Sparse Reconstruction Challenge for diffusion MRI: Validation on a physical phantom to determine which acquisition scheme and analysis method to use?
Diffusion magnetic resonance imaging (dMRI) is the modality of choice for investigating in-vivo white matter connectivity and neural tissue architecture of the brain. The diffusion-weighted signal in dMRI reflects the diffusivity of water molecules in brain tissue and can be utilized to produce image-based biomarkers for clinical research. Due to the constraints on scanning time, a limited number of measurements can be acquired within a clinically feasible scan time. In order to reconstruct the dMRI signal from a discrete set of measurements, a large number of algorithms have been proposed in recent years in conjunction with varying sampling schemes, i.e., with varying b-values and gradient directions. Thus, it is imperative to compare the performance of these reconstruction methods on a single data set to provide appropriate guidelines to neuroscientists on making an informed decision while designing their acquisition protocols. For this purpose, the SPArse Reconstruction Challenge (SPARC) was held along with the workshop on Computational Diffusion MRI (at MICCAI 2014) to validate the performance of multiple reconstruction methods using data acquired from a physical phantom. A total of 16 reconstruction algorithms (9 teams) participated in this community challenge. The goal was to reconstruct single b-value and/or multiple b-value data from a sparse set of measurements. In particular, the aim was to determine an appropriate acquisition protocol (in terms of the number of measurements, b-values) and the analysis method to use for a neuroimaging study. The challenge did not delve on the accuracy of these methods in estimating model specific measures such as fractional anisotropy (FA) or mean diffusivity, but on the accuracy of these methods to fit the data. This paper presents several quantitative results pertaining to each reconstruction algorithm. The conclusions in this paper provide a valuable guideline for choosing a suitable algorithm and the corresponding data-sampling scheme for clinical neuroscience applications.


Efficacy and cost of acoustic-informed and wind speed-only turbine curtailment to reduce bat fatalities at a wind energy facility in Wisconsin.
Current research estimates hundreds of thousands of turbine-related bat fatalities in North America annually. In an effort to reduce impacts of wind energy production on bat populations, many facilities implement operational curtailment strategies that limit turbine blade rotation during conditions when nighttime wind speeds are low. Incorporating real-time bat activity data into wind speed-only curtailment (WOC) strategies may increase operational flexibility by allowing turbines to operate normally when bats are not present near turbines. We evaluated costs and benefits of implementing the Turbine Integrated Mortality Reduction (TIMR) system, an approach that informs a curtailment-triggering algorithm based on wind speed and real-time bat acoustic data, compared to a WOC strategy in which turbines were curtailed below 4.5 meters per second (m/s) at a wind energy facility in Fond Du Lac County, Wisconsin. TIMR is a proprietary system and we had no access to the acoustic data or bat call analysis software. Operational parameters for the TIMR system were set to allow curtailment at all wind speeds below 8.0 m/s during the study period when bats were acoustically detected. Overall, the TIMR system reduced fatalities by 75% compared to control turbines, while the WOC strategy reduced fatalities by 47%. An earlier analysis of the same TIMR data neglected to account for carcasses occurring outside the plot boundary and estimated an 84.5% fatality reduction due to the TIMR system. Over the study period, bat activity led to curtailment of TIMR turbines during 39.4% of nighttime hours compared to 31.0% of nighttime hours for WOC turbines, and revenue losses were approximately 280% as great for TIMR turbines as for turbines operated under the WOC strategy. The large cost difference between WOC and TIMR was driven by the 4.5 m/s versus 8.0 m/s wind speed thresholds for curtailment, but our study site has a relatively low average wind speed, which may also have contributed; other wind operators considering the TIMR system will need to consider their ability to absorb production losses in relation to their need to reduce bat fatality rates.


The Danish Twin Registry: 127 birth cohorts of twins.
The Danish Twin Registry is the oldest national twin register in the world, initiated in 1954 by ascertainment of twins born from 1870 to 1910. During a number of studies birth cohorts have been added to the register, and by the recent addition of birth cohorts from 1931 to 1952 the Registry now comprizes 127 birth cohorts of twins from 1870 to 1996, with a total of more than 65,000 twin pairs included. In all cohorts the ascertainment has been population-based and independent of the traits studied, although different procedures of ascertainment have been employed. In the oldest cohorts only twin pairs with both twins surviving to age 6 have been included while from 1931 all ascertained twins are included. The completeness of the ascertainment after adjustment for infant mortality is high, with approximately 90% ascertained up to 1968, and complete ascertainment of all liveborn twin pairs since 1968. The Danish Twin Registry is used as a source for large studies on genetic influence on aging and age-related health problems, normal variation in clinical parameters associated with the metabolic syndrome and cardiovascular diseases, and clinical studies of specific diseases. The combination of survey data with data obtained by linkage to national health related registers enables follow-up studies both of the general twin population and of twins from clinical studies.


Hyperspectral image reconstruction for diffuse optical tomography.
We explore the development and performance of algorithms for hyperspectral diffuse optical tomography (DOT) for which data from hundreds of wavelengths are collected and used to determine the concentration distribution of chromophores in the medium under investigation. An efficient method is detailed for forming the images using iterative algorithms applied to a linearized Born approximation model assuming the scattering coefficient is spatially constant and known. The L-surface framework is employed to select optimal regularization parameters for the inverse problem. We report image reconstructions using 126 wavelengths with estimation error in simulations as low as 0.05 and mean square error of experimental data of 0.18 and 0.29 for ink and dye concentrations, respectively, an improvement over reconstructions using fewer specifically chosen wavelengths.


Farnesyltransferase inhibitor R115777 (Zarnestra, Tipifarnib) synergizes with paclitaxel to induce apoptosis and mitotic arrest and to inhibit tumor growth of multiple myeloma cells.
Despite major advances, multiple myeloma (MM) remains an incurable malignancy. Recently we have found that disease stabilization was achieved in 64% of patients with advanced MM treated with the farnesyltransferase inhibitor R115777 (Zarnestra) in a phase 2 clinical trial. In order to enhance R115777 antitumor activity in MM, we examined the combination of this novel agent with other anticancer drugs in MM cell lines. In this study, R115777 was found to synergize with paclitaxel and docetaxel, but not with other chemotherapy agents, including doxorubicin, 5-fluorouracil, cisplastin, melphalan, mitoxantrone, and dexamethasone. R115777 synergized with paclitaxel to inhibit MM cell proliferation and to induce apoptosis. Synergism in the induction of apoptosis was accompanied by increase in cytochrome c release and caspase-3 activation. Furthermore, flow cytometry analysis also showed that paclitaxel and R115777 synergized to induce G(2)/M cell-cycle arrest. Importantly, synergism was observed in taxane- and R115777-resistant MM cells. In the human severe combined immunodeficient (SCID-hu) bone model of myeloma growth, the ability of paclitaxel to inhibit tumor growth in vivo was enhanced by R115777. Combination of paclitaxel or docetaxel with R115777 in the treatment of MM cells from patients with multiple myeloma was more beneficial than treatment with single agents. Our results provide the basis for combination therapy clinical trials with paclitaxel or docetaxel with R115777 in MM patients.


Predicting outcome of epilepsy after meningioma resection.
Surgical excision is the standard treatment for intracranial meningiomas. Epilepsy is a major cause of morbidity in meningioma patients, but postoperative control of epilepsy is not achieved in a substantial fraction of patients. The purpose of this study was to define risk factors for postoperative epilepsy. Patients treated for histologically confirmed intracranial meningioma at the University Hospital Zurich between 2000 and 2013 were retrospectively analyzed. Demographic, clinical, imaging, and electroencephalographic data were assessed. A binary regression model was applied to identify risk factors for postoperative epilepsy. Of the 779 patients analyzed, epileptic seizures occurred in 244 (31.3%) patients before surgery and in 204 (26.6%) patients after surgery. Of the 244 patients with preoperative epilepsy, 144 (59.0%) became seizure-free after surgery; of the 535 patients without preoperative seizures, 104 (19.4%) suffered from epilepsy after surgery. Risk factors for postoperative epilepsy were preoperative epilepsy (odds ratio [OR]: 3.46 [95% confidence interval {CI}: 2.32-5.16]), major surgical complications including CNS infections (OR: 5.89 [95% CI: 1.53-22.61]), hydrocephalus (OR: 3.27 [95% CI: 1.35-7.95]), recraniotomy (OR: 2.91 [95% CI: 1.25-6.78]), and symptomatic intracranial hemorrhage (OR: 2.60 [95% CI: 1.17-5.76]) as well as epileptiform EEG potentials (OR: 2.52 [95% CI: 1.36-4.67]), younger age (OR: 1.74 [(95% CI: 1.18-2.58]), and tumor progression (OR: 1.92 [95% CI: 1.16-3.18]). Postoperative improvement or recovery from preoperative neurologic deficits was associated with improved seizure control (OR: 0.46 [95% CI: 0.25-0.85], P = .013). We suggest prospective validation of a score ("STAMPE2") based on clinical findings, EEG, and brain-imaging measures to estimate postoperative seizure risk and guide anticonvulsant treatment in meningioma patients.


A coordinated preventive care approach for healthy ageing in five European cities: A mixed methods study of process evaluation components.
To evaluate specific process components of the Urban Health Centres Europe (UHCE) approach; a coordinated preventive care approach aimed at healthy ageing by decreasing falls, polypharmacy, loneliness and frailty among older persons in community settings of five cities in the United Kingdom, Greece, Croatia, the Netherlands and Spain. Mixed methods evaluation of specific process components of the UHCE approach: reach of the target population, dose of the intervention actually delivered and received by participants and satisfaction and experience of main stakeholders involved in the approach. The UHCE approach intervention consisted of a preventive assessment, shared decision-making on a care plan and enrolment in one or more of four coordinated care-pathways that targeted falls, polypharmacy, loneliness and frailty. Quantitative data from a questionnaire and quantitative/qualitative data from logbooks were collected among older persons involved in the approach. Qualitative data from focus groups were collected among older persons, informal caregivers and professionals involved in the approach. Quantitative data were analysed by means of descriptive statistics and multilevel logistic regression models. Qualitative data were analysed through thematic analysis. Having limited function was associated with non-enrolment in falls and loneliness care-pathways (both p < .01). The mean rating of the approach was 8.3/10 (SD 1.9). Feeling supported by a care professional and meeting people were main benefits for older persons. Mistrust towards unfamiliar care providers, lack of confidence to engage in care activities and health constraints were main barriers towards engagement in care. Although the UHCE approach was received generally positively, health constraints and psychosocial barriers prevented older person's engagement in care. Coordinated preventive care approaches for older community-dwelling persons should address health constraints and psychosocial barriers that hinder older person's engagement in care. ISRCTN registry number is ISRCTN52788952. Date of registration is 13/03/2017.


