSPS) of caged glutamate in conjunction with whole-cell patch-clamp electrophysiology to probe the integration of pyramidal cells in the sensorimotor regions of the mouse neocortex. In the days immediately after postnatal day 5 (P5) the origin of the LSPS-evoked AMPA receptor (AMPAR)-mediated synaptic inputs were diffuse and poorly defined with considerable variability between cells. Over the subsequent week this coalesced and shifted, primarily influenced by an increased contribution from layers 2/3 cells, which became a prominent motif of the afferent input onto layer 5 pyramidal cells regardless of cortical region. To further investigate this particular emergent translaminar connection, we alternated our mapping protocol between two holding potentials (-70 and +40 mV) allowing us to detect exclusively NMDA receptor (NMDAR)-mediated inputs. This revealed distal MK-801-sensitive synaptic inputs that predict the formation of the mature, canonical layer 2/3 to 5 pathway. However, these were a transient feature and had been almost entirely converted to AMPAR synapses at a later age (P16). To examine the role of activity in the recruitment of early NMDAR synapses, we evoked brief periods (20 min) of rhythmic bursting. Short intense periods of activity could cause a prolonged augmentation of the total input onto pyramidal cells up until P12; a time point when the canonical circuit has been instated and synaptic integration shifts to a more consolidatory phase.


The beginning of the end for chimpanzee experiments?
The advanced sensory, psychological and social abilities of chimpanzees confer upon them a profound ability to suffer when born into unnatural captive environments, or captured from the wild--as many older research chimpanzees once were--and when subsequently subjected to confinement, social disruption, and involuntary participation in potentially harmful biomedical research. Justifications for such research depend primarily on the important contributions advocates claim it has made toward medical advancements. However, a recent large-scale systematic review indicates that invasive chimpanzee experiments rarely provide benefits in excess of their profound animal welfare, bioethical and financial costs. The approval of large numbers of these experiments--particularly within the US--therefore indicates a failure of the ethics committee system. By 2008, legislative or policy bans or restrictions on invasive great ape experimentation existed in seven European countries, Japan, Australia and New Zealand. In continuing to conduct such experiments on chimpanzees and other great apes, the US was almost completely isolated internationally. In 2007, however, the US National Institutes of Health National Center for Research Resources implemented a permanent funding moratorium on chimpanzee breeding, which is expected to result in a major decline in laboratory chimpanzee numbers over the next 30 years, as most are retired or die. Additionally, in 2008, The Great Ape Protection Act was introduced to Congress. The bill proposed to end invasive research and testing on an estimated 1,200 chimpanzees confined within US laboratories, and, for approximately 600 federally-owned, to ensure their permanent retirement to sanctuaries. These events have created an unprecedented opportunity for US legislators, researchers, and others, to consider a global ban on invasive chimpanzee research. Such a ban would not only uphold the best interests of chimpanzees, and other research fields presently deprived of funding, but would also increase the compliance of US animal researchers with internationally-accepted animal welfare and bioethical standards. It could even result in the first global moratorium on invasive research, for any non-human species, unless conducted in the best interests of the individual or species.


2C or not 2C: phenethylamine designer drug review.
New groups of synthetic "designer drugs" have increased in popularity over the past several years. These products mimic the euphoric effects of other well-known illicit drugs but are advertised as "legal" highs and are sold over the internet, at raves and night clubs, and in head shops. The 2C series drugs are ring-substituted phenethylamines that belong to a group of designer agents similar in structure to 3,4-methylenedioxy-N-methylamphetamine (MDMA, Ecstasy). Understanding the pharmacology and toxicology of these agents is essential in order to provide the best medical care for these patients. This review focuses on the pharmacology, pharmacokinetics, clinical effects, and treatment of 2C drug intoxication based on available published literature. Multiple names under which 2C drugs are sold were identified and tabulated. Common features identified in patients intoxicated with 2Cs included hallucinations, agitation, aggression, violence, dysphoria, hypertension, tachycardia, seizures, and hyperthermia. Patients may exhibit sympathomimetic symptoms or symptoms consistent with serotonin toxicity, but an excited delirium presentation seems to be consistent amongst deaths attributed to 2C drugs; at least five deaths have been reported in the literature in patients intoxicated with 2C drugs. 2C drugs are a group of designer intoxicants, many of which are marketed as legal, but may carry risks that consumers are unaware of. These drugs may be characterized by either serotonergic toxicity or a sympathomimetic toxidrome, but a presentation consistent with excited delirium is consistent amongst the reported 2C-related deaths. Treatment of 2C intoxication is primarily supportive, but immediate action is required in the context of excited delirium, hyperthermia, and seizure activity.


