Harderian Gland Tumorigenesis: Low-Dose and LET Response.
Increased cancer risk remains a primary concern for travel into deep space and may preclude manned missions to Mars due to large uncertainties that currently exist in estimating cancer risk from the spectrum of radiations found in space with the very limited available human epidemiological radiation-induced cancer data. Existing data on human risk of cancer from X-ray and gamma-ray exposure must be scaled to the many types and fluences of radiations found in space using radiation quality factors and dose-rate modification factors, and assuming linearity of response since the shapes of the dose responses at low doses below 100 mSv are unknown. The goal of this work was to reduce uncertainties in the relative biological effect (RBE) and linear energy transfer (LET) relationship for space-relevant doses of charged-particle radiation-induced carcinogenesis. The historical data from the studies of Fry et al. and Alpen et al. for Harderian gland (HG) tumors in the female CB6F1 strain of mouse represent the most complete set of experimental observations, including dose dependence, available on a specific radiation-induced tumor in an experimental animal using heavy ion beams that are found in the cosmic radiation spectrum. However, these data lack complete information on low-dose responses below 0.1 Gy, and for chronic low-dose-rate exposures, and there are gaps in the LET region between 25 and 190 keV/μm. In this study, we used the historical HG tumorigenesis data as reference, and obtained HG tumor data for 260 MeV/u silicon (LET ∼70 keV/μm) and 1,000 MeV/u titanium (LET ∼100 keV/μm) to fill existing gaps of data in this LET range to improve our understanding of the dose-response curve at low doses, to test for deviations from linearity and to provide RBE estimates. Animals were also exposed to five daily fractions of 0.026 or 0.052 Gy of 1,000 MeV/u titanium ions to simulate chronic exposure, and HG tumorigenesis from this fractionated study were compared to the results from single 0.13 or 0.26 Gy acute titanium exposures. Theoretical modeling of the data show that a nontargeted effect model provides a better fit than the targeted effect model, providing important information at space-relevant doses of heavy ions.


Genetic transmission of reading ability.
Reading is the processing of written language. Family resemblance for reading (dis)ability might be due to transmission of a genetic liability or due to family environment, including cultural transmission from parents to offspring. Familial-risk studies exploring neurobehavioral precursors for dyslexia and twin studies can only speak to some of these issues, but a combined twin-family study can resolve the nature of the transmitted risk. Word-reading fluency scores of 1100 participants from 431 families (with twins, siblings and their parents) were analyzed to estimate genetic and environmental sources of variance, and to test the presence of assortative mating and cultural transmission. Results show that variation in reading ability is mainly caused by additive and non-additive genetic factors (64%). The substantial assortative mating (rfather-mother=0.38) has scientific and clinical implications. We conclude that parents and offspring tend to resemble each other for genetic reasons, and not due to cultural transmission.


Acceptability of alginate enriched bread and its effect on fat digestion in humans.
Lifestyle interventions and physical activity remain the cornerstone of obesity management, as pharmacological therapies (orlistat) are associated with gastrointestinal (GI) side effects. Combining orlistat with fibers can reduce side effects, improving compliance. Therefore, a fiber that inhibits lipase without side effects could help treat obesity. The aims of the present work were to assess whether alginate enriched bread could inhibit fat digestion, and assess the acceptability of alginate bread and its effect on GI wellbeing. A double-blind, randomised, controlled cross-over pilot study (NCT03350958) assessed the impact of an alginate bread meal on; lipid content in ileal effluent and circulating triacylglycerol levels. This was compared against the same meal with non-enriched (control) bread. GI wellbeing and acceptability of alginate bread was compared to control bread through daily wellbeing questionnaires and food diaries (NCT03477981). Control bread followed by alginate bread were consumed for two weeks respectively. Consumption of alginate bread reduced circulating triacylglycerol compared to control (2% reduction in AUC) and significantly increased lipid content in ileal effluent (3.8 g ± 1.6 after 210 min). There were no significant changes to GI wellbeing when comparing alginate bread to control bread. A significant increase in the feeling of fullness occurred with alginate bread compared to baseline and the first week of control bread consumption. This study showed that sustained consumption of alginate enriched bread does not alter GI wellbeing and can decrease lipolysis, increasing lipid leaving the small intestine. Further studies are required to demonstrate that reduced fat digestion through the action of alginate can reduce fat mass or body weight.


Tonal expectations influence early pitch processing.
The present study investigated the ERP correlates of the influence of tonal expectations on pitch processing. Participants performed a pitch discrimination task between penultimate and final tones of melodies. These last two tones were a repetition of the same musical note, but penultimate tones were always in tune whereas final tones were slightly out of tune in half of the trials. The pitch discrimination task allowed us to investigate the influence of tonal expectations in attentive listening and, for penultimate tones, without being confounded by decisional processes (occurring on final tones). Tonal expectations were manipulated by a tone change in the first half of the melodies that changed their tonality, hence changing the tonal expectedness of penultimate and final tones without modifying them acoustically. Manipulating tonal expectations with minimal acoustic changes allowed us to focus on the cognitive expectations based on listeners' knowledge of tonal structures. For penultimate tones, tonal expectations modulated processing within the first 100 msec after onset resulting in an Nb/P1 complex that differed in amplitude between tonally related and less related conditions. For final tones, out-of-tune tones elicited an N2/P3 complex and, on in-tune tones only, tonal manipulation elicited an ERAN/RATN-like negativity overlapping with the N2. Our results suggest that cognitive tonal expectations can influence pitch perception at several steps of processing, starting with early attentional selection of pitch.


Stoichiometry of laser ablated brass nanoparticles in water and air.
We report on the stoichiometric analysis of laser ablated brass plasma nanoparticles (NPs) in water and ambient air. Morphological study of the deposited NPs in water showed smaller spherical NPs compared to micrometer sized spherical particles in air. The smaller particles were Zn enriched and the concentration decreased with increases in size. Photoluminescence of particles at 380 nm corresponding to ZnO showed higher concentrations of Zn with smaller sized deposited NPs, whereas the micrometer sized particles showed multiple peaks at 415 and 440 nm, which implied that there was an abundance of the Cu fraction in the NPs. Plasma plume parameters, electron temperature, electron density, and evolution of the plasma plume were studied using optical emission spectroscopy and 2-dimensional imaging of the plume. The mass ablation rate in water was observed to be greater than that in air. Higher electron density and temperature of the plasmoid in water was attributed to confinement of the plasma plume near the target surface in water.