Differences in Multidisciplinary and Interdisciplinary Treatment Programs for Fibromyalgia: A Mapping Review.
Fibromyalgia is a multifaceted chronic pain syndrome and the integration of different health disciplines is strongly recommended for its care. The interventions based on this principle are very heterogeneous and the difference across their structures has not been extensively studied, leading to incorrect conclusions when their outcomes are pooled. The objective of this mapping review was to summarize the characteristics of these programs, with particular focus on the integration of their components. We performed a search of the literature about treatments for fibromyalgia involving multiple disciplines on PubMed and Scopus. Starting from 560 articles, we included 22 noncontrolled studies, 10 controlled studies, and 17 RCTs evaluating the effects of 38 multidisciplinary or interdisciplinary interventions. The average quality of the studies was low. Their outcomes were usually pain intensity, quality of life, and psychological variables. We created a map of the programs based on the degree of integration of the included disciplines, which ranged from a juxtaposition of few components to a complex harmonization of different perspectives obtained through teamwork strategies. The rehabilitation programs were then thoroughly described with regard to the duration, setting, therapeutic components, and professionals included. The implications for future quantitative reviews are discussed.


Challenges and possible solutions to colorectal cancer screening for the underserved.
Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. CRC incidence and mortality can be reduced through screening. However, in the United States, screening participation remains suboptimal, particularly among underserved populations such as the uninsured, recent immigrants, and racial/ethnic minority groups. Increasing screening rates among underserved populations will reduce the US burden of CRC. In this commentary focusing on underserved populations, we highlight the public health impact of CRC screening, list key challenges to screening the underserved, and review promising approaches to boost screening rates. We identify four key policy and research priorities to increase screening among underserved populations: 1) actively promote the message, "the best test is the one that gets done"; 2) develop and implement methods to identify unscreened individuals within underserved population groups for screening interventions; 3) develop and implement approaches for organized screening delivery; and 4) fund and enhance programs and policies that provide access to screening, diagnostic follow-up, and CRC treatment for underserved populations. This commentary represents the consensus of a diverse group of experts in cancer control and prevention, epidemiology, gastroenterology, and primary care from across the country who formed the Coalition to Boost Screening among the Underserved in the United States. The group was organized and held its first annual working group meeting in conjunction with the World Endoscopy Organization's annual Colorectal Cancer Screening Committee meeting during Digestive Disease Week 2012 in San Diego, California.


Characterisation and expression of microRNAs in developing wings of the neotropical butterfly Heliconius melpomene.
Heliconius butterflies are an excellent system for studies of adaptive convergent and divergent phenotypic traits. Wing colour patterns are used as signals to both predators and potential mates and are inherited in a Mendelian manner. The underlying genetic mechanisms of pattern formation have been studied for many years and shed light on broad issues, such as the repeatability of evolution. In Heliconius melpomene, the yellow hindwing bar is controlled by the HmYb locus. MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that have key roles in many biological processes, including development. miRNAs could act as regulators of genes involved in wing development, patterning and pigmentation. For this reason we characterised miRNAs in developing butterfly wings and examined differences in their expression between colour pattern races. We sequenced small RNA libraries from two colour pattern races and detected 142 Heliconius miRNAs with homology to others found in miRBase. Several highly abundant miRNAs were differentially represented in the libraries between colour pattern races. These candidates were tested further using Northern blots, showing that differences in expression were primarily due to developmental stage rather than colour pattern. Assembly of sequenced reads to the HmYb region identified hme-miR-193 and hme-miR-2788; located 2380 bp apart in an intergenic region. These two miRNAs are expressed in wings and show an upregulation between 24 and 72 hours post-pupation, indicating a potential role in butterfly wing development. A search for miRNAs in all available H. melpomene BAC sequences (~2.5 Mb) did not reveal any other miRNAs and no novel miRNAs were predicted. Here we describe the first butterfly miRNAs and characterise their expression in developing wings. Some show differences in expression across developing pupal stages and may have important functions in butterfly wing development. Two miRNAs were located in the HmYb region and were expressed in developing pupal wings. Future work will examine the expression of these miRNAs in different colour pattern races and identify miRNA targets among wing patterning genes.


Differentiation of ovarian development and the evolution of fecundity in rapidly diverging exotic beetle populations.
Fecundity is a fundamental determinant of fitness, yet the proximate developmental and physiological mechanisms that enable its often rapid evolution in natural populations are poorly understood. Here, we investigated two populations of the dung beetle Onthophagus taurus that were established in exotic ranges in the early 1970s. These populations are subject to drastically different levels of resource competition in the field, and have diverged dramatically in female fecundity. Specifically, Western Australian O. taurus experience high levels of resource competition, and exhibit greatly elevated reproductive output compared to beetles from the Eastern US, where resource competition is minimal and female fecundity is low. We compared patterns of ovarian maturation, relative investment into and timing of egg production, and potential trade-offs between ovarian investment and the duration of larval development and adult body size between populations representative of both exotic ranges. We found that the rapid divergence in fecundity between exotic populations is associated with striking differences in several aspects of ovarian development: (1) Western Australian females exhibit accelerated ovarian development, (2) produce more eggs, (3) bigger eggs, and (4) start laying eggs earlier compared to their Eastern US counterparts. At the same time, divergence in ovarian maturation patterns occurred alongside changes in (5) larval developmental time, and (6) adult body size, and (7) mass. Western Australian females take longer to complete larval development and, surprisingly, emerge into smaller yet heavier adults than size-matched Eastern US females. We discuss our results in the context of the evolutionary developmental biology of fecundity in exotic populations.


"Rescue" of Nonparticipants in Colorectal Cancer Screening: A Randomized Controlled Trial of Three Noninvasive Test Options.
Few studies have directly targeted nonparticipants in colorectal cancer screening to identify effective engagement strategies. We undertook a randomized controlled trial that targeted nonparticipants in a previous trial of average-risk subjects which compared participation rates for mailed invitations offering a fecal test, a blood test or a choice of either. Nonparticipants (n = 899) were randomized to be offered a kit containing a fecal immunochemical test (FIT), directions on how to arrange a blood DNA test, or the option of doing either. Screening participation was assessed 12 weeks after the offer. To assess the cognitive and attitudinal variables related to participation and invitee choice, invitees were surveyed after 12 weeks, and associations were investigated using multinomial logistic regression. Participation rates were similar between groups (P = 0.88): 12.0% for FIT (35/292), 13.3% for the blood test (39/293), and 13.4% for choice (39/290). Within the choice group, participation was significantly higher with FIT (9.7%, 28/290) compared with the blood test (3.8%, 11/290, P = 0.005). The only variable significantly associated with participation was socioeconomic status when offered FIT, and age when offered choice but there was none when offered the blood test. Survey respondents indicated that convenience, time-saving, comfort, and familiarity were major influences on participation. There was no clear advantage between a fecal test, blood test, or choice of test although, when given a choice, the fecal test was preferred. Differences in variables associated with participation according to invitation strategy warrant consideration when deciding upon an invitation strategy for screening nonparticipants. PREVENTION RELEVANCE: This trial of screening for those at average risk for colorectal cancer targeted past fecal-test nonparticipants and compared participation rates for mailed invitations offering a fecal test, blood test, or choice of either. Although there was no clear advantage between strategies, factors associated with participation differed between each strategy.


Cooperative signaling by alpha 5 beta 1 and alpha 4 beta 1 integrins regulates metalloproteinase gene expression in fibroblasts adhering to fibronectin.
Rabbit synovial fibroblasts (RSF) express basal levels of the metalloproteinases (MMP) collagenase, stromelysin-1 and 92-kD gelatinase when plated on intact fibronectin (FN), but elevated levels when plated on either the central RGD-containing cell-binding region of FN (120FN) or antibody against the alpha 5 beta 1 integrin, suggesting that domains outside 120FN may suppress the induction of MMP (Werb, Z., P. M. Tremble, O. Behrendtsen, E. Crowley, and C.H. Damsky. 1989. J. Cell Biol. 109:877-889). We therefore attempted to reconstitute the basal signaling of intact FN by plating RSF on 120FN together with domains of FN outside this region. Large COOH-terminal fragments containing both the heparin-binding and HICS domains suppressed MMP when combined with 120FN. To map the active sequences, peptides from this region and larger fragments that did, or did not, include the CS-1 portion of IIICS were tested. Only CS-1 peptide, or larger fragments containing CS-1, suppressed MMP expression induced by 120FN. In contrast, peptide V from the heparin-binding region, shown previously to stimulate focal contact formation, further enhanced MMP expression by RSF when present on the substrate with 120FN. RSF expressed alpha 4 beta 1 integrin, the receptor for CS-1, and the anti-alpha 4 mAb blocked the ability of CS-1 to suppress MMP induction by 120FN. These results show that signals modulating MMP expression and focal contact assembly are regulated independently, and that cooperative signaling by alpha 5 beta 1 and alpha 4 beta 1 integrins plays a dominant role in regulating expression of these extracellular matrix-remodeling genes in response to FN. This work demonstrates directly the modular way in which information in the extracellular matrix is detected and processed by cell surface receptors.