Prophylactic Irradiation of Tracts in Patients With Malignant Pleural Mesothelioma: An Open-Label, Multicenter, Phase III Randomized Trial.
Prophylactic irradiation to the chest wall after diagnostic or therapeutic procedures in patients with malignant pleural mesothelioma (MPM) has been a widespread practice across Europe, although the efficacy of this treatment is uncertain. In this study, we aimed to determine the efficacy of prophylactic radiotherapy in reducing the incidence of chest wall metastases (CWM) after a procedure in MPM. After undergoing a chest wall procedure, patients with MPM were randomly assigned to receive prophylactic radiotherapy (within 42 days of the procedure) or no radiotherapy. Open thoracotomies, needle biopsies, and indwelling pleural catheters were excluded. Prophylactic radiotherapy was delivered at a dose of 21 Gy in three fractions over three consecutive working days, using a single electron field adapted to maximize coverage of the tract from skin surface to pleura. The primary outcome was the incidence of CWM within 6 months from random assignment, assessed in the intention-to-treat population. Stratification factors included epithelioid histology and intention to give chemotherapy. Between July 30, 2012, and December 12, 2015, 375 patients were recruited from 54 centers and randomly assigned to receive prophylactic radiotherapy (n = 186) or no prophylactic radiotherapy (n = 189). Participants were well matched at baseline. No significant difference was seen in the incidence of CWM at 6 months between the prophylactic radiotherapy and no radiotherapy groups (no. [%]: 6 [3.2] v 10 [5.3], respectively; odds ratio, 0.60; 95% CI, 0.17 to 1.86; P = .44). Skin toxicity was the most common radiotherapy-related adverse event in the prophylactic radiotherapy group, with 96 patients (51.6%) receiving grade 1; 19 (10.2%), grade 2; and 1 (0.5%) grade 3 radiation dermatitis (Common Terminology Criteria for Adverse Events, version 4.0). There is no role for the routine use of prophylactic irradiation to chest wall procedure sites in patients with MPM.


Effects of estradiol on cognition and hippocampal pathology after lateral fluid percussion brain injury in female rats.
Studies involving animal models of acute central nervous system (CNS) stroke and trauma strongly indicate that sex and/or hormonal status are important determinants of outcome after brain injury. The present study was undertaken to examine the ability of estradiol to protect hippocampal neurons from lateral fluid percussion brain injury. Sprague-Dawley female rats (211-285 g; n = 119) were ovariectomized, and a subset (n = 66) were implanted with 17beta-estradiol pellets to provide near physiological levels of estradiol. Animals were subjected to lateral fluid percussion brain injury or sham injury 1 week later. Activation of caspase-3 (n = 26) and TUNEL staining (n = 21) were assessed at 3 and 12 h after injury, respectively, in surviving control and estradiol-treated animals. Memory retention was examined using a Morris water maze test in a separate subset of animals (n = 43) at 8 days after injury. Activated caspase-3 and TUNEL staining were observed in the dentate hilus, granule cell layer, and CA3 regions in all injured rats, indicative of selective hippocampal cell apoptosis in the acute posttraumatic period. Estradiol did not significantly alter the number of hippocampal neurons exhibiting caspase-3 activity or TUNEL staining. Brain injury impaired cognitive ability, assessed at 1 week post-injury (p < 0.001). However, estradiol at physiological levels did not significantly alter injury-induced loss of memory. These data indicate that estradiol at physiological levels does not ameliorate trauma-induced hippocampal injury or cognitive deficits in ovariectomized female rats.


Debriefing interventions for the prevention of psychological trauma in women following childbirth.
Childbirth is a complex life event that can be associated with both positive and negative psychological responses. When giving birth is experienced as particularly traumatic this can have a negative impact on a woman's postnatal emotional well-being. There has been an increasing focus on women's psychological trauma symptoms following childbirth, including the relatively rare phenomenon of post-traumatic stress disorder (PTSD), and the benefit of debriefing interventions to prevent this. In this review we examined the evidence for debriefing as a preventative intervention for psychological trauma following childbirth. To assess the effects of debriefing interventions compared with standard postnatal care for the prevention of psychological trauma in women following childbirth. The trials registers of the Cochrane Depression, Anxiety and Neurosis Group (CCDANCTR-References and CCDANCTR-Studies) and the Cochrane Pregnancy and Childbirth Group were searched up to 4 March 2015. These registers include relevant randomised controlled trials from the following bibliographic databases: the Cochrane Library (all years to date), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). Additional searches were conducted in CENTRAL, MEDLINE, EMBASE, PsycINFO, and Maternity and Infant Care. The reference lists of all included studies were checked for additional published reports and citations of unpublished research. Experts in the field were contacted. We included randomised controlled trials (RCTs) and quasi-randomised trials comparing postnatal debriefing interventions with standard postnatal care for the prevention of psychological trauma of women following childbirth. The intervention consisted of at least one debriefing intervention session, which had the purpose of allowing women to describe their experience and to normalise their emotional reaction to that experience. Three authors independently assessed trial quality and extracted data. Meta-analysis was conducted where there were more than two trials examining the same outcomes. We included seven trials (eight articles) from three countries (UK, Australia and Sweden) that fulfilled the inclusion criteria. The number of women contributing data to each outcome varied from 102 to 1745. Methodological quality was variable and most of the studies were of low quality. The quality of evidence for the prevalence of psychological trauma (primary outcome) and the prevalence of depression symptoms was rated low or very low, based on few studies (ranging from a single study to three studies) with high risk of bias in main domains such as performance bias, random sequence generation, allocation concealment and incomplete outcome data. The quality of evidence for the remaining outcomes (that is prevalence of anxiety, prevalence of fear of childbirth, prevalence of general psychological morbidity, health service utilization and attrition from treatment) was not assessed as data were not available.Among women who had a high level of obstetric intervention during labour and birth, we found no difference between standard postnatal care with debriefing and standard postnatal care without debriefing on psychological trauma symptoms within three months postpartum (RR 0.61; 95% CI 0.28 to 1.31; n = 425) or at three to six months postpartum (RR 0.62; 95% CI 0.27 to 1.42; n = 246). The results were based on two trials, respectively. Among women who experienced a distressing or traumatic birth, there was no evidence of an effect of psychological debriefing on the prevention of PTSD (measured by the MINI-PTSD) at four to six weeks postpartum (RR 1.15; 95% CI 0.66 to 2.01; n = 102) or at six months (RR 0.35; 95% CI 0.10 to 1.23; n = 103). The results were based on one small trial. One trial involving low-risk women who delivered healthy infants at or near term reported no significant difference between the intervention group and the control group in the proportion of women who met the diagnostic criteria for psychological trauma during the year following childbirth (RR 1.06; 95% CI 0.88 to 1.28; n = 1745). We did not find any information about attrition rates. We did not find any high quality evidence to inform practice, with substantial heterogeneity being found between the studies conducted to date. There is little or no evidence to support either a positive or adverse effect of psychological debriefing for the prevention of psychological trauma in women following childbirth. There is no evidence to support routine debriefing for women who perceive giving birth as psychologically traumatic.Future research should provide greater detail of the outcome measures used, and with scales for measuring psychological trauma validated against clinical diagnostic interviews. High rates of obstetric intervention in some birth settings may mean that women require improved emotional care from health professionals to reduce the risk of childbirth being experienced as traumatic. As all included trials excluded women unable to communicate in the native language of the study setting, there is no information on the response of these women to psychological debriefing. No included studies were conducted in low or middle-income countries.