Registration Techniques for Clinical Applications of Three-Dimensional Augmented Reality Devices.
Many clinical procedures would benefit from direct and intuitive real-time visualization of anatomy, surgical plans, or other information crucial to the procedure. Three-dimensional augmented reality (3D-AR) is an emerging technology that has the potential to assist physicians with spatial reasoning during clinical interventions. The most intriguing applications of 3D-AR involve visualizations of anatomy or surgical plans that appear directly on the patient. However, commercially available 3D-AR devices have spatial localization errors that are too large for many clinical procedures. For this reason, a variety of approaches for improving 3D-AR registration accuracy have been explored. The focus of this review is on the methods, accuracy, and clinical applications of registering 3D-AR devices with the clinical environment. The works cited represent a variety of approaches for registering holograms to patients, including manual registration, computer vision-based registration, and registrations that incorporate external tracking systems. Evaluations of user accuracy when performing clinically relevant tasks suggest that accuracies of approximately 2 mm are feasible. 3D-AR device limitations due to the vergence-accommodation conflict or other factors attributable to the headset hardware add on the order of 1.5 mm of error compared to conventional guidance. Continued improvements to 3D-AR hardware will decrease these sources of error.


Optics. Observation of optical polarization Möbius strips.
Möbius strips are three-dimensional geometrical structures, fascinating for their peculiar property of being surfaces with only one "side"—or, more technically, being "nonorientable" surfaces. Despite being easily realized artificially, the spontaneous emergence of these structures in nature is exceedingly rare. Here, we generate Möbius strips of optical polarization by tightly focusing the light beam emerging from a q-plate, a liquid crystal device that modifies the polarization of light in a space-variant manner. Using a recently developed method for the three-dimensional nanotomography of optical vector fields, we fully reconstruct the light polarization structure in the focal region, confirming the appearance of Möbius polarization structures. The preparation of such structured light modes may be important for complex light beam engineering and optical micro- and nanofabrication.


Impact of male circumcision on the HIV epidemic in Papua New Guinea: a country with extensive foreskin cutting practices.
The degree to which adult medical male circumcision (MC) programs can reduce new HIV infections in a moderate HIV prevalence country like Papua New Guinea (PNG) are uncertain especially given the widespread prevalence of longitudinal foreskin cuts among adult males. We estimated the likely impact of a medical MC intervention in PNG using a mathematical model of HIV transmission. The model was age-structured and incorporated separate components for sex, rural/urban, men who have sex with men and female sex workers. Country-specific data of the prevalence of foreskin cuts, sexually transmitted infections, condom usage, and the acceptability of MC were obtained by our group through related studies. If longitudinal foreskin cutting has a protective efficacy of 20% compared to 60% for MC, then providing MC to 20% of uncut males from 2012 would require 376,000 procedures, avert 7,900 HIV infections by 2032, and require 143 MC per averted infection. Targeting uncut urban youths would achieve the most cost effective returns of 54 MC per HIV infection averted. These numbers of MC required to avert an HIV infection change little even with coverage up to 80% of men. The greater the protective efficacy of longitudinal foreskin cuts against HIV acquisition, the less impact MC interventions will have. Dependent on this efficacy, increasing condom use could have a much greater impact with a 10 percentage point increase averting 18,400 infections over this same period. MC programs could be effective in reducing HIV infections in PNG, particularly in high prevalence populations. However the overall impact is highly dependent on the protective efficacy of existing longitudinal foreskin cutting in preventing HIV.


Cysteamine treatment restores the in vitro ability to differentiate along the osteoblastic lineage of mesenchymal stromal cells isolated from bone marrow of a cystinotic patient.
Cystinosis is a rare autosomal recessive disease caused by mutations of the CTNS gene, which encodes for a lysosomal cystine/H(+) symporter. In mice, inactivation of the CTNS gene causes intralysosomal cystine accumulation and progressive organ damage that can be reversed, at least in part, by infusion of mesenchymal stromal cells (MSCs). Little is known on the mesenchymal compartment of cystinotic patients. The aim of the study was to test the phenotypical and functional properties of cystinotic MSCs (Cys-MSCs) isolated from bone marrow (BM) aspirate of a patient with nephropathic cystinosis. Morphology, proliferative capacity (measured as population doublings), immunophenotype (by flow-cytometry) and immunomodulatory properties (as phytohemagglutinin-induced peripheral blood mononuclear cell proliferation) were analyzed. The osteogenic differentiation potential of Cys-MSCs was evaluated by histological staining (alkaline phosphatase activity, Alzarin Red and von Kossa staining) spectrophotometry and Quantitative Reverse Transcriptase Polymerase Chain Reaction for osteigenic markers in the presence and in the absence of cysteamine. Cys-MSCs were compared with those isolated and expanded ex vivo from three healthy donors (HD-MSCs). Despite a slightly lower proliferative capacity, Cys-MSCs displayed a characteristic spindle-shaped morphology and similar immunephenotype as HD-MSCs. Cys-MSCs and HD-MSCs prevented proliferation of PHA-stimulated allogeneic peripheral blood mononuclear cells to the same extent. After in vitro induction into osteoblasts, Cys-MSCs showed reduced alkaline phosphatase (ALP) activity, calcium depositions and expression of ALP and collagen type 1. When Cys-MSCs were treated in vitro with increasing doses of cysteamine (50-100-200 μM/L) during the differentiation assay, recovery of Cys-MSCs differentiation capacity into osteoblasts was observed. No difference in adipogenic differentiation was found between Cys-MSCs and HD-MSCs. Our results indicate that, as compared to HD-MSCs, Cys-MSCs show reduced ability to differentiate into osteoblasts, which can be reverted after cysteamine treatment.