The Cation-π Interaction Enables a Halo-Tag Fluorogenic Probe for Fast No-Wash Live Cell Imaging and Gel-Free Protein Quantification.
The design of fluorogenic probes for a Halo tag is highly desirable but challenging. Previous work achieved this goal by controlling the chemical switch of spirolactones upon the covalent conjugation between the Halo tag and probes or by incorporating a "channel dye" into the substrate binding tunnel of the Halo tag. In this work, we have developed a novel class of Halo-tag fluorogenic probes that are derived from solvatochromic fluorophores. The optimal probe, harboring a benzothiadiazole scaffold, exhibits a 1000-fold fluorescence enhancement upon reaction with the Halo tag. Structural, computational, and biochemical studies reveal that the benzene ring of a tryptophan residue engages in a cation-π interaction with the dimethylamino electron-donating group of the benzothiadiazole fluorophore in its excited state. We further demonstrate using noncanonical fluorinated tryptophan that the cation-π interaction directly contributes to the fluorogenicity of the benzothiadiazole fluorophore. Mechanistically, this interaction could contribute to the fluorogenicity by promoting the excited-state charge separation and inhibiting the twisting motion of the dimethylamino group, both leading to an enhanced fluorogenicity. Finally, we demonstrate the utility of the probe in no-wash direct imaging of Halo-tagged proteins in live cells. In addition, the fluorogenic nature of the probe enables a gel-free quantification of fusion proteins expressed in mammalian cells, an application that was not possible with previously nonfluorogenic Halo-tag probes. The unique mechanism revealed by this work suggests that incorporation of an excited-state cation-π interaction could be a feasible strategy for enhancing the optical performance of fluorophores and fluorogenic sensors.


LPS-induced 111In-eosinophil accumulation in guinea-pig skin: evidence for a role for TNF-alpha.
Lipopolysaccharide (LPS) is a major component of the cell wall of Gram-negative bacteria with powerful pro-inflammatory activities. Although the mechanisms involved in LPS-induced neutrophil accumulation have been studied extensively, few reports have focused on the effects of LPS on eosinophil infiltration. In this study we have used an in vivo model of local 111In-eosinophil accumulation in the guinea-pig to investigate the mechanisms of LPS-induced eosinophilia. Using a 4-hr in vivo test period, the intradermal injection of LPS (50-1000 ng/site) led to a marked and dose-dependent accumulation of 111In-eosinophils into guinea-pig skin sites. Time-course experiments revealed that this cell infiltration was delayed in onset, becoming significant 1 hr after the intradermal administration of LPS. The slow development of the response and its sensitivity to the locally administered protein synthesis inhibitor, actinomycin D, suggested that the LPS-induced 111In-eosinophil accumulation in vivo is mediated by the generation of de novo proteins. The intravenous pretreatment of guinea-pigs with a soluble tumour necrosis factor-alpha (TNF-alpha) receptor fusion protein (TNFR-IgG, 1 mg/kg), potently inhibited the 111In-eosinophil accumulation induced by LPS. Our results demonstrate that LPS can induce 111In-eosinophil accumulation in vivo in guinea-pig skin, and that this process is mediated by TNF-alpha.


Grief and Solidarity Reactions 1 Week After an On-Campus Shooting.
The impact of interpersonal violence extends beyond the victims and perpetrator(s). The purpose of this research was threefold: (a) to identify whether college students' very early reactions to an on-campus shooting were associated with well-known predictors of distress, (b) to examine whether grief and distress reactions were distinguishable in the early days following a shooting, and (c) to investigate whether a compassionate self-identity was uniquely associated with grief but not distress. Beginning just 3 days after an early morning shooting that killed one student and injured three others, university students (N = 408) completed an online questionnaire. Grief, but not distress, was associated with a sense of solidarity with other students and a compassionate self-identity. General distress was associated with prior mental health difficulties and exposure to the shooting. Acute stress was positively associated with being female, having prior mental health difficulties, media exposure, perceived similarity to victims, less victim blame, social support, and social strain. Results suggest that grief reactions that arise in the early days following a collective loss may serve as important psychosocial resources in coping with interpersonal violence.


Clinical importance of zona pellucida-induced acrosome reaction and its predictive value for IVF.
The study aimed to establish zona pellucida induced acrosome reaction response (ZIAR) among 35 couples with normal and G-pattern sperm morphology and repeated poor fertilization results during assisted reproduction treatment. ZIAR tests were performed using 0.25 zona pellucida/microliter co-incubated with spermatozoa for 60 min. Acrosome reactions were measured with FITC-PSA staining, and expressed as the difference between stimulated and unstimulated (spontaneous) sperm populations. Results were compared with IVF rates of metaphase II oocytes. Interactive dot diagrams divided the patients into two groups, i.e. ZIAR <15% and ZIAR > 15%, with mean fertilization rates of 49 and 79% respectively. The sensitivity and specificity for ZIAR results versus fertilization were 93 and 100% respectively. The area under the curve was 99% and the 95% confidence interval did not include 0.5 which implies that the ZIAR test is able to predict fertilization failure among IVF patients. In conclusion, the ZIAR test has diagnostic potential since it can assist the clinician to identify couples that will benefit from intracytoplasmic sperm injection therapy.


Differences between Takotsubo cardiomyopathy and reverse Takotsubo cardiomyopathy associated with subarachnoid hemorrhage.
Both Takotsubo cardiomyopathy (TTC) and reverse TTC (r-TTC) are characterized by reversible regional wall motion abnormalities of the heart unrelated to coronary artery pathology. It remains unclear whether and/or how r-TTC differs from TTC. Subarachnoid hemorrhage (SAH) is occasionally causative of TTC/r-TTC, and this study was conducted to detect possible differences between TTC and r-TTC associated with SAH. A single-center retrospective study was conducted on 328 consecutive SAH patients. They routinely underwent transthoracic echocardiography (TTE), ECG, and measurements of plasma catecholamines and other cardiac biomarkers within 24 h of admission. Demographic, echocardiographic, electrocardiographic and neurochemical profiles were compared between patients with TTC and r-TTC. The diagnosis of TTC/r-TTC was based on the revised Mayo Clinic Criteria. Data of 21 SAH-induced TTC and 10 SAH-induced r-TTC patients admitted between January 2009 and December 2014 were analyzed. The patients with r-TTC were significantly younger than those with TTC (51.8 ± 10.9 vs. 63.5 ± 14.4 years, p = 0.04). The former exhibited significantly higher plasma epinephrine levels than the latter (809 ± 710 vs. 380 ± 391 pg/mL, p = 0.04). Plasma norepinephrine levels did not differ significantly (2421 ± 1374 vs. 1724 ± 1591 pg/mL, p = 0.25). No significant differences were observed in other demographic/physiologic variables, echocardiographic parameters, frequency of ECG abnormalities, and 90-day mortality. Moreover, none of the patients who underwent a follow-up TTE exhibited morphologic change from one type to the other. The pathomechanisms in TTC and r-TTC may not be identical: however, distinguishing the two conditions may not have great importance from the standpoint of clinical management and prognostication.


Apoptosis of mouse mast cells is reciprocally regulated by the IgG receptors FcγRIIB and FcγRIIIA.
Mast cells are important effector cells in allergy. They usually have a long life span and resist cell death induction. Fcγ receptor- and IgG immune complex-mediated apoptosis has been demonstrated in B-lineage cells, but not in mast cells. The aim of the current study was to investigate whether mast cells could respond to apoptosis induction by IgG immune complex aggregation of Fcγ receptors. It is known that mouse mast cells express the low-affinity Fcγ receptors FcγRIIB and FcγRIIIA, which bind IgG especially in the form of antigen-IgG immune complexes. Mouse bone marrow-derived cultured mast cells were examined for surface expression of FcγRIIB and FcγRIIIA. Apoptosis of such cells from wild-type, FcγRIIB(-/-) or FcγRIIIA(-/-) mice was measured following receptor aggregation by IgG immune complexes. Our data demonstrate that aggregation of either FcγRIIB or FcγRIIIA by IgG immune complexes induced apoptosis of mouse bone marrow-derived cultured mast cells. However, mast cells expressing both FcγRIIB and FcγRIIIA were able to resist cell death induction by IgG immune complexes. Our findings reveal a fine-tuning system for regulating mast cell apoptosis through aggregating Fcγ receptors by IgG immune complexes. Such apoptosis regulation may have a substantial impact on mast cell homeostasis during allergic inflammation.


DataGenno: building a new tool to bridge molecular and clinical genetics.
Clinical genetics is one of the most challenging fields in medicine, with thousands of children born every year with congenital defects that have no satisfactory diagnosis. There are more than 6,000 known single-gene disorders that can cause birth defects or diseases in approximately 1 in every 200 births. Clinical and molecular information on genetic diseases and syndromes are widespread in the literature, and there are few databases combining this information. Therefore, it is very challenging for health care professionals and researchers to translate the latest advances in science and medicine into effective clinical interventions and new treatments. In order to overcome this obstacle and promote networking, we are building DataGenno, an online medical and scientific portal. DataGenno has been developed to be a source of information on genetic diseases and syndromes for the needs of all heath care professionals and researchers. Our database will be able to integrate both clinical and molecular aspects of genetic diseases in a fully interactive environment. DataGenno's system already contains clinical and molecular information for 300 diseases, with approximately 6,000 signs and symptoms of these diseases in a database combined with a search engine. Our main goal is to cover all genetic diseases described to date, providing not only clinical information such as morphological and anatomical features but also the most comprehensive molecular genetics/genomics features and available testing information. We are also developing ways to connect DataGenno's portal with Electronic Health Records in order to improve the efficiency of patient care. Additionally, DataGenno's system and search engine will be able to provide tools that will facilitate the discovery and description of new genetic syndromes. In conclusion, we believe that DataGenno's portal will be a helpful and innovative tool for health care professionals, scientists, genetic counselors, and other professionals in the clinical genetics field.


Binding to G-quadruplex RNA activates the mitochondrial GTPase NOA1.
NOA1 is an evolutionary conserved, nuclear encoded GTPase essential for mitochondrial function and cellular survival. The function of NOA1 for assembly of mitochondrial ribosomes and regulation of OXPHOS activity depends on its GTPase activity, but so far no ligands have been identified that regulate the GTPase activity of NOA1. To identify nucleic acids that bind to the RNA-binding domain of NOA1 we employed SELEX (Systemic Evolution of Ligands by EXponential Enrichment) using recombinant mouse wildtype NOA1 and the GTPase mutant NOA1-K353R. We found that NOA1 binds specifically to oligonucleotides that fold into guanine tetrads (G-quadruplexes). Binding of G-quadruplex oligonucleotides stimulated the GTPase activity of NOA1 suggesting a regulatory link between G-quadruplex containing RNAs, NOA1 function and assembly of mitochondrial ribosomes.