Signal presequences increase mitochondrial permeability and open the multiple conductance channel.
We have reported that the signal presequence of cytochrome oxidase subunit IV from Neurospora crassa increases the permeability of isolated rat liver mitochondria [P. M. Sokolove and K. W. Kinnally (1996) Arch. Biochem. Biophys. 336, 69] and regulates the behavior of the mutiple conductance channel (MCC) of yeast inner mitochondrial membrane [T. A. Lohret and K. W. Kinnally (1995) J. Biol. Chem. 270, 15950]. Here we examine in greater detail the action of a number of mitochondrial presequences from various sources and of several control peptides on the permeability of isolated rat liver mitochondria and on MCC activity monitored via patch-clamp techniques in both mammalian mitoplasts and a reconstituted yeast system. The data indicate that the ability to alter mitochondrial permeability is a property of most, but not all, signal peptides. Furthermore, it is clear that, although signal peptides are characterized by positive charge and the ability to form amphiphilic alpha helices, these two characteristics are not sufficient to guarantee mitochondrial effects. Finally, the results reveal a strong correlation between peptide effects on the permeability of isolated mitochondria and on MCC activity: peptides that induced swelling of mouse and rat mitochondria also activated the quiescent MCC of mouse mitoplasts and induced flickering of active MCC reconstituted from yeast mitochondrial membranes. Moreover, relative peptide efficacies were very similar for mitochondrial swelling and both types of patch-clamp experiments. We propose that patch-clamp recordings of MCC activity and the high-amplitude swelling induced by signal peptides reflect the opening of a single channel. Based on the selective responsiveness of that channel to signal peptides and the dependence of its opening in isolated mitochondria on membrane potential, we further suggest that the channel is involved in the mitochondrial protein import process.


Escherichia coli K-12 tolZ mutants tolerant to colicins E2, E3, D, Ia, and Ib: defect in generation of the electrochemical proton gradient.
Spontaneous Escherichia coli K-12 mutants tolerant to colicin E3 were isolated, and on the basis of their tolerance patterns to 19 kinds of colicins, a new phenotypic class of tolZ mutants was found. The tolZ gene was located between min 77 and 78 on the E. coli K-12 genetic map. The tolZ mutants were tolerant to colicins E2, E3, D, Ia, and Ib, and showed an increased sensitivity to ampicillin, neomycin, and EDTA, but not to deoxycholate; they were able to grow on glucose minimal medium, but not on nonfermentable carbon sources (succinate, acetate, pyruvate, lactate, malate, etc.). The pleiotropic phenotype of the tolZ mutant was due to a single mutation. Both respiration and membrane ATPase activity of the tolZ mutant were normal. The tolZ mutant had a defect in the uptake of proline, glutamine, thiomethyl-beta-D-galactoside, and triphenylmethylphosphonium ion; these uptake systems are driven by an electrochemical proton gradient (delta-mu H+) or a membrane potential (delta psi). In contrast, the uptake of methionine and alpha-methyl-D-glucoside, which is not dependent on delta-mu H+ and delta psi, was normal in the tolZ mutant. Glucose 6-phosphate uptake at pH 5.5, which is driven by a transmembrane pH gradient, in the tolZ mutant was similar to the parent level. These results indicate that the tolZ mutant has a defect in the generation of delta-mu H+ and delta psi.


40-Gb/s directly-modulated photonic crystal lasers under optical injection-locking.
CMOS integrated circuits (IC) usually requires high data bandwidth for off-chip input/output (I/O) data transport with sufficiently low power consumption in order to overcome pin-count limitation. In order to meet future requirements of photonic network interconnect, we propose an optical output device based on an optical injection-locked photonic crystal (PhC) laser to realize low-power and high-speed off-chip interconnects. This device enables ultralow-power operation and is suitable for highly integrated photonic circuits because of its strong light-matter interaction in the PhC nanocavity and ultra-compact size. High-speed operation is achieved by using the optical injection-locking (OIL) technique, which has been shown as an effective means to enhance modulation bandwidth beyond the relaxation resonance frequency limit. In this paper, we report experimental results of the OIL-PhC laser under various injection conditions and also demonstrate 40-Gb/s large-signal direct modulation with an ultralow energy consumption of 6.6 fJ/bit.