Role of percutaneous needle core biopsy in diagnosis and clinical management of renal masses.
Percutaneous needle core biopsies are routinely performed for renal mass diagnosis in some institutions. Because of limited tissue availability, accurate diagnosis can be challenging, and the role of needle core biopsy (NCB) remains debatable in kidney tumor management. In the present study, we reported our experience in diagnosing renal masses via percutaneous NCB and the role it plays in clinical management of these masses. We studied 301 consecutive cases of percutaneous NCBs performed for 280 renal masses from 269 patients between year 2008 and 2011 by reviewing final pathology diagnosis, hematoxylin and eosin slides, and ancillary studies. Diagnostic accuracy was determined by comparing biopsy and nephrectomy diagnoses in a subset of renal masses. Clinical data including demographic information, clinical presentation, radiographic findings, and treatment information were reviewed subsequently if available. The size of renal masses in our study cohort ranged from 0.5 to 24 cm, and 78% of them were small renal masses. Definite diagnoses were rendered in 89% of the renal masses by NCBs, and 23% of them were benign. Renal mass NCB was 100% accurate in diagnosing primary renal malignancy and 93% accurate in determining histologic subtypes. Clinical management was analyzed for 180 renal masses. There was significant difference in clinical management between different diagnostic groups. We conclude that percutaneous NCB is a powerful tool not only for definite tissue diagnosis of renal masses before treatment but also plays an important role in guiding patient management and obtaining material for future molecular studies for targeted therapies.


GWAS for quantitative resistance phenotypes in Mycobacterium tuberculosis reveals resistance genes and regulatory regions.
Drug resistance diagnostics that rely on the detection of resistance-related mutations could expedite patient care and TB eradication. We perform minimum inhibitory concentration testing for 12 anti-TB drugs together with Illumina whole-genome sequencing on 1452 clinical Mycobacterium tuberculosis (MTB) isolates. We evaluate genome-wide associations between mutations in MTB genes or non-coding regions and resistance, followed by validation in an independent data set of 792 patient isolates. We confirm associations at 13 non-canonical loci, with two involving non-coding regions. Promoter mutations are measured to have smaller average effects on resistance than gene body mutations. We estimate the heritability of the resistance phenotype to 11 anti-TB drugs and identify a lower than expected contribution from known resistance genes. This study highlights the complexity of the genomic mechanisms associated with the MTB resistance phenotype, including the relatively large number of potentially causal loci, and emphasizes the contribution of the non-coding portion of the genome.


Psoriasis and the risk of incident diabetes mellitus: a population-based study.
Cross-sectional studies, mostly in hospitalized patients, reported a possible positive association between psoriasis and diabetes mellitus (DM). However, information on the temporal relation is scarce, and incidence rates of new-onset DM in patients with psoriasis are lacking. To assess and compare incidence rates of new-onset DM between patients with psoriasis and a comparison group without psoriasis, and to explore the role of psoriasis severity and body mass index (BMI). We conducted a follow-up study with a nested case-control analysis within the U.K.-based General Practice Research Database. The study population consisted of patients with a first-time diagnosis of psoriasis between 1994 and 2005 and a matched group of psoriasis-free patients. We used psoriasis duration and treatment as proxy for disease severity, and we applied conditional logistic regression to obtain odds ratios (ORs) with 95% confidence intervals (CIs). Within the study population of 65 449 patients we identified 1061 incident cases of DM. Of these, 59% had a history of psoriasis, yielding a crude incidence rate ratio of 1.36 (95% CI 1.20-1.53). The adjusted OR for patients with >or=2 years disease duration and >2 prescriptions per year for oral psoriasis treatment was 2.56 (95% CI 1.11-5.92). In an analysis restricted to patients with normal BMI, the adjusted OR was 2.02 (95% CI 1.31-3.10). In this large observational study the risk of incident DM was increased for patients with psoriasis as compared with a psoriasis-free comparison group. The risk increased with psoriasis duration and severity and was not driven by high BMI alone.


The neurotropic parasite Toxoplasma gondii increases dopamine metabolism.
The highly prevalent parasite Toxoplasma gondii manipulates its host's behavior. In infected rodents, the behavioral changes increase the likelihood that the parasite will be transmitted back to its definitive cat host, an essential step in completion of the parasite's life cycle. The mechanism(s) responsible for behavioral changes in the host is unknown but two lines of published evidence suggest that the parasite alters neurotransmitter signal transduction: the disruption of the parasite-induced behavioral changes with medications used to treat psychiatric disease (specifically dopamine antagonists) and identification of a tyrosine hydroxylase encoded in the parasite genome. In this study, infection of mammalian dopaminergic cells with T. gondii enhanced the levels of K+-induced release of dopamine several-fold, with a direct correlation between the number of infected cells and the quantity of dopamine released. Immunostaining brain sections of infected mice with dopamine antibody showed intense staining of encysted parasites. Based on these analyses, T. gondii orchestrates a significant increase in dopamine metabolism in neural cells. Tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis, was also found in intracellular tissue cysts in brain tissue with antibodies specific for the parasite-encoded tyrosine hydroxylase. These observations provide a mechanism for parasite-induced behavioral changes. The observed effects on dopamine metabolism could also be relevant in interpreting reports of psychobehavioral changes in toxoplasmosis-infected humans.


Family response to critical illness: postintensive care syndrome-family.
The family response to critical illness includes development of adverse psychological outcomes such as anxiety, acute stress disorder, posttraumatic stress, depression, and complicated grief. This cluster of complications from exposure to critical care is now entitled postintensive care syndrome-family. Adverse psychological outcomes occur in parents of neonatal and pediatric patients and in family members of adult patients, and may be present for >4 yrs after intensive care unit discharge. Psychological repercussions of critical illness affect the family member's ability to fully engage in necessary care-giving functions after hospitalization. It has been suggested that the manner in which healthcare workers communicate with family members and the way in which families are included in care and decision-making, may affect long-term outcomes. Preventive strategies for optimal communication and inclusion in care are reviewed. Many tools are available to assess the risk for and to diagnose postintensive care syndrome-family conditions during hospitalization and at intervals after discharge. Visits after discharge, support groups, and clinics have been proposed for assessing the need for professional referrals as well as for treating family members when psychological illness persists. Studies evaluating these measures are reviewed.


Crowdsourcing dialect characterization through Twitter.
We perform a large-scale analysis of language diatopic variation using geotagged microblogging datasets. By collecting all Twitter messages written in Spanish over more than two years, we build a corpus from which a carefully selected list of concepts allows us to characterize Spanish varieties on a global scale. A cluster analysis proves the existence of well defined macroregions sharing common lexical properties. Remarkably enough, we find that Spanish language is split into two superdialects, namely, an urban speech used across major American and Spanish citites and a diverse form that encompasses rural areas and small towns. The latter can be further clustered into smaller varieties with a stronger regional character.