Effect of pharmacological chaperones on brain tyrosine hydroxylase and tryptophan hydroxylase 2.
Phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH) and the tryptophan hydroxylases (TPH1 and TPH2) are structurally and functionally related enzymes that share a number of ligands, such as amino acid substrates, pterin cofactors and inhibitors. We have recently identified four compounds (I-IV) with pharmacological chaperone effect for PAH and phenylketonuria mutants (Pey et al. (2008) J. Clin. Invest. 118, 2858-2867). We have now investigated the effect of these compounds on the brain enzymes TH and TPH2, comparative to hepatic PAH. As assayed by differential scanning fluorimetry each of the purified human PAH, TH and TPH2 was differently stabilized by the compounds and only 3-amino-2-benzyl-7-nitro-4-(2-quinolyl)-1,2-dihydroisoquinolin-1-one (compound III) stabilized the three enzymes. We also investigated the effect of compounds II-IV in wild-type mice upon oral loading with 5 mg/kg/day. Significant effects were obtained by treatment with compound III - which increased total TH activity in mouse brain extracts by 100% but had no measurable effects either on TPH activity nor on monoamine neurotransmitter metabolites dopamine, dihydroxyphenylacetic acid, homovanillic acid, serotonin and 5-hydroxyindolacetic acid - and with 5,6-dimethyl-3-(4-methyl-2-pyridinyl)-2-thioxo-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one (compound IV) - which led to a 10-30% decrease of these metabolites. Our results indicate that pharmacological chaperones aiming the stabilization of one of the aromatic amino acid hydroxylases should be tested on other members of the enzyme family. Moreover, compound III stabilizes in vitro the human TH mutant R202H, associated to autosomal recessive L-DOPA-responsive dystonia, revealing the potential of pharmacological chaperones for the treatment of disorders associated with TH misfolding.


Errors-in-variables jump regression using local clustering.
Errors-in-variables (EIV) regression is widely used in econometric models. The statistical analysis becomes challenging when the regression function is discontinuous and the distribution of measurement error is unknown. In the literature, most existing jump regression methods either assume that there is no measurement error involved or require that jumps are explicitly detected before the regression function can be estimated. In some applications, however, the ultimate goal is to estimate the regression function and to preserve the jumps in the process of estimation. In this paper, we are concerned with reconstructing jump regression curve from data that involve measurement error. We propose a direct jump-preserving method that does not explicitly detect jumps. The challenge of restoring jump structure masked by measurement error is handled by local clustering. Theoretical analysis shows that the proposed curve estimator is statistically consistent. A numerical comparison with an existing jump regression method highlights its jump-preserving property. Finally, we demonstrate our method by an application to a health tax policy study in Australia.


Fetal-maternal interactions during the establishment of pregnancy in ruminants.
This review integrates established information with new insights into molecular and physiological mechanisms responsible for events leading to pregnancy recognition, endometrial receptivity, and implantation with emphasis on sheep. After formation of the corpus luteum, progesterone acts on the endometrium and stimulates blastocyst growth and elongation to form a filamentous conceptus (embryo/fetus and associated extraembryonic membranes). Recurrent early pregnancy loss in the uterine gland knockout ewe model indicates that endometrial epithelial secretions are essential for peri-implantation blastocyst survival and growth. The elongating sheep conceptus secretes interferon tau (IFNT) that acts on the endometrium to inhibit development of the luteolytic mechanism by inhibiting transcription of the estrogen receptor alpha (ESR1) gene in the luminal (LE) and superficial ductal glandular (sGE) epithelia, which prevents estrogen-induction of oxytocin receptors (OXTR) and production of luteolytic prostaglandin F2-alpha pulses. Progesterone downregulates its receptors (PGR) in LE and then GE, correlating with a reduction of anti-adhesive MUC1 (mucin glycoprotein one) and induction of secreted LGALS15 (galectin 15) and SPP1 (secreted phosphoprotein one), that are proposed to regulate trophectoderm growth and adhesion. IFNT acts on the LE to induce WNT7A (wingless-type MMTV integration site family member 7A) and to stimulate LGALS15, CTSL (cathepsin L), and CST3 (cystatin C), which may regulate conceptus development and implantation. During the peri-implantation period, trophoblast giant binucleate cells (BNC) begin to differentiate from mononuclear trophectoderm cells, migrate and then fuse with the uterine LE as well as each other to form multinucleated syncytial plaques. Trophoblast giant BNC secrete chorionic somatomammotropin (CSH1 or placental lactogen) that acts on the endometrial glands to stimulate their morphogenesis and differentiated function. The interactive, coordinated and stage-specific effects of ovarian and placental hormones regulate endometrial events necessary for fetal-maternal interactions and successful establishment of pregnancy.


Identification and Comparative Analysis of Differential Gene Expression in Soybean Leaf Tissue under Drought and Flooding Stress Revealed by RNA-Seq.
Drought and flooding are two major causes of severe yield loss in soybean worldwide. A lack of knowledge of the molecular mechanisms involved in drought and flood stress has been a limiting factor for the effective management of soybeans; therefore, it is imperative to assess the expression of genes involved in response to flood and drought stress. In this study, differentially expressed genes (DEGs) under drought and flooding conditions were investigated using Illumina RNA-Seq transcriptome profiling. A total of 2724 and 3498 DEGs were identified under drought and flooding treatments, respectively. These genes comprise 289 Transcription Factors (TFs) representing Basic Helix-loop Helix (bHLH), Ethylene Response Factors (ERFs), myeloblastosis (MYB), No apical meristem (NAC), and WRKY amino acid motif (WRKY) type major families known to be involved in the mechanism of stress tolerance. The expression of photosynthesis and chlorophyll synthesis related genes were significantly reduced under both types of stresses, which limit the metabolic processes and thus help prolong survival under extreme conditions. However, cell wall synthesis related genes were up-regulated under drought stress and down-regulated under flooding stress. Transcript profiles involved in the starch and sugar metabolism pathways were also affected under both stress conditions. The changes in expression of genes involved in regulating the flux of cell wall precursors and starch/sugar content can serve as an adaptive mechanism for soybean survival under stress conditions. This study has revealed the involvement of TFs, transporters, and photosynthetic genes, and has also given a glimpse of hormonal cross talk under the extreme water regimes, which will aid as an important resource for soybean crop improvement.


Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: a complex association.
Long-chain omega-3 fatty acids could have neuroprotective properties against dementia, which is becoming a major global public health issue. We conducted a systematic review of the literature to establish the association between eating fish (a source of long-chain omega-3 fatty acids) or taking long-chain omega-3 fatty acid supplements and the risk of cognitive decline or Alzheimer disease (AD). We identified eleven observational studies and four clinical trials. All three observational studies that used cognitive decline as an outcome reported significant benefits, whereas only four of eight observational studies that used incidence of AD or dementia as an outcome reported positive findings. None of four small clinical trials provided convincing evidence for the use of this approach in the prevention or treatment of any form of dementia. In summary, the existing data favor a role for long-chain omega-3 fatty acids in slowing cognitive decline in elderly individuals without dementia, but not for the prevention or treatment of dementia (including AD). This apparent dichotomy might reflect differences in study designs with regard to participants, dosages, the ratio of long-chain omega-3 to omega-6 fatty acids, or the choice of outcome measurements. Large clinical trials of extended duration should help to provide definitive answers.


Exploring the Cross-Sectional Association between Transit-Oriented Development Zoning and Active Travel and Transit Usage in the United States, 2010-2014.
In response to traditional zoning codes that contribute to car-dependent sprawling and disconnected neighborhoods, communities are reforming their land use laws to create pedestrian-friendly areas that promote physical activity. One such reform is the adoption of transit-oriented developments or districts (TODs). TODs are higher density, compact, and mixed use areas located around transit stops that are designed to encourage walking. To identify the characteristics of communities that have adopted TODs in their land use laws and examine if communities that have included TODs in their zoning codes are more likely to have adults that commute by any form of active transportation (i.e., walking, biking, or public transportation) or by using public transportation specifically. Zoning codes effective as of 2010 were obtained for a purposeful sample of the largest 3,914 municipal jurisdictions located in 473 of the most populous U.S. counties and consolidated cities within 48 states and the District of Columbia. They were evaluated to determine whether they included TOD districts or regulations using a coding tool developed by the study team. Descriptive statistics together with t-tests and Pearson's chi-squared independence test were used to compare characteristics of jurisdictions with and without TOD zoning. Multivariate linear regressions were used to compute the adjusted association between TOD zoning and taking public or active transportation to work. Jurisdictions with TOD zoning were located more in the South and West than non-TOD jurisdictions and were more populous, higher income, more racially diverse, and younger. Jurisdictions with TOD zoning had significantly higher percentages of occupied housing with no vehicle than those without TOD zoning. TOD zoning was associated with significantly higher rates of public transportation to work (β = 2.10, 95% CI = 0.88, 3.32) and active transportation to work (β = 2.48, 95% CI = 1.03, 3.94). Communities that have or are considering developing public transit infrastructure may want to modify their zoning codes to include TODs to promote physical activity and active travel to work.


Genome Sequence of the Multiantibiotic-Resistant Enterococcus faecium Strain C68 and Insights on the pLRM23 Colonization Plasmid.
Enterococcus faecium infections are a rising concern in hospital settings. Vancomycin-resistant enterococci colonize the gastrointestinal tract and replace nonresistant strains, complicating the treatment of debilitated patients. Here, we present a polished genome of the multiantibiotic-resistant strain C68, which was obtained as a clinical isolate and is a useful experimental strain.


Accelerated Hydrolysis of Aspirin Using Alternating Magnetic Fields.
The major problem of current drug-based therapy is selectivity. As in other areas of science, a combined approach might improve the situation decisively. The idea is to use the pro-drug principle together with an alternating magnetic field as physical stimulus, which can be applied in a spatially and temporarily controlled manner. As a proof of principle, the neutral hydrolysis of aspirin in physiological phosphate buffer of pH 7.5 at 40 degrees C was chosen. The sensor and actuator system is a commercially available gold nanoparticle (NP) suspension which is approved for animal usage, stable in high concentrations and reproducibly available. Applying the alternating magnetic field of a conventional NMR magnet system accelerated the hydrolysis of aspirin in solution.