Every Step Counts: Understanding the Success of Implementing The 10,000 Steps Project.
The 10,000 Steps program originated from a landmark whole-of-community multi-strategy intervention to increase physical activity (PA) in Rockhampton, Australia in 2001-2003. It used a social ecological framework to promote physical activity at the individual, population, environmental and policy level. Two of the fundamental aspects of the original program were goal setting (10,000 steps per day) and self-monitoring (use of a pedometer for daily step counts). A project website (www.10000steps.org.au) allowed registered participants to record their physical activity. Over time the program morphed into an e- & mHealth intervention without face-to-face elements. The program is now delivered via website and smartphone apps and employs activity trackers (pedometers, Fitbit, Garmin). To date the project has signed-up over 425,000 members who have logged 221 billion steps (∼43 million a day) on the website or app. More than 14,000 workplaces and community organisations have been involved with the program. A central element of the program, the 'Workplace Challenge' has been used by ∼65% of 10,000 Steps members, which on average increases physical activity by 159 min/week for those who participate in it. In 2011, the Queensland Government designated the 10,000 Steps program as their key physical activity workplace health promotion strategy. Multiple factors underpin the success of the program. The message is simple and clear: the project name, with its distinctive logo and tagline ('Every Step Counts') provides a clear and prescriptive target for the physical activity 'dose'. Using effective behaviour change techniques: goal setting (the 10,000 Steps concept), self-monitoring (steps are tracked), social support (participants organise as 'teams' to reach certain step goals) and gamification (teams competing against each other creating 'friendly competition'). Ongoing redevelopment: since inception, there have been three complete redesigns of the website (including a branding redesign), and new smartphone apps. More recently, the website was modified to allow syncing of steps using popular activity trackers. Resources to support implementation: the program provides resources (e.g. 'Active Workplace Guide') and has dedicated staff to respond to queries from workplaces and individuals to help overcome implementation barriers. Project staff continuously promote the program via media interviews, attendance at events, social media and marketing, advertising, and networking and collaboration. Ongoing evaluation has contributed to continuous funding: to ensure the program remains successful in a fast-changing technology environment, continuous evaluation has been necessary. These evaluation strategies, the success of the original project and the strong partnership with the program funder (Queensland Health) have all contributed to the long-term (19 years) support for the project.


Visualization of the hexagonal lattice in the erythrocyte membrane skeleton.
The isolated membrane skeleton of human erythrocytes was studied by high resolution negative staining electron microscopy. When the skeletal meshwork is spread onto a thin carbon film, clear images of a primarily hexagonal lattice of junctional F-actin complexes crosslinked by spectrin filaments are obtained. The regularly ordered network extends over the entire membrane skeleton. Some of the junctional complexes are arranged in the form of pentagons and septagons, approximately 3 and 8%, respectively. At least five forms of spectrin crosslinks are detected in the spread skeleton including a single spectrin tetramer linking two junctional complexes, three-armed Y-shaped spectrin molecules linking three junctional complexes, three-armed spectrin molecules connecting two junctional complexes with two arms bound to one complex and the third arm bound to the adjacent complex, double spectrin filaments linking two junctional complexes, and four-armed spectrin molecules linking two junctional complexes. Of these, the crosslinks of single spectrin tetramers and three-armed molecules are the most abundant and represent 84 and 11% of the total crosslinks, respectively. These observations are compatible with the presence of spectrin tetramers and oligomers in the erythrocyte membrane skeleton. Globular structures (9-12 nm in diameter) are attached to the majority of the spectrin tetramers or higher order oligomer-like molecules, approximately 80 nm from the distal ends of the spectrin tetramers. These globular structures are ankyrinor ankyrin/band 3-containing complexes, since they are absent when ankyrin and residual band 3 are extracted from the skeleton under hypertonic conditions.


Nanoparticle-proteome in vitro and in vivo.
The protein corona is a concept central to a range of disciplines exploiting the bio-nano interface. As the literature continues to expand in this field, it is essential to condense and contextualize the in vitro and in vivo proteome databases accumulated over the past decade: a goal which this review intends to achieve for the benefit of nanomedicine and nanobiotechnology. The parameters used for our review are the physicochemical characteristics of the nanoparticles, their surface ligands, the biological matrix from which a corona was formed, methods employed, plus the top-ten enriched corona proteins. In addition, the protein coronal networks and their implications in vivo are highlighted for selected studies.