Musicians and the metric structure of words.
The present study aimed to examine the influence of musical expertise on the metric and semantic aspects of speech processing. In two attentional conditions (metric and semantic tasks), musicians listened to short sentences ending in trisyllabic words that were semantically and/or metrically congruous or incongruous. Both ERPs and behavioral data were analyzed and the results were compared to previous nonmusicians' data. Regarding the processing of meter, results showed that musical expertise influenced the automatic detection of the syllable temporal structure (P200 effect), the integration of metric structure and its influence on word comprehension (N400 effect), as well as the reanalysis of metric violations (P600 and late positivities effects). By contrast, results showed that musical expertise did not influence the semantic level of processing. These results are discussed in terms of transfer of training effects from music to speech processing.


The relationship between aging, performance, and the neural correlates of successful memory encoding.
The present functional magnetic resonance imaging (fMRI) study investigated whether age-related differences in the neural correlates of successful memory encoding are modulated by memory performance. Young (mean age 22 years; N = 16) and older (mean age 69 years; N = 32) subjects were scanned while making animacy decisions on visually presented words. Memory for the words was later assessed in a recognition test, allowing fMRI activity elicited by study words to be contrasted according to subsequent memory performance. Young and older adults exhibited equivalent subsequent memory effects (enhanced activity for later remembered items) in an extensive network that included left inferior prefrontal cortex and anterior hippocampus. In posterior cingulate cortex, reversed subsequent memory effects (greater activity for later forgotten items) were of greater magnitude in young subjects. A voxel-of-interest analysis conducted on left and right prefrontal subsequent memory effects revealed that the effects were distributed more bilaterally in older than in young subjects, replicating previous findings. This age-related difference was confined to older subjects with relatively poor recognition performance, who were also the only group to demonstrate statistically significant right prefrontal subsequent memory effects. The findings suggest that relative preservation of memory performance with increasing age does not depend upon right prefrontal "over-recruitment."


Nr4a1 siRNA expression attenuates α-MSH regulated gene expression in 3T3-L1 adipocytes.
Several recent investigations have underscored the growing role of melanocortin signaling in the peripheral regulation of lipid, glucose, and energy homeostasis. In addition, the melanocortins play a critical role in the central control of satiety. These observations, and the latest reports highlighting the emerging role of the nuclear hormone receptor (NR) 4A subgroup in metabolism, have prompted us to investigate the cross talk between [Nle(4), d-Phe(7)] (NDP)-α-MSH and Nr4a signaling in adipose. We have shown that NDP-MSH strikingly and preferentially induces the expression of the NR4A subgroup (but not any other members of the NR superfamily) in differentiated 3T3-L1 adipocytes. Utilization of quantitative PCR on custom-designed metabolic TaqMan low-density arrays identified the concomitant and marked induction of the mRNAs encoding Il-6, Cox2, Pdk4, and Pck-1 after NDP-MSH treatment. Similar experiments demonstrated that the mRNA expression profile induced by cAMP and NDP-MSH treatment displayed unique but also overlapping properties and suggested that melanocortin-mediated induction of gene expression involves cAMP-dependent and -independent signaling. Nr4a1/Nur77 small interfering RNA (siRNA) expression suppressed NDP-MSH-mediated induction of Nr4a1/Nur77 and Nr4a3/Nor-1 (but not Nr4a2/Nurr1). Moreover, expression of the siRNA-attenuated NDP-MSH mediated induction of the mRNAs encoding Il-6, Cox2/Ptgs2, and Pck-1 expression. In addition, Nur77 siRNA expression attenuated NDP-MSH-mediated glucose uptake. In vivo, ip administration of NDP-MSH to C57 BL/6J (male) mice significantly induced the expression of the mRNA encoding Nur77 and increased IL-6, Cox2, Pck1, and Pdk4 mRNA expression in (inguinal) adipose tissue. We conclude that Nur77 expression is necessary for MSH-mediated induction of gene expression in differentiated adipocytes. Furthermore, this study demonstrates cross talk between MSH and Nr4a signaling in adipocytes.


Research activities of full-time faculty in academic departments of psychiatry.
Using data collected by a 1989 American Psychiatric Association survey of full-time, salaried faculty in departments of psychiatry at US medical schools, we examined the number of faculty engaged in research, their levels of involvement in research, distribution, sources of funding, fields and topics studied, and training. Using a three-level measure of research involvement, we categorized 39.1% of the respondents as "researchers," 36% as "limited commitment researchers," and 25.1% as not involved in research. In a pattern similar to that observed for research funding in other studies, half of the researchers were concentrated in the top 15 of the 116 responding departments. Level of research involvement varied by degree type (joint-program MD/PhDs were most involved), sources of funding, fields, and topics. Among faculty with MDs, having had research experiences in medical school or postdoctoral research training was associated with a higher level of research involvement. The findings underscore the need to expand and improve postdoctoral research training--especially for MDs--and programs to recruit college and medical students into psychiatric research.


Regional trends in awards of incapacity benefit by cause.
Since the early 1990s, rates of incapacity benefit (IB) in Britain for musculoskeletal complaints have declined, and they have been overtaken by mental and behavioural disorders as the main reason for award of IB. To explore reasons for this change. Using data supplied by the Department for Work and Pensions, we analysed trends in the ratio of new IB awards for mental and behavioural disorders to those for musculoskeletal disorders during 1997-2007 by Government region. In Great Britain overall, the above ratio more than doubled over the study period, as a consequence of falling numbers of new awards for musculoskeletal disorders. The extent to which the ratio increased was smallest in London (50%) and South-East England (56%), and was progressively larger in more northerly regions (>150% in North-East England and Scotland). The differences in trends between regions seem too large to be explained by differential changes in working conditions, patterns of employment or the rigour with which claims were assessed. An alternative explanation could be that the main driver for the trends has been culturally determined changes in health beliefs and expectations, and that these cultural changes began in London and the South-East, only later spreading to other parts of Britain.


Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD.
Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD. ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days). In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) (P = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, P = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, P < .001), and the SGFS was better (97.7% v 58.7%, P < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients. Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.


Differential in vivo activation of the class II and class III snRNA genes by the POU-specific domain of Oct-1.
Many snRNA genes contain binding sites for the ubiquitous transcription factor Oct-1. In vitro studies have shown that this factor potentiates binding of an essential transcription factor (PTF) to the proximal sequence element (PSE) of snRNA genes, and activates transcription. Using Gal4 fusion proteins, I show here that the POU-specific region of the DNA-binding domain of Oct-1 is sufficient both to potentiate PTF binding in vitro and to transactivate pol II- and pol III-dependent snRNA genes in vivo . A single amino acid change in this domain abrogates both activation and interaction with PTF. The N- and C-terminal regions of Oct-1 also activate transcription of both classes of snRNA genes. Wild-type levels of Pol II-dependent U2 expression require all activation domains, whereas efficient activation of the pol III-dependent 7SK and U6 genes is effected by the POU-specific domain alone. These results indicate that contacts between PTF and amino acids in the POU-specific domain of Oct-1 are critical for efficient transactivation of snRNA genes in vivo. The POU-specific domain of Oct-2A also activates these genes, but the N- and C-terminal domains are relatively inactive.


Subgroup economic analysis for glioblastoma in a health resource-limited setting.
The aim of this research was to evaluate the economic outcomes of radiotherapy (RT), temozolomide (TMZ) and nitrosourea (NT) strategies for glioblastoma patients with different prognostic factors. A Markov model was developed to track monthly patient transitions. Transition probabilities and utilities were derived primarily from published reports. Costs were estimated from the perspective of the Chinese healthcare system. The survival data with different prognostic factors were simulated using Weibull survival models. Costs over a 5-year period and quality-adjusted life years (QALYs) were estimated. Probabilistic sensitivity and one-way analyses were performed. The baseline analysis in the overall cohort showed that the TMZ strategy increased the cost and QALY relative to the RT strategy by $25,328.4 and 0.29, respectively; and the TMZ strategy increased the cost and QALY relative to the NT strategy by $23,906.5 and 0.25, respectively. Therefore, the incremental cost effectiveness ratio (ICER) per additional QALY of the TMZ strategy, relative to the RT strategy and the NT strategy, amounts to $87,940.6 and $94,968.3, respectively. Subgroups with more favorable prognostic factors achieved more health benefits with improved ICERs. Probabilistic sensitivity analyses confirmed that the TMZ strategy was not cost-effective. In general, the results were most sensitive to the cost of TMZ, which indicates that better outcomes could be achieved by decreasing the cost of TMZ. In health resource-limited settings, TMZ is not a cost-effective option for glioblastoma patients. Selecting patients with more favorable prognostic factors increases the likelihood of cost-effectiveness.


Searching mixed DNA profiles directly against profile databases.
DNA databases have revolutionised forensic science. They are a powerful investigative tool as they have the potential to identify persons of interest in criminal investigations. Routinely, a DNA profile generated from a crime sample could only be searched for in a database of individuals if the stain was from single contributor (single source) or if a contributor could unambiguously be determined from a mixed DNA profile. This meant that a significant number of samples were unsuitable for database searching. The advent of continuous methods for the interpretation of DNA profiles offers an advanced way to draw inferential power from the considerable investment made in DNA databases. Using these methods, each profile on the database may be considered a possible contributor to a mixture and a likelihood ratio (LR) can be formed. Those profiles which produce a sufficiently large LR can serve as an investigative lead. In this paper empirical studies are described to determine what constitutes a large LR. We investigate the effect on a database search of complex mixed DNA profiles with contributors in equal proportions with dropout as a consideration, and also the effect of an incorrect assignment of the number of contributors to a profile. In addition, we give, as a demonstration of the method, the results using two crime samples that were previously unsuitable for database comparison. We show that effective management of the selection of samples for searching and the interpretation of the output can be highly informative.


Cervical lymph nodes.
The lymph node staging is a very important prognostic parameter for patients with presenting with head neck cancer and is influencing the selection of the different therapeutic strategies including surgery, chemotherapy, radiotherapy or a combination of them. The accuracy of imaging techniques, such as US, MR imaging, and CT, depends on the appropriateness of radiological criteria used for diagnosing lymph node metastases. Size of nodes and evidence of necrosis are still the most important radiological criteria. However, the size shows great variability. A spherical lymph node larger than 10mm is an indicator for a malignant node, whereas an oval shape and/or a fatty hilus are more benign signs. But there are many limitations and different cut offs published in the literature, indicating that the size of a lymph node is not a reliable criteria for the assessment of lymph nodes in the head and neck region. Today new high-resolution MRI sequences and the development of specific contrast agents are offering new possibilities in the diagnostic work-up of head and neck lymph nodes. Ultrasmall superparamagnetic iron oxide particles (USPIO's) are resulting after intravenous application in a reduction of the T2 relaxation time. This is causing a signal decrease on T2-weighted MR images in benign lymph nodes after administration of USPIO's, whereas malignant lymph nodes do not show a significant signal decrease. Some clinical studies presented already very promising results. Based on the fact, that the size evaluation of lymph nodes in the head and neck has not changed during the last decade, this paper will mainly focus on MRI with new contrast agents and new techniques as diffusion weighted imaging (DWI).


U.S. Adults With Pain, a Group Increasingly Vulnerable to Nonmedical Cannabis Use and Cannabis Use Disorder: 2001-2002 and 2012-2013.
Given changes in U.S. marijuana laws, attitudes, and use patterns, individuals with pain may be an emerging group at risk for nonmedical cannabis use and cannabis use disorder. The authors examined differences in the prevalence of nonmedical cannabis use and cannabis use disorder among U.S. adults with and without pain, as well as whether these differences widened over time. Data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC, 2001-2002; N=43,093) and NESARC-III (2012-2013; N=36,309) were analyzed using logistic regression. Risk differences of past-year nonmedical cannabis use, frequent (at least three times a week) nonmedical use, and DSM-IV cannabis use disorder were estimated for groups with and without moderate to severe pain, and these risk differences were tested for change over time. Any nonmedical cannabis use was more prevalent in respondents with than without pain (2001-2002: 5.15% compared with 3.74%; 2012-2013: 12.42% compared with 9.02%), a risk difference significantly greater in the 2012-2013 data than in the 2001-2002 data. The prevalence of frequent nonmedical cannabis use did not differ by pain status in the 2001-2002 survey, but was significantly more prevalent in those with than without pain in the 2012-2013 survey (5.03% compared with 3.45%). Cannabis use disorder was more prevalent in respondents with than without pain (2001-2002: 1.77% compared with 1.35%; 2012-2013: 4.18% compared with 2.74%), a significantly greater risk difference in the data from 2012-2013 than from 2001-2002. The results suggest that adults with pain are a group increasingly vulnerable to adverse cannabis use outcomes, warranting clinical and public health attention to this risk. Psychiatrists and other health care providers treating patients with pain should monitor such patients for signs and symptoms of cannabis use disorder.