The emerging regulatory potential of SCFMet30 -mediated polyubiquitination and proteolysis of the Met4 transcriptional activator.
The yeast SCFMet30 ubiquitin ligase plays a critical role in cell division by regulating the Met4 transcriptional activator of genes that control the uptake and assimilation of sulfur into methionine and S-adenosyl-methionine. The initial view on how SCFMet30 performs its function has been driven by the assumption that SCFMet30 acts exclusively as Met4 inhibitor when high levels of methionine drive an accumulation of cysteine. We revisit this model in light of the growing evidence that SCFMet30 can also activate Met4. The notion that Met4 can be inhibited or activated depending on the sulfur metabolite context is not new, but for the first time both aspects have been linked to SCFMet30, creating an interesting regulatory paradigm in which polyubiquitination and proteolysis of a single transcriptional activator can play different roles depending on context. We discuss the emerging molecular basis and the implications of this new regulatory phenomenon.


Cyclin-dependent kinase 5--a neuronal killer?
In dividing cells, cyclin-dependent kinases (Cdks) are cell cycle-associated protein kinases that regulate proliferation, differentiation, senescence, and apoptosis. In neurons that no longer divide, deregulation of Cdks, especially Cdk5, occurs in many neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Cdk5 is a unique member of the Cdk family because it does not play a critical role in cell cycle progression, and it is not activated by a cyclin. Instead, Cdk5 normally is activated by the regulatory protein p35. This Cdk5/p35 activity has emerged as an important regulator of proper development of the mammalian central nervous system. In vitro studies suggest that aberrant activation of Cdk5 by an endogenous truncated version (p25) of p35 might be a key event in the process of neurodegeneration. One enzyme responsible for cleavage of p35 to form p25 is calpain, a calcium-activated protease that has been shown to be involved in neuronal cell death. Recent studies provided important in vivo evidence that hyperactivation and redistribution of Cdk5 by p25 plays an essential role in the phosphorylation of "pathological" substrates (such as tau) and the cell death of neurons in experimental models of AD and PD. Because amyloid beta peptide, the primary neurotoxic component of amyloid plaques in AD, has been shown to increase the conversion of p35 to p25, aberrant activation of Cdk5 by p25 might be a pathway connecting amyloid beta toxicity to tau hyperphosphorylation in AD.


Characterization and quantification of proteins secreted by single human embryos prior to implantation.
The use of in vitro fertilization (IVF) has revolutionized the treatment of infertility and is now responsible for 1-5% of all births in industrialized countries. During IVF, it is typical for patients to generate multiple embryos. However, only a small proportion of them possess the genetic and metabolic requirements needed in order to produce a healthy pregnancy. The identification of the embryo with the greatest developmental capacity represents a major challenge for fertility clinics. Current methods for the assessment of embryo competence are proven inefficient, and the inadvertent transfer of non-viable embryos is the principal reason why most IVF treatments (approximately two-thirds) end in failure. In this study, we investigate how the application of proteomic measurements could improve success rates in clinical embryology. We describe a procedure that allows the identification and quantification of proteins of embryonic origin, present in attomole concentrations in the blastocoel, the enclosed fluid-filled cavity that forms within 5-day-old human embryos. By using targeted proteomics, we demonstrate the feasibility of quantifying multiple proteins in samples derived from single blastocoels and that such measurements correlate with aspects of embryo viability, such as chromosomal (ploidy) status. This study illustrates the potential of high-sensitivity proteomics to measure clinically relevant biomarkers in minute samples and, more specifically, suggests that key aspects of embryo competence could be measured using a proteomic-based strategy, with negligible risk of harm to the living embryo. Our work paves the way for the development of "next-generation" embryo competence assessment strategies, based on functional proteomics.


KQA: A Knowledge Quality Assessment Model for Clinical Decision Support Systems.
Informatics researchers have developed many methods for using computers to utilize knowledge in decision making in the form of clinical decision support systems (CDSSs). These systems can enhance human decision making in the healthcare domain. The knowledge acquisition bottleneck is one of the well-known issues in developing knowledge-based systems such as CDSS. It can be considered as a flow of knowledge from different knowledge sources to the main system. Most existing methods for extracting knowledge from knowledge resources suffer from the lack of a proper mechanism for extracting high-quality knowledge. In this paper, we propose a framework to discover high-quality knowledge by utilizing Semantic Web technologies.


Concordant evolutionary patterns among Indo-West Pacific butterflyfishes.
Genetic differences within a 495 base pair section of the mitochondrial cytochrome b gene reveal a striking concordance among species in two monophyletic groups of Indo-west Pacific butterflyfishes. In both species groups, an approximately 2.0% genetic break clearly partitions individuals between the Indian Ocean and Pacific Ocean. However, levels of intra-Pacific mtDNA variation are low, on average less than 1.0%, and fail to cluster by species boundaries defined by colour pattern. Individuals from different species, separated by thousands of kilometers, often possess identical cytochrome b sequences, whereas conspecifics from the same reefs can show up to 1.5% difference. The discrepancy between the mtDNA gene tree and species boundaries may reflect retained ancestral variation or may be the result of hybridization. The strong temporal and phylogenetic concordance between these two independent species groups suggests that genetic differentiation was influenced by common environmental factors. Low levels of within- and between-species genetic differences imply a recent divergence time and suggest a link between speciation within each group and Pleistocene climatic fluctuations. These results paint a turbulent picture of the recent evolutionary history of the Indo-West Pacific.


Energy-dependent modulation of glucagon-like signaling in Drosophila via the AMP-activated protein kinase.
Adipokinetic hormone (AKH) is the equivalent of mammalian glucagon, as it is the primary insect hormone that causes energy mobilization. In Drosophila, current knowledge of the mechanisms regulating AKH signaling is limited. Here, we report that AMP-activated protein kinase (AMPK) is critical for normal AKH secretion during periods of metabolic challenges. Reduction of AMPK in AKH cells causes a suite of behavioral and physiological phenotypes resembling AKH cell ablations. Specifically, reduced AMPK function increases life span during starvation and delays starvation-induced hyperactivity. Neither AKH cell survival nor gene expression is significantly impacted by reduced AMPK function. AKH immunolabeling was significantly higher in animals with reduced AMPK function; this result is paralleled by genetic inhibition of synaptic release, suggesting that AMPK promotes AKH secretion. We observed reduced secretion in AKH cells bearing AMPK mutations employing a specific secretion reporter, confirming that AMPK functions in AKH secretion. Live-cell imaging of wild-type AKH neuroendocrine cells shows heightened excitability under reduced sugar levels, and this response was delayed and reduced in AMPK-deficient backgrounds. Furthermore, AMPK activation in AKH cells increases intracellular calcium levels in constant high sugar levels, suggesting that the underlying mechanism of AMPK action is modification of ionic currents. These results demonstrate that AMPK signaling is a critical feature that regulates AKH secretion, and, ultimately, metabolic homeostasis. The significance of these findings is that AMPK is important in the regulation of glucagon signaling, suggesting that the organization of metabolic networks is highly conserved and that AMPK plays a prominent role in these networks.


A specialization for vertical disparity discontinuities.
Because our eyes are set apart horizontally in our head, most disparities between the retinal images are horizontal. However, vertical disparities also occur, and can influence depth perception. The classic example is Ogle's induced effect (K. N. Ogle, 1938), in which applying a uniform vertical magnification to one eye's image produces the illusion that the surface has been rotated around a vertical axis. This is thought to be because uniform vertical magnifications can be produced in natural viewing when the eyes are in eccentric gaze (J. E. Mayhew, 1982; J. E. Mayhew & H. C. Longuet-Higgins, 1982). Thus, vertical magnification is taken by the visual system as indicating that the viewed surface is slanted away from the line of sight. Here, we demonstrate that the induced effect becomes stronger when the sign of the magnification alternates across the visual field. That is, as one moves horizontally across the screen, the left eye's image is alternately stretched and squashed vertically relative to the right eye's image, producing the illusion of a surface folded into triangular corrugations (H. Kaneko & I. P. Howard, 1997). For most subjects, slant judgments in this folded surface have lower thresholds and greater reliability than the classic induced effect, where magnification is applied uniformly across the whole visual field. This is remarkable, given that the disparity pattern of the classic induced effect can be produced by real surfaces with the eyes in eccentric gaze, whereas it is not clear that stripes of alternating vertical disparity could be produced by any physically realizable situation. The analogous improvement for alternating horizontal magnification is attributed to neuronal mechanisms which detect the jumps in horizontal disparity that occur at object boundaries. Our results suggest that a similar, previously unreported system may exist for vertical disparity. Jumps in vertical disparity do occur at object boundaries, and we suggest that our surprising results may reflect the activation of neuronal mechanisms designed to detect these.


Comparison of 16S rRNA sequences of segmented filamentous bacteria isolated from mice, rats, and chickens and proposal of "Candidatus Arthromitus".
Segmented filamentous bacteria (SFB) are nonpathogenic bacteria that are commonly found attached to the intestinal walls of many animals. Until now, these bacteria have not been cultured in vitro. Recently, a 16S rRNA sequence analysis revealed that SFB isolated from mice represent a distinct subline within the Clostridium subphylum of the gram-positive bacteria. Since SFB isolated from mice, rats, and chickens are known to be host specific, we investigated the phylogenetic relationships among SFB obtained from these three hosts. Total DNAs from the intestinal floras of chickens and rats were used as templates for PCR amplification of 16S rRNA genes. PCR products were cloned and screened by a dot blot hybridization procedure to identify homologous sequences that cross-reacted with mouse SFB-specific oligonucleotide probes. A phylogenetic analysis of these 16S ribosomal DNA sequences revealed that SFB isolated from these three hosts form a natural group, which is peripherally related to the genus Clostridium sensu stricto (group I Clostridium). The SFB obtained from chickens, rats, and mice had closely related, albeit different, 16S rRNA gene sequences. The observed levels of 16S rRNA sequence divergence, ca. 1.5 to 3%, together with host specificity, suggest that SFB isolated from mice, rats, and chickens represent different species and that coevolution of the SFB and their hosts occurred. "Candidatus Arthromitus" is proposed as the provisional generic name for this group of organisms.