First Report of Colletotrichum acutatum on Tomato and Apple Fruits in the Czech Republic.
Apple (Malus domestica Borkh.) is a fruit traditionally grown in the Czech Republic, and tomatoes (Solanum lycopersicum Mill.), too, are widely raised in this region. Colletotrichum acutatum J. H. Simmonds is a polyphagous fungal plant pathogen. Earlier, this pathogen caused disease on strawberry in the Czech Republic (2), and now it has become an important pathogen on safflower (4). During the 2010 harvest, anthracnose symptoms were noticed on the fruits of apple and tomato. Infected apples fruits (localities Velká Bíteš and Znojmo) and tomatoes (localities Velká Bíteš and Žabčice) were collected. Typical symptoms on fruit surfaces were round, brown, shriveled and sunken spots, 1.2 to 2.0 cm, with orange conidial masses appearing on the spots. A fungus was isolated from each host on potato dextrose agar and cultured at 25 ± 2°C for 10 days. Mycelium was superficial, partly immersed, and white to gray with occurrence of orange conidial masses. Conidia of the tomato and apple isolates were colorless and fusiform. The size of conidia from the apple and tomato isolates, respectively, ranged from 11 to 15 × 2.5 to 3.5 μm and 11 to 16 × 2.5 to 4 μm. Morphological characteristics suggested that the isolated fungi was a Colletotrichum sp. To fulfill Koch's postulates, healthy tomato and apple fruits were disinfected with 3% sodium hypochlorite for 2 min and rinsed in sterile distilled water. Fruits were pinpricked with a sterile needle and 10 μl of a spore suspension (1 × 105 conidia ml-1) was inoculated by pipetting into the wound. Control fruits were treated with sterile distilled water. The fruits were transferred to a growth cabinet and maintained at a temperature of 25 ± 2°C, relative humidity of 70 ± 5%, and a photoperiod of 12 h. Similar disease symptoms as in the collected fruits were observed on tomato fruits at 7 days and apple fruits at 20 days after inoculation, while no symptoms appeared on control fruits. The pathogen was reisolated from infected fruits. Species determination of the isolates was confirmed by PCR. Specific primers designed in region ITS1, the 5.8S RNA gene, and region ITS2 of the pathogen DNA were selected. Specific primers CaInt2 and ITS4 were used to identify C. acutatum (3), and primers CgInt and ITS4 were used to determine C. gloeosporioides isolate CCM 177 (1), which was used as a control. Our isolates yielded PCR products (490 bp) only with primers designed for C. acutatum. The C. gloeosporioides isolate yielded a PCR product (450 bp) only with CgInt and ITS4 primers. PCR products were sequenced and identified with the BLAST program. The sequence of the tomato fruit isolate (Accession No. JN676199) and apple fruit isolate (Accession No. JN676198) matched with 100% similarity to the C. acutatum sequences in GenBank. The control isolate of C. gloeosporioides matched 100% to sequences AJ749682 and AJ749692. To our knowledge, this is the first report of C. acutatum on tomato and apple fruits in the Czech Republic. This pathogen can endanger the production and storage of apples and tomatoes in this region. References: (1) P. R. Mills et al. FEMS Microbiol. Lett. 98:137, 1992. (2) D. Novotný et al. Plant Dis. 91:1516, 2007. (3) S. Sreenivasaprasad et al. Plant Pathol. 45:650, 1996. (4) J. Víchová et al. Plant Dis. 95:79, 2011.


Tree of life based on genome context networks.
Efforts in phylogenomics have greatly improved our understanding of the backbone tree of life. However, due to the systematic error in sequence data, a sequence-based phylogenomic approach leads to well-resolved but statistically significant incongruence. Thus, independent test of current phylogenetic knowledge is required. Here, we have devised a distance-based strategy to reconstruct a highly resolved backbone tree of life, on the basis of the genome context networks of 195 fully sequenced representative species. Along with strongly supporting the monophylies of three superkingdoms and most taxonomic sub-divisions, the derived tree also suggests some intriguing results, such as high G+C gram positive origin of Bacteria, classification of Symbiobacterium thermophilum and Alcanivorax borkumensis in Firmicutes. Furthermore, simulation analyses indicate that addition of more gene relationships with high accuracy can greatly improve the resolution of the phylogenetic tree. Our results demonstrate the feasibility of the reconstruction of highly resolved phylogenetic tree with extensible gene networks across all three domains of life. This strategy also implies that the relationships between the genes (gene network) can define what kind of species it is.


Estimating the current mean age of mothers at the birth of their first child from household surveys.
Estimates of the period mean age at first birth are readily available for countries with accurate vital statistics (i.e., in much of the developed world). In contrast, in most developing countries vital statistics are lacking or incomplete and estimates of the period mean age at first birth are therefore often unavailable. The Demographic and Health Surveys (DHS) program provides a large set of demographic and health statistics for many developing countries, but not the mean age at childbearing or the mean age at first birth. We propose two different methods for the estimation of the period mean age at first birth from information collected in DHS surveys. The first method is the same as the one used in populations with accurate vital statistics and is based on a weighted average of single year of age first birth rates. The second is the singulate mean age at first birth. A comparison of the two estimates obtained from the latest surveys in 62 countries shows excellent agreement in countries in which there is no evidence of a rise in childlessness. But, as expected on theoretical grounds, there is less agreement in populations that have experienced an increase in the proportion childless. Based on these results, we recommend the first method. The measure is relatively straightforward to calculate and, since it refers to recent births, is presumably more accurately reported than indicators based on events that occurred in the more distant past. This measure makes it possible for the first time to assess recent trends in the onset of childbearing in developing countries with multiple DHS surveys and to compare recent period estimates of the mean age at first birth among countries.


Etiology of persistent mathematics difficulties from childhood to adolescence following very preterm birth.
Children born very preterm (VP; <32 weeks' gestation) have poorer mathematics achievement than term-born peers. This study aimed to determine whether VP children's mathematics difficulties persist from primary to secondary school and to explore the nature of mathematics difficulties in adolescence. For this study, 127 VP and 95 term-born adolescents were assessed at age 11-15 years. Mathematics achievement was assessed using the Wechsler Individual Achievement Test-II. Specific mathematics skills and general cognitive skills were assessed using standardized and experimental tests. VP adolescents had poorer mathematics achievement than term-born adolescents (-10.95 points; 95% CI -16.18, -5.73) and poorer number fact knowledge, understanding of arithmetic concepts, written arithmetic, counting, reading and writing large numbers, and algebra. Between-group differences in mathematics skills were no longer significant when working memory and visuospatial skills were controlled for (p's >0.05), with the exception of writing large numbers and conceptual understanding of arithmetic. In a previous study, 83 of the VP adolescents and 49 of the term-born adolescents were assessed at age 8-10 years using measures of the same skills. Amongst these, the between-group difference in mathematics achievement remained stable over time. This study extends findings of a persistent deficit in mathematics achievement among VP children over the primary and secondary school years, and provides evidence of a deficit in factual, procedural and conceptual mathematics skills and in higher order mathematical operations among VP adolescents. We provide further evidence that VP children's mathematics difficulties are driven by deficits in domain-general rather than domain-specific cognitive skills.