Congenital central hypoventilation syndrome and sudden infant death syndrome: disorders of autonomic regulation.
Long considered a rare and unique disorder of respiratory control, congenital central hypoventilation syndrome has recently been further distinguished as a disorder of autonomic regulation. Similarly, more recent evidence suggests that sudden infant death syndrome is also a disorder of autonomic regulation. Congenital central hypoventilation syndrome typically presents in the newborn period with alveolar hypoventilation, symptoms of autonomic dysregulation and, in a subset of cases, Hirschsprung disease or tumors of neural crest origin or both. Genetic investigation identified PHOX2B, a crucial gene during early autonomic development, as disease defining for congenital central hypoventilation syndrome. Although sudden infant death syndrome is most likely defined by complex multifactorial genetic and environmental interactions, it is also thought to result from central deficits in the control of breathing and autonomic regulation. The purpose of this article is to review the current understanding of these autonomic disorders and discuss the influence of this information on clinical practice and future research directions.


Residential mobility within England and urban-rural inequalities in mortality.
This study is situated within the international literature on geographic health inequalities between urban and rural areas. Using data from the Office for National Statistics Longitudinal Study (ONS LS), this paper assesses the role of residential mobility within England between 1981 and 2001 in explaining geographic inequalities in all-cause mortality between urban and rural Local Authority Districts at the end of the period (deaths occurring between 2001 and 2005). First, the pattern of directly age-standardised death rates (2001-2005) in urban and rural areas of residence in 2001 is examined and compared with the pattern that would have been seen if the observed death/survival of individuals had occurred in their original place of residence in 1981, or in 1991. Secondly, logistic regression is applied to examine whether individuals' residential mobility between urban and rural areas predict the risk of mortality, adjusting for people's socio-demographic characteristics. Findings show that, for this sample, residential mobility 1981-2001 accounts for about 30% of the urban-rural inequalities in mortality observed at the end of the period. LS members who were residentially mobile between urban and rural areas were relatively healthier than long-term urban residents, with better mortality outcomes among rural in-migrants. In age-stratified analysis, LS members of working age (20-64 years) moving out of rural areas, and LS members of retirement age (65 years and older) moving into rural areas, were shown to be healthier. Processes of selective migration in and out of rural areas in England are complex and may partly explain urban-rural health inequalities. In terms of varying mortality risk, findings also highlight the possible marginalisation and disadvantage of sub-groups of the rural population.


FnrL and Three Dnr Regulators Are Used for the Metabolic Adaptation to Low Oxygen Tension in Dinoroseobacter shibae.
The heterotrophic marine bacterium Dinoroseobacter shibae utilizes aerobic respiration and anaerobic denitrification supplemented with aerobic anoxygenic photosynthesis for energy generation. The aerobic to anaerobic transition is controlled by four Fnr/Crp family regulators in a unique cascade-type regulatory network. FnrL is utilizing an oxygen-sensitive Fe-S cluster for oxygen sensing. Active FnrL is inducing most operons encoding the denitrification machinery and the corresponding heme biosynthesis. Activation of gene expression of the high oxygen affinity cbb3-type and repression of the low affinity aa3-type cytochrome c oxidase is mediated by FnrL. Five regulator genes including dnrE and dnrF are directly controlled by FnrL. Multiple genes of the universal stress protein (USP) and cold shock response are further FnrL targets. DnrD, most likely sensing NO via a heme cofactor, co-induces genes of denitrification, heme biosynthesis, and the regulator genes dnrE and dnrF. DnrE is controlling genes for a putative Na+/H+ antiporter, indicating a potential role of a Na+ gradient under anaerobic conditions. The formation of the electron donating primary dehydrogenases is coordinated by FnrL and DnrE. Many plasmid encoded genes were DnrE regulated. DnrF is controlling directly two regulator genes including the Fe-S cluster biosynthesis regulator iscR, genes of the electron transport chain and the glutathione metabolism. The genes for nitrate reductase and CO dehydrogenase are repressed by DnrD and DnrF. Both regulators in concert with FnrL are inducing the photosynthesis genes. One of the major denitrification operon control regions, the intergenic region between nirS and nosR2, contains one Fnr/Dnr binding site. Using regulator gene mutant strains, lacZ-reporter gene fusions in combination with promoter mutagenesis, the function of the single Fnr/Dnr binding site for FnrL-, DnrD-, and partly DnrF-dependent nirS and nosR2 transcriptional activation was shown. Overall, the unique regulatory network of the marine bacterium D. shibae for the transition from aerobic to anaerobic growth composed of four Crp/Fnr family regulators was elucidated.


Mutations in the protamine 1 gene associated with male infertility.
In elongating spermatids, human sperm chromatin undergoes a complex compaction in which the transition proteins are extensively replaced by the protamine proteins. Several human studies demonstrate that expression of the protamine proteins is altered in some men with male infertility. For this study, we screened the PRM1 (protamine 1) gene for mutations in a large cohort of 281 men seeking infertility treatment. We identified the c.102G>T transversion that results in an p.Arg34Ser amino acid change in two men. One of these patients presented with oligozoospermia associated with increased sperm DNA fragmentation. The second individual was normospermic but together with his partner sought treatment for idiopathic couple infertility. We also identified a novel missense mutation (c.119G>A, p.Cys40Tyr) in a man with oligoasthenozoospermia. These mutations were not observed in control populations. Interestingly, we also detected variants both 5' and 3' to the PRM1 open-reading frame specifically in infertile individuals. Four individuals with unexplained severe oligozoospermia were heterozygote for a c.-107G>C change that is located at -15 bp from the transcription initiation site of the gene. This mutation may influence PRM1 expression. In addition, a c.*51G>C variant was detected in the 3'UTR of PRM1 specifically in a man with severe oligoasthenozoospermia.


SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer.
Activation of the canonical TGF-β signaling pathway provides growth inhibitory signals in the normal intestinal epithelium. Colorectal cancers (CRCs) frequently harbor somatic mutations in the pathway members TGFBR2 and SMAD4, but to what extent mutations in SMAD2 or SMAD3 contribute to tumorigenesis is unclear. A cohort of 744 primary CRCs and 36 CRC cell lines were sequenced for SMAD4, SMAD2, and SMAD3 and analyzed for allelic loss by single-nucleotide polymorphism (SNP) microarray analysis. Mutation spectra were compared between the genes, the pathogenicity of mutations was assessed, and relationships with clinicopathologic features were examined. The prevalence of SMAD4, SMAD2, and SMAD3 mutations in sporadic CRCs was 8.6% (64 of 744), 3.4% (25 of 744), and 4.3% (32 of 744), respectively. A significant overrepresentation of two genetic hits was detected for SMAD4 and SMAD3, consistent with these genes acting as tumor suppressors. SMAD4 mutations were associated with mucinous histology. The mutation spectra of SMAD2 and SMAD3 were highly similar to that of SMAD4, both in mutation type and location within the encoded proteins. In silico analyses suggested the majority of the mutations were pathogenic, with most missense changes predicted to reduce protein stability or hinder SMAD complex formation. The latter altered interface residues or disrupted the phosphorylation-regulated Ser-Ser-X-Ser motifs within SMAD2 and SMAD3. Functional analyses of selected mutations showed reductions in SMAD3 transcriptional activity and SMAD2-SMAD4 complex formation. Joint biallelic hits in SMAD2 and SMAD3 were overrepresented and mutually exclusive to SMAD4 mutation, underlining the critical roles of these three proteins within the TGF-β signaling pathway.


Using virtual reality to provide health care information to people with intellectual disabilities: acceptability, usability, and potential utility.
People with intellectual disabilities have poor access to health care, which may be further compromised by a lack of accessible health information. To be effective, health information must be easily understood and remembered. People with intellectual disabilities learn better from multimodal information sources, and virtual reality offers a 3-dimensional (3D) computer-generated environment that can be used for providing information and learning. To date, research into virtual reality experiences for people with intellectual disabilities has been limited to skill-based training and leisure opportunities within the young to mid age ranges. This study assessed the acceptability, usability, and potential utility of a virtual reality experience as a means of providing health care-related information to people with intellectual disabilities. We designed a prototype multimodal experience based on a hospital scenario and situated on an island in the Second Life 3D virtual world. We wanted to know how people of different ages and with varying levels of cognitive function would participate in the customized virtual environment, what they understood from being there, and what they remembered a week later. The study drew on qualitative data. We used a participatory research approach that involved working alongside people with intellectual disabilities and their supporters in a community setting. Cognitive function was assessed, using the Matrix Analogies Test and the British Picture Vocabulary Scale, to describe the sample. Participants, supported by facilitators, were video recorded accessing and engaging with the virtual environment. We assessed recall 1 week later, using a specialized interview technique. Data were downloaded into NVivo 8 and analyzed using the framework analysis technique. Study participants were 20 people aged between 20 and 80 years with mild to severe intellectual disabilities. All participants were able to access the environment and voluntarily stayed there for between 23 and 57 minutes. With facilitator support, all participants moved the avatar themselves. Participants engaged with the scenario as if they were actually there, indicating cognitive presence. Some referred back to previous medical experiences, indicating the potential for experiential knowledge to become the foundation of new learning and retention of knowledge. When interviewed, all participants remembered some aspects of the environment. A sample of adults with intellectual disabilities of all ages, and with varying levels of cognitive function, accessed and enjoyed a virtual-world environment that drew on a health care-related scenario, and remembered aspects of it a week later. The small sample size limits generalizability of findings, but the potential shown for experiential learning to aid retention of knowledge on which consent is based appears promising. Successfully delivering health care-related information in a non-National Health Service setting indicates potential for delivery in institutional, community, or home settings, thereby widening access to the information.


Chromatin states of developmentally-regulated genes revealed by DNA and histone methylation patterns in zebrafish embryos.
Embryo development proceeds from a cascade of gene activation and repression events controlled by epigenetic modifications of DNA and histones. Little is known about epigenetic states in the developing zebrafish, despite its importance as a model organism. We report here DNA methylation and histone modification profiles of promoters of developmentally-regulated genes (pou5f1, sox2, sox3, klf4, nnr, otx1b, nes, vasa), as well as tert and bactin2, in zebrafish embryos at the mid-late blastula transition, shortly after embryonic genome activation. We identify four classes of promoters based on the following profiles: (i) those enriched in marks of active genes (H3K9ac, H4ac, H3K4me3) without transcriptionally repressing H3K9me3 or H3K27me3; (ii) those enriched in H3K9ac, H4ac and H3K27me3, without H3K9me3; one such gene was klf4, shown by in situ hybridization to be mosaically expressed, likely accounting for the detection of both activating and repressive marks on its promoter; (iii) those enriched in H3K4me3 and H3K27me3 without acetylation; and (iv) those enriched in all histone modifications examined. Culture of embryo-derived cells under differentiation conditions leads to H3K9 and H4 deacetylation and H3K9 and H3K27 trimethylation on genes that are inactivated, yielding an epigenetic profile similar to those of fibroblasts or muscle. All promoters however retain H3K4me3, indicating an uncoupling of H3K4me3 occupancy and gene expression. All non-CpG island developmentally-regulated promoters are DNA unmethylated in embryos, but hypermethylated in fibroblasts. Our results suggest that differentially expressed embryonic genes are regulated by various patterns of histone modifications on unmethylated DNA, which create a developmentally permissive chromatin state.