Soil bacterial and fungal community responses to nitrogen addition across soil depth and microhabitat in an arid shrubland.
Arid shrublands are stressful environments, typified by alkaline soils low in organic matter, with biologically-limiting extremes in water availability, temperature, and UV radiation. The widely-spaced plants and interspace biological soil crusts in these regions provide soil nutrients in a localized fashion, creating a mosaic pattern of plant- or crust-associated microhabitats with distinct nutrient composition. With sporadic and limited rainfall, nutrients are primarily retained in the shallow surface soil, patterning biological activity. We examined soil bacterial and fungal community responses to simulated nitrogen (N) deposition in an arid Larrea tridentata-Ambrosia dumosa field experiment in southern Nevada, USA, using high-throughput sequencing of ribosomal RNA genes. To examine potential interactions among the N application, microhabitat and soil depth, we sampled soils associated with shrub canopies and interspace biological crusts at two soil depths (0-0.5 or 0-10 cm) across the N-amendment gradient (0, 7, and 15 kg ha(-1) yr(-1)). We hypothesized that localized compositional differences in soil microbiota would constrain the impacts of N addition to a microhabitat distribution that would reflect highly localized geochemical conditions and microbial community composition. The richness and community composition of both bacterial and fungal communities differed significantly by microhabitat and with soil depth in each microhabitat. Only bacterial communities exhibited significant responses to the N addition. Community composition correlated with microhabitat and depth differences in soil geochemical features. Given the distinct roles of soil bacteria and fungi in major nutrient cycles, the resilience of fungi and sensitivity of bacteria to N amendments suggests that increased N input predicted for many arid ecosystems could shift nutrient cycling toward pathways driven primarily by fungal communities.


Distinct mechanisms of nuclear accumulation regulate the functional consequence of E2F transcription factors.
Transcription factor E2F plays an important role in coordinating and integrating early cell cycle progression with the transcription apparatus. It is known that physiological E2F arises when a member of two families of proteins, E2F and DP, interact as E2F/DP heterodimers and that transcriptional activity is regulated through the physical association of pocket proteins such as pRb. However, little information is available regarding the mechanisms which control the levels of functional E2F. In this study, we have characterised one such mechanism which regulates the nuclear accumulation and activity of E2F. Specifically, we show that E2F proteins fall into two distinct categories according to their ability to accumulate in nuclei, one being exemplified by E2F-1 and the other by E2F-4 and -5. Thus, E2F-1 possesses an intrinsic nuclear localization signal whereas E2F-4 and -5 are devoid of such a signal. Furthermore, we find for E2F-4 and -5 that two distinct processes govern their nuclear accumulation whereby the nuclear localization signal is supplied in trans from either a DP heterodimer partner or a physically associated pocket protein. It is consistent with the role of pocket proteins in regulating nuclear accumulation that we find E2F-5 to be nuclear during early cell cycle progression with an increased cytoplasmic concentration in cycling cells. Our data show that the mechanism of nuclear accumulation determines the functional consequence of E2F on cell cycle progression: pocket protein-mediated accumulation impedes cell cycle progression, whereas DP-regulated nuclear accumulation promotes cell cycle progression. Moreover, the inactivation of pocket proteins by the adenovirus Ela protein, and subsequent release of E2F, failed to displace nuclear E2F. Our study identifies a new level of regulation in the control of E2F activity exerted at the level of nuclear accumulation where subunit composition and interaction with pocket proteins dictates the functional consequence on cell cycle progression.


Molecular imaging with 123I-FIAU, 18F-FUdR, 18F-FET, and 18F-FDG for monitoring herpes simplex virus type 1 thymidine kinase and ganciclovir prodrug activation gene therapy of cancer.
The ability to monitor tumor responses during prodrug activation gene therapy and other anticancer gene therapies is critical for their translation into clinical practice. Previously, we demonstrated the feasibility of noninvasive in vivo imaging with 131I-5-iodo-2'-fluoro-1-beta-D-arabinofuranosyluracil (131I-FIAU) for monitoring herpes simplex virus type 1 thymidine kinase (HSV1-tk) cancer gene expression in an experimental animal model. Here we tested the efficacy of SPECT with 123I-FIAU and PET with 5-18F-fluoro-2'-deoxyuridine (18F-FUdR), 2-18F-fluoroethyl-L-tyrosine (18F-FET), and 18F-FDG for monitoring tumor responses during prodrug activation gene therapy with HSV1-tk and ganciclovir (GCV). In the flanks of FVB/N female mice, 4 tumors per animal were established by subcutaneous injection of 1 x 10(5) cells of NG4TL4 sarcoma cells, HSV1-tk-transduced NG4TL4-STK cells, or a mixture of these cells in different proportions to model different efficacies of transfection and HSV1-tk gene expression levels in tumors. Ten days later, the animals were treated with GCV (10 mg/kg/d intraperitoneally) for 7 d. Gamma-Imaging with 123I-FIAU and PET with 18F-FUdR, 18F-FET, and 18F-FDG were performed before and after initiation of therapy with GCV in the same animal. Before GCV treatment, no significant difference in weight and size was found in tumors that expressed different HSV1-tk levels, suggesting similar in vivo proliferation rates for NG4TL4 and NG4TL4-STK sarcomas. The accumulation of 123I-FIAU at 24 h after injection was directly proportional to the percentage of NG4TL4-STK cells in the tumors. The 123I-FIAU accumulation at 4 and 7 d of GCV therapy decreased significantly compared with pretreatment levels and was proportional to the percentage of HSV1-tk-positive tumor cells. Tumor uptake of 18F-FUdR in all HSV1-tk-expressing tumors also decreased significantly compared with pretreatment levels and was proportional to the percentage of HSV1-tk-positive tumor cells. The accumulation of 18F-FET decreased minimally (about 1.5-fold) and 18F-FDG decreased only 2-fold after 7 d of GCV therapy, and the degree of reduction was proportional to the percentage of HSV1-tk-positive tumor cells. We have shown that gamma-camera imaging with 123I-FIAU was the most reliable method for prediction of tumor response to GCV therapy, which was proportional to the magnitude of HSV1-tk expression in tumor tissue. 123I-FIAU imaging can be used to verify the efficacy of elimination of HSV1-tk-expressing cells by therapy with GCV. PET with 18F-FUdR reliably visualizes proliferating tumor tissue and is most suitable for the assessment of responses in tumors undergoing HSV1-tk plus GCV prodrug activation gene therapy. PET with 18F-FDG or 18F-FET can be used as additional "surrogate" biomarkers of the treatment response, although these radiotracers are less sensitive than 18F-FUdR for monitoring tumor responses to prodrug activation gene therapy with HSV1-tk and GCV in this sarcoma model.


The initiation of embryonic-like collagen fibrillogenesis by adult human tendon fibroblasts when cultured under tension.
Tendon fibroblasts synthesize collagen and form fibrils during embryonic development, but to what extent mature fibroblasts are able to recapitulate embryonic development and develop normal tendon structure is unknown. The present study examined the capability of mature human tendon fibroblasts to initiate collagen fibrillogenesis when cultured in fixed-length fibrin gels. Fibroblasts were dissected from semitendinosus and gracilis tendons from healthy humans and cultured in 3D linear fibrin gels. The fibroblasts synthesized an extracellular matrix of parallel collagen fibrils that were aligned along the axis of tension. The fibrils had a homogeneous narrow diameter that was similar to collagen fibrils occurring in embryonic tendon. Immunostaining showed colocalization of collagen type I with collagen III, XII and XIV. A fibronectin network was formed in parallel with the collagen, and fibroblasts stained positive for integrin alpha(5). Finally, the presence of cell extensions into the extracellular space with membrane-enclosed fibrils in fibripositors indicated characteristics of embryonic tendon. We conclude that mature human tendon fibroblasts retain an intrinsic capability to perform collagen fibrillogenesis similar to that of developing tendon, which implies that the hormonal/mechanical milieu, rather than intrinsic cellular function, inhibits regenerative potential in mature tendon.


The stimulating effect of bright light on physical performance depends on internal time.
The human circadian clock regulates the daily timing of sleep, alertness and performance and is synchronized to the 24-h day by the environmental light-dark cycle. Bright light exposure has been shown to positively affect sleepiness and alertness, yet little is known about its effects on physical performance, especially in relation to chronotype. We, therefore, exposed 43 male participants (mean age 24.5 yrs ± SD 2.3 yrs) in a randomized crossover study to 160 minutes of bright (BL: ≈ 4.420 lx) and dim light (DL: ≈ 230 lx). During the last 40 minutes of these exposures, participants performed a bicycle ergometer test. Time-of-day of the exercise sessions did not differ between the BL and DL condition. Chronotype (MSF(sc), mid-sleep time on free days corrected for oversleep due to sleep debt on workdays) was assessed by the Munich ChronoType Questionnaire (MCTQ). Total work was significantly higher in BL (median 548.4 kJ, min 411.82 kJ, max 875.20 kJ) than in DL (median 521.5 kJ, min 384.33 kJ, max 861.23 kJ) (p = 0.004) going along with increased exhaustion levels in BL (blood lactate (+12.7%, p = 0.009), heart rate (+1.8%, p = 0.031), and Borg scale ratings (+2.6%, p = 0.005)) in all participants. The differences between total work levels in BL and DL were significantly higher (p = 0.004) if participants were tested at a respectively later time point after their individual mid-sleep (chronotype). These novel results demonstrate, that timed BL exposure enhances physical performance with concomitant increase in individual strain, and is related not only to local (external) time, but also to an individual's internal time.


Sensitive bioluminescence imaging of fungal dissemination to the brain in mouse models of cryptococcosis.
Cryptococcus neoformans is a leading cause of fungal brain infection, but the mechanism of dissemination and dynamics of cerebral infection following pulmonary disease are poorly understood. To address these questions, non-invasive techniques that can study the dynamic processes of disease development and progression in living animal models or patients are required. As such, bioluminescence imaging (BLI) has emerged as a powerful tool to evaluate the spatial and temporal distribution of infection in living animals. We aimed to study the time profile of the dissemination of cryptococcosis from the lung to the brain in murine models by engineering the first bioluminescent C. neoformans KN99α strain, expressing a sequence-optimized red-shifted luciferase. The high pathogen specificity and sensitivity of BLI was complemented by the three-dimensional anatomical information from micro-computed tomography (μCT) of the lung and magnetic resonance imaging (MRI) of the brain. These non-invasive imaging techniques provided longitudinal readouts on the spatial and temporal distribution of infection following intravenous, intranasal or endotracheal routes of inoculation. Furthermore, the imaging results correlated strongly with the fungal load in the respective organs. By obtaining dynamic and quantitative information about the extent and timing of brain infections for individual animals, we found that dissemination to the brain after primary infection of the lung is likely a late-stage event with a timeframe that is variable between animals. This novel tool in Cryptococcus research can aid the identification of host and pathogen factors involved in this process, and supports development of novel preventive or therapeutic approaches.