Neural correlates of task switching in paternal 15q11-q13 deletion Prader-Willi syndrome.
We report a first study of brain activity linked to task switching in individuals with Prader-Willi syndrome (PWS). PWS individuals show a specific cognitive deficit in task switching which may be associated with the display of temper outbursts and repetitive questioning. The performance of participants with PWS and typically developing controls was matched in a cued task switching procedure, and brain activity was contrasted on switching and non-switching blocks using fMRI. Individuals with PWS did not show the typical frontal-parietal pattern of neural activity associated with switching blocks, with significantly reduced activation in regions of the posterior parietal and ventromedial prefrontal cortices. We suggest that this is linked to a difficulty in PWS in setting appropriate attentional weights to enable task-set reconfiguration. In addition to this, PWS individuals did not show the typical pattern of deactivation, with significantly less deactivation in an anterior region of the ventromedial prefrontal cortex. One plausible explanation for this is that individuals with PWS show dysfunction within the default mode network, which has been linked to attentional control. The data point to functional changes in the neural circuitry supporting task switching in PWS even when behavioural performance is matched to controls and thus highlight neural mechanisms that may be involved in a specific pathway between genes, cognition and behaviour.


Interleukin-1beta selectively expands and sustains interleukin-22+ immature human natural killer cells in secondary lymphoid tissue.
Among human natural killer (NK) cell intermediates in secondary lymphoid tissue (SLT), stage 3 CD34(-)CD117(+)CD161(+)CD94(-) immature NK (iNK) cells uniquely express aryl hydrocarbon receptor (AHR) and interleukin-22 (IL-22), supporting a role in mucosal immunity. The mechanisms controlling proliferation and differentiation of these cells are unknown. Here we demonstrate that the IL-1 receptor IL-1R1 was selectively expressed by a subpopulation of iNK cells that localized proximal to IL-1beta-producing conventional dendritic cells (cDCs) within SLT. IL-1R1(hi) iNK cells required continuous exposure to IL-1beta to retain AHR and IL-22 expression, and they proliferate in direct response to cDC-derived IL-15 and IL-1beta. In the absence of IL-1beta, a substantially greater fraction of IL-1R1(hi) iNK cells differentiated to stage 4 NK cells and acquired the ability to kill and secrete IFN-gamma. Thus, cDC-derived IL-1beta preserves and expands IL-1R1(hi)IL-22(+)AHR(+) iNK cells, potentially influencing human mucosal innate immunity during infection.


Temporal response of the human virome to immunosuppression and antiviral therapy.
There are few substantive methods to measure the health of the immune system, and the connection between immune strength and the viral component of the microbiome is poorly understood. Organ transplant recipients are treated with posttransplant therapies that combine immunosuppressive and antiviral drugs, offering a window into the effects of immune modulation on the virome. We used sequencing of cell-free DNA in plasma to investigate drug-virome interactions in a cohort of organ transplant recipients (656 samples, 96 patients) and find that antivirals and immunosuppressants strongly affect the structure of the virome in plasma. We observe marked virome compositional dynamics at the onset of the therapy and find that the total viral load increases with immunosuppression, whereas the bacterial component of the microbiome remains largely unaffected. The data provide insight into the relationship between the human virome, the state of the immune system, and the effects of pharmacological treatment and offer a potential application of the virome state to predict immunocompetence.


A Novel Patient-Specific Computational Fluid Dynamics Study of the Activation of Primary Collateral Pathways in the Circle of Willis During Vasospasm.
The Circle of Willis (CoW) is a redundant network of blood vessels that perfuses the brain. The ringlike anatomy mitigates the negative effects of stroke by activating collateral pathways that help maintain physiological perfusion. Previous studies have investigated the activation of these pathways during embolic stroke and internal carotid artery occlusion. However, the role of collateral pathways during cerebral vasospasm-an involuntary constriction of blood vessels after subarachnoid hemorrhage-is not well-documented. This study presents a novel technique to create patient-specific computational fluid dynamics (CFD) simulations of the Circle of Willis before and during vasospasm. Computed tomographic angiography (CTA) scans are segmented to model the vasculature, and transcranial Doppler ultrasound (TCD) measurements of blood flow velocity are applied as boundary conditions. Bayesian analysis leverages information about the uncertainty in the measurements of vessel diameters and velocities to find an optimized parameter set that satisfies mass conservation and that is applied in the final simulation. With this optimized parameter set, the diameters, velocities, and flow rates fall within typical literature values. Virtual angiograms modeled using passive scalar transport agree closely with clinical angiography. A sensitivity analysis quantifies the changes in collateral flow rates with respect to changes in the inlet and outlet flow rates. This analysis can be applied in the future to a cohort of patients to investigate the relationship between the locations and severities of vasospasm, the patient-to-patient anatomical variability in the Circle of Willis, and the activation of collateral pathways.