Associations of three erythrocyte cation transport systems with plasma lipids in Utah subjects.
To investigate the pathophysiology of essential hypertension, detailed biochemical and clinical variables were collected and analyzed for 2091 Utah subjects aged 3 to 83 years. Three different measurements of erythrocyte cation transport were obtained: Na+-Li+ countertransport, Li+-K+ cotransport, and furosemide-insensitive Li+ efflux into MgCl2. Total plasma cholesterol, triglycerides, and high density lipoprotein cholesterol levels were obtained from fasting subjects. Levels of high density lipoprotein subfractions 2 and 3 were also obtained from 350 subjects. Standardized data collection also included blood pressure, height, weight, and presence or absence of a diagnosis or treatment of essential hypertension. In univariate analyses of all 1420 adults, each of the three transport systems showed the same significant correlations with triglyceride levels (r = 0.33-0.35, p less than 0.0001), high density lipoprotein concentration (r = -0.19 to -0.21, p less than 0.001), and weight (r = 0.22-0.28, p less than 0.0001). In multivariate regression analyses, values for each transport system were significantly higher in hypertensive subjects; values for triglycerides, high density lipoprotein, and usually, the high density lipoprotein subfractions continued to have strong significant independent associations with all three transport systems; and weight remained significantly related only to Na+-Li+ countertransport. In separate logistic regressions, plasma triglyceride levels (positively, p less than 0.001) and high density lipoprotein subfraction 3 levels (inversely, p less than 0.03) were associated with hypertension itself. In multivariate analyses among 671 children, high density lipoprotein and high density lipoprotein subfraction 3 levels showed significant (p less than 0.05) inverse correlations with Na+-Li+ countertransport and furosemide-insensitive Li+ efflux.(ABSTRACT TRUNCATED AT 250 WORDS)


Ly-6A.2 expression regulates antigen-specific CD4+ T cell proliferation and cytokine production.
Ly-6 proteins appear to serve cell adhesion and cell signaling function, but the precise role of Ly-6A.2 in CD4+ T lymphocytes is still unclear. Overexpression of Ly-6A.2 in T lymphocytes has allowed us to analyze the influence of elevated Ly-6A.2 expression on T cell function. In this study we report reduced proliferation of CD4+ T cells overexpressing Ly-6A.2 in response to a peptide Ag. Moreover, the Ly-6A.2-overexpressing CD4+ cells generated elevated levels of IL-4, a key factor that propels the differentiation of naive CD4+ T cells into Th2 subset. The hyporesponsiveness of Ly-6A.2 transgenic CD4+ T cells is dependent on the interaction of Ly-6A.2 T cells with the APCs and can be reversed by blocking the interaction between Ly-6A.2 and a recently reported candidate ligand. Overexpression of Ly-6A.2 in CD4+ T cells reduced their Ca(2+) responses to TCR stimulation, therefore suggesting effects of Ly-6A.2 signaling on membrane proximal activation events. In contrast to the observed Ag-specific hyporesponsiveness, the Ly-6A.2 transgenic CD4+ T cells produced IL-4 independent of the interactions between Ly-6A.2 and the candidate Ly-6A.2 ligand. Our results suggest that 1) interaction of Ly-6A.2 with a candidate ligand regulates clonal expansion of CD4+ Th cells in response to an Ag (these results also provide further functional evidence for presence of Ly-6A.2 ligand on APC); and 2) Ly-6A.2 expression on CD4+ T cells promotes production of IL-4, a Th2 differentiation factor.


The identification and characterisation of novel bioactive peptides derived from porcine liver.
Bioactive peptides (BAPs) can be derived from a variety of sources; these could be from dietary proteins which are then broken down in the gastrointestinal tract to release BAPs, or they can be isolated from various sources ex vivo. Sources include plant-based proteins such as soy, and chickpeas, and animal proteins from waste from the meat industry and from fish skin. Bioinformatics is also a useful approach to assess the peptides released from digests due to the great number of possible sequences that can be isolated from proteins. Therefore, an in silico analysis of peptides could potentially lead to a more rapid discovery of BAPs. This article investigates a "crude" liver peptide mixture derived from papain hydrolysis of porcine liver and purified peptides derived from the hydrolysates following HPLC fractionation and in silico digestion of the host proteins identified using LC-MS/MS. This allowed the identification of two proteins (cytosol aminopeptidase and haemoglobin subunit alpha) present in the "crude" mixture after LC-MS/MS. In silico hydrolysis of these proteins identified that several peptides were predicted to be both present in the crude mixture using the BIOPEP database and to have potential bioactivity using the Peptide Ranker tool. Peptides (FWG, MFLG and SDPPLVFVG) with the greatest potential bioactivity and which had not previously been reported in the literature were then synthesised. The results indicated that the predicted bioactivity of the synthetic peptides would likely include antioxidant activity. FWG and MFLG derived from the in silico papain hydrolysis of cytosol aminopeptidase showed activity better or comparable to Trolox in the Oxygen Radical Absorbance Capacity (ORAC) assay. The use of these in silico tools, alongside a robust range of biochemical assays which cover a wider range of bioactivities would be a way of improving the discovery of novel bioactive peptides.


Genetically engineering plants for crop improvement.
Dramatic progress has been made in the development of gene transfer systems for higher plants. The ability to introduce foreign genes into plant cells and tissues and to regenerate viable, fertile plants has allowed for explosive expansion of our understanding of plant biology and has provided an unparalleled opportunity to modify and improve crop plants. Genetic engineering of plants offers significant potential for seed, agrichemical, food processing, specialty chemical, and pharmaceutical industries to develop new products and manufacturing processes. The extent to which genetically engineered plants will have an impact on key industries will be determined both by continued technical progress and by issues such as regulatory approval, proprietary protection, and public perception.


Palmitoylation of TNF alpha is involved in the regulation of TNF receptor 1 signalling.
The pleiotropic pro-inflammatory cytokine tumour necrosis factor alpha (TNF) is synthesised as a transmembrane protein that is subject to palmitoylation. In this study, the roles of this acylation on TNF-mediated biological effects were investigated. We found that the lipid raft partitioning of TNF is regulated by its palmitoylation. Furthermore, we demonstrated that this palmitoylation process interferes with the cleavage/degradation of TNF intracellular fragments but is not involved in the regulation of its ectodomain shedding. Moreover, we found that the palmitoylation of TNF hinders the binding of soluble TNF to TNFR1 and regulates the integration/retention of TNFR1 into lipid rafts. Finally, we demonstrate that the transmembrane forms of wild-type and palmitoylation-defective TNF interact differently with TNFR1 and regulate NFκB activity, Erk1/2 phosphorylation and interleukin-6 synthesis differently, strongly suggesting that palmitoylation of TNF is involved in the regulation of TNFR1 signalling. An evidence for the physiological intervention of this regulation is provided by the fact that, in macrophages, the binding of endogenous soluble TNF to TNFR1 is enhanced by inhibition of palmitoylation. Therefore, our data introduce the new concept that palmitoylation of TNF is one of the means by which TNF-producing cells regulate their sensitivity to soluble TNF.


Using gene therapy to protect and restore cartilage.
Numerous gene products have the potential to help protect cartilage from degradation and to repair cartilage that has become damaged as a result of disease or injury. The genes that encode these products thus may serve as chondroprotective and chondroregenerative medicines. To bring these agents into clinical use, it is necessary to screen candidate genes for efficacy under in vitro and in vivo conditions, to determine the best cells to target, and to develop appropriate gene transfer technologies. As discussed in the current review, progress has been made in each of these areas. Various viral and nonviral vectors are able to deliver genes to synoviocytes, articular chondrocytes, and mesenchymal stem cells. There also is evidence to suggest that ex vivo and in vivo approaches can be used for gene transfer to articular cartilage, synovium, and meniscus. Moreover various cytokine antagonists and growth factors have been shown to protect cartilage and stimulate chondrogenesis. In vivo methods and strategies that target synovium may be useful in a chondroprotective mode but because they do not increase the number of chondrogenic cells within lesions, they may be ill-equipped to repair large defects. Ex vivo methods however, provide cells and genes. It also is important to distinguish the treatment of isolated lesions occurring as a result of injury from the treatment of lesions resulting from underlying disease processes. Additional development of these approaches should result in clinically useful genetic methods for the protection and regeneration of cartilagenous tissues.


A dynamic noise level algorithm for spectral screening of peptide MS/MS spectra.
High-throughput shotgun proteomics data contain a significant number of spectra from non-peptide ions or spectra of too poor quality to obtain highly confident peptide identifications. These spectra cannot be identified with any positive peptide matches in some database search programs or are identified with false positives in others. Removing these spectra can improve the database search results and lower computational expense. A new algorithm has been developed to filter tandem mass spectra of poor quality from shotgun proteomic experiments. The algorithm determines the noise level dynamically and independently for each spectrum in a tandem mass spectrometric data set. Spectra are filtered based on a minimum number of required signal peaks with a signal-to-noise ratio of 2. The algorithm was tested with 23 sample data sets containing 62,117 total spectra. The spectral screening removed 89.0% of the tandem mass spectra that did not yield a peptide match when searched with the MassMatrix database search software. Only 6.0% of tandem mass spectra that yielded peptide matches considered to be true positive matches were lost after spectral screening. The algorithm was found to be very effective at removal of unidentified spectra in other database search programs including Mascot, OMSSA, and X!Tandem (75.93%-91.00%) with a small loss (3.59%-9.40%) of true positive matches.


The two types of 3-dehydroquinase have distinct structures but catalyze the same overall reaction.
The structures of enzymes catalyzing the reactions in central metabolic pathways are generally well conserved as are their catalytic mechanisms. The two types of 3-dehydroquinate dehydratase (DHQase) are therefore most unusual since they are unrelated at the sequence level and they utilize completely different mechanisms to catalyze the same overall reaction. The type I enzymes catalyze a cis-dehydration of 3-dehydroquinate via a covalent imine intermediate, while the type II enzymes catalyze a trans-dehydration via an enolate intermediate. Here we report the three-dimensional structures of a representative member of each type of biosynthetic DHQase. Both enzymes function as part of the shikimate pathway, which is essential in microorganisms and plants for the biosynthesis of aromatic compounds including folate, ubiquinone and the aromatic amino acids. An explanation for the presence of two different enzymes catalyzing the same reaction is presented. The absence of the shikimate pathway in animals makes it an attractive target for antimicrobial agents. The availability of these two structures opens the way for the design of highly specific enzyme inhibitors with potential importance as selective therapeutic agents.


Analytical form for a Bayesian wavelet estimator of images using the Bessel K form densities.
A novel Bayesian nonparametric estimator in the Wavelet domain is presented. In this approach, a prior model is imposed on the wavelet coefficients designed to capture the sparseness of the wavelet expansion. Seeking probability models for the marginal densities of the wavelet coefficients, the new family of Bessel K forms (BKF) densities are shown to fit very well to the observed histograms. Exploiting this prior, we designed a Bayesian nonlinear denoiser and we derived a closed form for its expression. We then compared it to other priors that have been introduced in the literature, such as the generalized Gaussian density (GGD) or the alpha-stable models, where no analytical form is available for the corresponding Bayesian denoisers. Specifically, the BKF model turns out to be a good compromise between these two extreme cases (hyperbolic tails for the alpha-stable and exponential tails for the GGD). Moreover, we demonstrate a high degree of match between observed and estimated prior densities using the BKF model. Finally, a comparative study is carried out to show the effectiveness of our denoiser which clearly outperforms the classical shrinkage or thresholding wavelet-based techniques.


How are we measuring physical activity and sedentary behaviour in the four home nations of the UK? A narrative review of current surveillance measures and future directions.
To explore and describe the comparability between the surveys of the UK home nations (England, Northern Ireland, Scotland, Wales) that monitor compliance with the Chief Medical Officers' physical activity (PA) recommendations. We also suggest ways to improve the UK national PA and sedentary behaviour (SB) surveillance systems. We identified national surveys that monitor PA and SB through searching UK-wide and devolved administration websites, the Global Observatory for Physical Activity Country Cards and the Active Healthy Kids Report Cards. Subsequently, we extracted information from survey documentation on the survey commissioners and contractors, method of administration, current questionnaire details relevant to the PA recommendations, questionnaire changes over the previous decade and the most recent prevalence figures. For adults and older adults, five surveys assess the moderate-to-vigorous PA (MVPA) recommendation, three assess muscle strengthening and three assess SB. For older adults only, three assess balance and co-ordination. For children, seven assess MVPA, none assess muscle strengthening and five assess SB. Only one survey reports on the under 5 PA recommendation. There is no part of the recommendations for which comparable estimates can be calculated across all four home nations. The greatest variation is among the SB questions and reporting. No survey has regularly used device-based measures. UK surveillance of the PA recommendations is complex, undertaken separately in the home nations, using multiple surveys that cover adults and children separately. We recommend that the costs and benefits of harmonising the existing questionnaires are considered, along with the potential introduction of device-based measures.


Effect of written feedback by editors on quality of reviews: two randomized trials.
Better peer review is needed, but proven methods to improve quality are unknown. Our objective was to determine whether written feedback to reviewers improves subsequent reviews. Eligible reviewers were randomized to intervention or control (receiving other reviewers' unscored reviews and the editor's decision letter). Study 1 (September 1998-September 2000) included reviewers with a median quality score of 3 or lower; study 2 (April 2000-January 2002), reviewers with median score of 4 or lower. Study 1 was designed with a power of 0.80 to detect a difference in score of 1; study 2, with a power of 0.80 to detect a difference of 0.5. All reviewers were at a peer-reviewed journal (Annals of Emergency Medicine). The main outcome measure was the editor's routine quality rating (1-5) of all reviews (blinded to study enrollment). For study 1, 51 reviewers were eligible and randomized and 35 had sufficient data (182 reviews) for analysis. The mean individual reviewer rating change was 0.16 (95% confidence interval [CI], -0.26 to 0.58) for control and -0.13 (-0.49 to 0.23) for intervention. For study 2, 127 reviewers were eligible and randomized, and 95 had sufficient data (324 reviews). Controls had a mean individual rating change of 0.12 (95% CI, -0.20 to 0.26) and intervention reviewers, 0.06 (-0.19 to 0.31). In study 1, minimal feedback from editors on review quality had no effect on subsequent performance of poor-quality reviewers, and the trend was toward a negative effect. In study 2, feedback to average reviewers was more extensive and supportive but produced no improvement in reviewer performance. Simple written feedback to reviewers seems to be an ineffective educational tool.


[Pathogenic factors of vibrios with special emphasis on Vibrio vulnificus].
Bacteria of the genus Vibrio are normal habitants of the aquatic environment and play roles for biocontrole of aquatic ecosystem, but some species are believed to be human pathogens. These species can be classified into two groups according to the types of diseases they cause: the gastrointestinal infections and the extraintestinal infections. The pathogenic species produce various pathogenic factors including enterotoxin, hemolysin, cytotoxin, protease, siderophore, adhesive factor, and hemagglutinin. We studied various pathogenic factors of vibrios with special emphasis on protease and hemolysin of V. vulnificus. V. vulnificus is now recognized as being among the most rapidly fatal of human pathogens, although the infection is appeared in patients having underlying disease(s) such as liver dysfunction, alcoholic cirrhosis or haemochromatosis. V. vulnificus protease (VVP) is thought to be a major toxic factor causing skin damage in the patients having septicemia. VVP is a metalloprotease and degrades a number of biologically important proteins including elastin, fibrinogen, and plasma proteinase inhibitors of complement components. VVP causes skin damages through activation of the Factor XII-plasma kallikrein-kinin cascade and/or exocytotic histamine release from mast cells, and a haemorrhagic lesion through digestion of the vascular basement membrane. Thus, the protease is the most probable candidate for tissue damage and bacterial invasion during an infection. Pathogenic roles and functional mechanism of other factors including hemolysins of V. vulnificus and V. mimicus are also shown in this review article.


Role of Risk of Bias in Systematic Review for Chemical Risk Assessment: A Case Study in Understanding the Relationship Between Congenital Heart Defects and Exposures to Trichloroethylene.
The National Academy of Science has recommended that a risk of bias (RoB; credibility of the link between exposure and outcome) assessment be conducted on studies that are used as primary data sources for hazard identification and dose-response assessment. Few applications of such have been conducted. Using trichloroethylene and congenital heart defects (CHDs) as a case study, we explore the role of RoB in chemical risk assessment using the National Toxicology Program's Office of Health Assessment and Translation RoB tool. Selected questions were tailored to evaluation of CHD and then applied to 12 experimental animal studies and 9 epidemiological studies. Results demonstrated that the inconsistent findings of a single animal study were likely explained by the limitations in study design assessed via RoB (eg, lack of concurrent controls, unvalidated method for assessing outcome, unreliable statistical methods, etc). Such limitations considered in the context of the body of evidence render the study not sufficiently reliable for the development of toxicity reference values. The case study highlights the utility of RoB as part of a robust risk assessment process and specifically demonstrates the role RoB can play in objectively selecting candidate data sets to develop toxicity values.


Effects of arterial blood gas levels on cerebral blood flow and oxygen transport.
Near Infra-Red Spectroscopy (NIRS) is a non-invasive technique which can be used to investigate cerebral haemodynamics and oxygenation with high temporal resolution. When combined with measures of Cerebral Blood Flow (CBF), it has the potential to provide information about oxygen delivery, utilization and metabolism. However, the interpretation of experimental results is complex. Measured NIRS signals reflect both scalp and cerebral haemodynamics and are influenced by many factors. The relationship between Arterial Blood Pressure (ABP) and CBF has been widely investigated and it central to cerebral autoregulation. Changes in arterial blood gas levels have a significant effect on ABP and CBF and these relationships have been quantified previously. The relationship between ABP and NIRS signals, however, has not been fully characterized. In this paper, we thus investigate the influence of changes in arterial blood gas levels both experimentally and theoretically, using an extended mathematical model of cerebral blood flow and metabolism, in terms of the phase angle at 0.1 Hz. The autoregulation response is found to be strongly dependent upon the carbon dioxide (CO2) partial pressure but much less so upon changes in arterial oxygen saturation (SaO2). The results for phase angle sensitivity to CO2 show good agreement between experimental and theory, but a poorer agreement is found for the sensitivity to SaO2.


Accessibility of cancer treatment services for Indigenous Australians in the Northern Territory: perspectives of patients and care providers.
Poorer cancer outcomes of Indigenous Australians in Australia's Northern Territory (NT) compared with their non-Indigenous counterparts are partially due to diminished access to cancer treatment services (CTS). Accessibility of health care is a multidimensional construct, including physical, logistical, psychosocial and cultural dimensions. While previous research has identified specific areas of reduced access to CTS for Indigenous Australians, the higher burden of cancer borne by Indigenous Australians warrants a more comprehensive understanding of access to CTS in the NT. The purpose of this study was to explore and map the accessibility of CTS for Indigenous Australians in the NT and to identify key access barriers. This predominantly qualitative study, complemented by a descriptive quantitative component, explored and mapped the accessibility of one CTS (CTS-NT) that services a large number of Indigenous Australians in the NT. Patient perspectives were obtained via secondary analysis of data from 75 face-to-face interviews with Indigenous Australian adults attending the CTS-NT. Care provider perspectives were obtained via primary analysis of data from 29 face-to-face interviews with care providers and staff working at CTS-NT. Data were analysed to identify issues of accessibility informed by Leveque and colleagues' conceptual framework of access to health care, which comprises five dimensions of accessibility of the health service and the ability of Indigenous patients to interact with these dimensions to generate access. Applied thematic analysis was conducted on the qualitative data and descriptive analysis was conducted on the quantitative data. The analysis of the patient and care provider reports identified multiple access barriers across all dimensions including: inadequate preparation of Indigenous patients for treatment; delayed and complicated commencement of treatment; dislocation from home; competing priorities; scarcity of Indigenous care providers and staff; lack of culturally-relevant care; challenges associated with language, accommodation, transport and finance; and disjointed and fraught relationships with care providers. These barriers posed significant challenges to Indigenous patients maintaining their engagement with treatment. This study provides a valuable snapshot of the barriers facing this population across the dimensions of health care access. Urgent action in addressing these issues is required at individual, service and state levels.