A Deliberate Choice? Exploring the Decision to Switch from Cigarettes to E-Cigarettes.
E-cigarettes are increasingly popular among both cigarette smokers and non-users. Although smoking cessation yields the most individual and population health benefits, switching to exclusive e-cigarette use offers some individual health benefits for cigarette smokers. However, e-cigarette use is not harmless, and its use among non-cigarette smokers should be prevented. Our study aims to explore the decision-making process about e-cigarettes among an e-cigarette users, cigarette smokers, and non-users. We conducted 12 semi-structured focus group interviews with e-cigarette users, cigarette smokers, and non-users. We performed a thematic analysis of the interview transcripts. First, knowledge reported by e-cigarette users was mainly based on other users' experiences. Second, cigarette smokers and non-users were more negative towards e-cigarettes than e-cigarette users. Third, e-cigarette users considered switching from cigarette smoking to e-cigarette use by deliberating relevant information, and weighing up the benefits and disadvantages of e-cigarette use versus smoking. Additionally, important factors in the decision-making process were a perception of risks and benefits of e-cigarettes compared to cigarettes, a supportive social environment about e-cigarette use, and trust in information offered about the risks and benefits of e-cigarettes. Our findings provide insight into what we can learn from the conscious decision-making process of e-cigarette users who switched from cigarettes to e-cigarettes. This information can be considered to develop targeted communications strategies to stimulate a conscious decision-making process, these may highlight benefits of switching to e-cigarettes for cigarette smokers, discussing the risks of smoking, and correcting misperceptions about the perceived risks and benefits of e-cigarette use.


Spiral artery blood volume in normal pregnancies and those compromised by pre-eclampsia.
The aim of this work was to use intravoxel incoherent motion (IVIM) to provide a non-invasive in vivo assessment of the function of the maternal spiral arteries that feed the placenta in normal pregnancy and in pre-eclampsia. Eleven normal pregnant women were scanned at 16, 22, 29 and 35 weeks gestation in a longitudinal study. Nine normal pregnant women and six women with pre-eclampsia were scanned in a cross-sectional study, within 10 days of delivery. The MRI IVIM technique was used to measure the moving blood fraction (f%) at the basal plate. There was no evidence that f% changed with gestational age (P = 0.84), but considering the cross-sectional groups, f% in women with pre-eclampsia was reduced compared with normal pregnancy (mean +/- SD: 36 +/- 5% and 27 +/- 5%; P < 0.005). In conclusion, pregnancies complicated by pre-eclampsia exhibit a reduced fraction of moving blood within the region of the spiral arteries. IVIM performed in the mid-trimester may provide an early means of predicting those pregnancies with an increased likelihood of being complicated by pre-eclampsia.


Independent origins of new sex-linked chromosomes in the melanica and robusta species groups of Drosophila.
Recent translocations of autosomal regions to the sex chromosomes represent important systems for identifying the evolutionary forces affecting convergent patterns of sex-chromosome heteromorphism. Additions to the sex chromosomes have been reported in the melanica and robusta species groups, two sister clades of Drosophila. The close relationship between these two species groups and the similarity of their rearranged karyotypes motivates this test of alternative hypotheses; the rearranged sex chromosomes in both groups are derived through a common origin, or the rearrangements are derived through at least two independent origins. Here we examine chromosomal arrangement in representatives of the melanica and the robusta species groups and test these alternative hypotheses using a phylogenetic approach. Two mitochondrial and two nuclear gene sequences were used to reconstruct phylogenetic relationships of a set of nine ingroup species having fused and unfused sex chromosomes and representing a broad sample of both species groups. Different methods of phylogenetic inference, coupled with concurrent cytogenetic analysis, indicate that the hypothesis of independent origins of rearranged sex chromosomes within each species group is significantly more likely than the alternative hypothesis of a single common origin. An estimate tightly constrained around 8 My was obtained for the age of the rearranged sex chromosomes in the melanica group; however, a more loosely constrained estimate of 10-15 My was obtained for the age of the rearrangement in the robusta group. Independent acquisition of new chromosomal arms by the sex chromosomes in the melanica and robusta species groups represents a case of striking convergence at the karyotypic level. Our findings indicate that the parallel divergence experienced by newly sex-linked genomic regions in these groups represents an excellent system for studying the tempo of sex chromosome evolution.


Anxiety, depression, fatigue, and headache burden in the pediatric hydrocephalus population.
Childhood hydrocephalus is a common chronic medical condition. However, little is known about the burden of headache and psychological comorbidities in children living with hydrocephalus. The purpose of this study was to determine the prevalence and severity of these conditions among the pediatric hydrocephalus population. During routine neurosurgery clinic visits from July 2017 to February 2018, the authors administered four surveys to children ages 7 years and older: Pediatric Migraine Disability Assessment (PedMIDAS), Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety, PROMIS Depression, and PROMIS Fatigue. The PedMIDAS is an assessment of headache disability in pediatric and adolescent patients. The PROMIS measures are pediatric self-reported instruments to assess social and emotional health. PROMIS measures utilize T-scores (mean 50, SD 10) to compare anxiety, depression, and fatigue in specific populations to those in the US general population. Clinical and demographic data were collected from the medical record (hydrocephalus etiology, shunt infection, race, etc.) and tested for associations with survey measure scores. Forty children completed the PedMIDAS. Ten percent of them were in the severe headache range, 5% were in the moderate range, and 5% were in the mild range. There was a statistically significant association between undergoing a cluster of shunt operations and headache burden (p = 0.003).Forty children completed all three PROMIS measures. The mean anxiety score was 45.8 (SD 11.7), and 2.5% of children scored in the severe anxiety range, 17.5% in the moderate range, and 20% in the mild range. The mean depression score was 42.7 (SD 10.0), with 2.5% of children scoring in the severe depression range, 5% in the moderate range, and 12.5% in the mild range. The mean fatigue score was 45.1 (SD 16.4), with 15% percent of children scoring in the severe fatigue range, 10% in the moderate range, and 7.5% in the mild range. There were no statistically significant associations between child anxiety, depression, or fatigue and clinical or demographic variables. Children with hydrocephalus have an average burden of headache, anxiety, depression, and fatigue as compared to the general population overall. Having a cluster of shunt operations correlates with a higher headache burden, but no clinical or demographic variable is associated with anxiety, depression, or fatigue.


Pitavastatin: a new HMG-CoA reductase inhibitor for the treatment of hypercholesterolemia.
Because of their good tolerability and their positive effect on lipid parameters and clinical outcomes, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have become the drugs of first choice for the management of dyslipidemia. Pitavastatin is the newest member in the statin family and received Food and Drug Administration approval for oral use in August 2009. Compared to other statins such as atorvastatin, simvastatin and pravastatin at specific doses, pitavastatin dosed at 1 to 4 mg daily showed similar efficacy in lowering low-density lipoprotein cholesterol (LDL-C) and altering other lipid parameters according to a number of studies. In addition, pitavastatin demonstrated cholesterol-lowering efficacy in special populations such as the elderly, patients with diabetes, and patients with higher cardiovascular risk. Because pitavastatin is minimally metabolized by the cytochrome P-450 isoenzymes, it is associated with a lower frequency of drug-drug interactions, and this may be a desirable characteristic of pitavastatin. Beneficial effects, such as reductions of coronary plaque volume and fibrofatty composition, have also been observed with pitavastatin. Thus far, the safety profile of pitavastatin is favorable and appears to be similar to those of other statins. Given its encouraging pharmacokinetic and pharmacodynamic characteristics, pitavastatin is likely to be a good alternative to other more established statins. The pharmacologic and pharmacokinetic properties of pitavastatin are reviewed in this article.


RHOA inactivation enhances Wnt signalling and promotes colorectal cancer.
Activation of the small GTPase RHOA has strong oncogenic effects in many tumour types, although its role in colorectal cancer remains unclear. Here we show that RHOA inactivation contributes to colorectal cancer progression/metastasis, largely through the activation of Wnt/β-catenin signalling. RhoA inactivation in the murine intestine accelerates the tumorigenic process and in human colon cancer cells leads to the redistribution of β-catenin from the membrane to the nucleus and enhanced Wnt/β-catenin signalling, resulting in increased proliferation, invasion and de-differentiation. In mice, RHOA inactivation contributes to colon cancer metastasis and reduced RHOA levels were observed at metastatic sites compared with primary human colon tumours. Therefore, we have identified a new mechanism of activation of Wnt/β-catenin signalling and characterized the role of RHOA as a novel tumour suppressor in colorectal cancer. These results constitute a shift from the current paradigm and demonstrate that RHO GTPases can suppress tumour progression and metastasis.


Distribution of serotonin (5-HT) and its receptors in the insect brain with focus on the mushroom bodies: lessons from Drosophila melanogaster and Apis mellifera.
The biogenic amine serotonin (5-hydroxytryptamine, 5-HT) plays a key role in regulating and modulating various physiological and behavioral processes in both protostomes and deuterostomes. The specific functions of serotonin are mediated by its binding to and subsequent activation of membrane receptors. The vast majority of these receptors belong to the superfamily of G-protein-coupled receptors. We report here the in vivo expression pattern of a recently characterized 5-HT(1) receptor of the honeybee Apis mellifera (Am5-HT(1A)) in the mushroom bodies. In addition, we summarize current knowledge on the distribution of serotonin and serotonin receptor subtypes in the brain and specifically in the mushroom bodies of the fruit fly Drosophila melanogaster and the honeybee. Functional studies in these two species have shown that serotonergic signaling participates in various behaviors including aggression, sleep, circadian rhythms, responses to visual stimuli, and associative learning. The molecular, pharmacological, and functional properties of identified 5-HT receptor subtypes from A. mellifera and D. melanogaster will also be summarized in this review.


Dendritic cells interact with CD4 T cells in intestinal mucosa.
Absence of lymph nodes in nonmammalian species, expression of MHCII by APCs in the periphery, and the recent findings that T cells can change their polarization status after presentation in the lymph nodes imply a role for MHCII-mediated presentation outside the organized lymphoid tissue. This study shows that MHCII(+) ECs and DCs from the intestinal mucosa of the pig can present antigen to T cells in vitro. In vivo, APCs colocalize with T cells in pig and mouse intestinal mucosa. In the pig, endothelium is involved in these interactions in neonates but not in adults, indicating different roles for stromal and professional APCs in the neonate compared with the adult. The ratio of expression of DQ and DR MHCII locus products was lower on ECs than on other mucosal APCs, indicating that the two types of cells present different peptide sets. Adult nonendothelial APCs expressed a higher ratio of DQ/DR than in neonates. These results suggest that mucosal DCs can present antigen locally to primed T cells and that stromal APCs are recruited to these interactions in some cases. This raises the possibility that local presentation may influence T cell responses at the effector stage after initial presentation in the lymph node.