Developing a questionnaire for conducting cross-national studies--'Self-reported health and needs among elderly Iranians and Swedes'.
This paper describes the process of developing and validating a questionnaire to investigate self-reported health and care needs of elders in Iran and Sweden. Both developing and developed countries face dilemmas under the current condition of increasing mental and physical health morbidity globally. In order to fully assess and understand the extent of these dilemmas and the global and local factors that alleviate or worsen them, a comparison of the self-reported health and care needs in a developed and a developing country is required. To these ends, two research teams within a joint international project worked together to construct a questionnaire to measure self-reported health in elders in Sweden and Iran. The questionnaire was developed according to a multiphase process, during which the researchers tested the validity and reliability of the questionnaire using various methods and modified it based on the test results. First, the concepts to be used were agreed upon and a literature review was conducted. Thereafter, face and content validity was measured in Iran, looking at the initial items that were developed. The questionnaire was then translated and back-translated. Finally, both teams conducted a test of content validity using target groups in Iran and Sweden, respectively. Validity was established by testing face and content validity with the use of expert groups. Reliability was also determined according to two different dimensions, stability and internal consistency. Both methods gave satisfactory results, indicating that the instrument was reliable. The questionnaire was thereby developed and titled, 'Self-reported health and health-care needs'. The results confirm validity and reliability of the final version of the questionnaire.


A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study.
In chronic lymphocytic leukemia (CLL) the level of minimal residual disease (MRD) after therapy is an independent predictor of outcome. Given the increasing number of new agents being explored for CLL therapy, using MRD as a surrogate could greatly reduce the time necessary to assess their efficacy. In this European Research Initiative on CLL (ERIC) project we have identified and validated a flow-cytometric approach to reliably quantitate CLL cells to the level of 0.0010% (10(-5)). The assay comprises a core panel of six markers (i.e. CD19, CD20, CD5, CD43, CD79b and CD81) with a component specification independent of instrument and reagents, which can be locally re-validated using normal peripheral blood. This method is directly comparable to previous ERIC-designed assays and also provides a backbone for investigation of new markers. A parallel analysis of high-throughput sequencing using the ClonoSEQ assay showed good concordance with flow cytometry results at the 0.010% (10(-4)) level, the MRD threshold defined in the 2008 International Workshop on CLL guidelines, but it also provides good linearity to a detection limit of 1 in a million (10(-6)). The combination of both technologies would permit a highly sensitive approach to MRD detection while providing a reproducible and broadly accessible method to quantify residual disease and optimize treatment in CLL.


Acute skeletal injury is necessary for human adipose-derived stromal cell-mediated calvarial regeneration.
Studies have demonstrated that human adipose-derived stromal cells (ASCs) are able to repair acute calvarial injuries. The more clinically relevant repair of an established skeletal defect, however, has not been addressed. The authors sought to determine whether human ASCs could heal chronic (established) calvarial defects. Critical-sized (4 mm) mouse parietal defects were created. Human ASCs were engrafted either immediately postoperatively (acute defect) or 8 weeks following defect creation (established defect). Methods of analysis included microcomputer tomography scans, histology, and in situ hybridization. Finally, human ASCs were treated in vitro with platelet-rich plasma to simulate an acute wound environment; proliferation and osteogenic differentiation were assessed (alkaline phosphatase, alizarin red, and quantitative reverse transcriptase polymerase chain reaction). Nearly complete osseous healing was observed when calvarial defects were immediately engrafted with human ASCs. In contrast, when human ASCs were engrafted into established defects, little bone formation occurred. Histological analysis affirmed findings by microcomputer tomography, showing more robust staining for alkaline phosphatase and picrosirius red in an acute than in an established human ASC-engrafted defect. In situ hybridization and quantitative reverse transcriptase polymerase chain reaction showed an increase in bone morphogenetic protein (BMP) expression (BMP-2, BMP-4, and BMP-7) acutely following calvarial defect creation. Finally, in vitro treatment of human ASCs with platelet-rich plasma enhanced osteogenic differentiation and increased BMP-2 expression. Although human ASCs can be utilized to heal an acute mouse calvarial defect, they do not enhance healing of an established (or chronic) defect. Endogenous BMP signaling activated after injury may explain these differences in healing. Platelet-rich plasma enhances osteogenic differentiation of human ASCs in vitro and may prove a promising therapy for future skeletal tissue engineering efforts.


Psychological and psychophysiological considerations regarding the maternal-fetal relationship.
The earliest relationship does not begin with birth. Pregnant women construct mental representations of the fetus, and feelings of affiliation or "maternal-fetal attachment" generally increase over the course of gestation. While there is a fairly substantial literature on the development and moderation of psychological features of the maternal-fetal relationship, including the role of ultrasound imaging, relatively little is known about the manner in which maternal psychological functioning influences the fetus. Dispositional levels of maternal stress and anxiety are modestly associated with aspects of fetal heart rate and motor activity. Both induced maternal arousal and relaxation generate fairly immediate alterations to fetal neurobehaviors; the most consistently observed fetal response to changes in maternal psychological state involves suppression of motor activity. These effects may be mediated, in part, by an orienting response of the fetus to changes in the intrauterine environment. Conversely, there is evidence that fetal behaviors elicit maternal physiological responses. Integration of this finding into a more dynamic model of the maternal-fetal dyad, and implications for the postnatal relationship are discussed. Research on the period before birth affords tremendous opportunity for developmental scientists to advance understanding of the origins of human attachment.


Coral reefs: threats and conservation in an era of global change.
Coral reefs are iconic, threatened ecosystems that have been in existence for approximately 500 million years, yet their continued ecological persistence seems doubtful at present. Anthropogenic modification of chemical and physical atmospheric dynamics that cause coral death by bleaching and newly emergent diseases due to increased heat and irradiation, as well as decline in calcification caused by ocean acidification due to increased CO(2), are the most important large-scale threats. On more local scales, overfishing and destructive fisheries, coastal construction, nutrient enrichment, increased runoff and sedimentation, and the introduction of nonindigenous invasive species have caused phase shifts away from corals. Already approximately 20% of the world's reefs are lost and approximately 26% are under imminent threat. Conservation science of coral reefs is well advanced, but its practical application has often been lagging. Societal priorites, economic pressures, and legal/administrative systems of many countries are more prone to destroy rather than conserve coral-reef ecosystems. Nevertheless, many examples of successful conservation exist from the national level to community-enforced local action. When effectively managed, protected areas have contributed to regeneration of coral reefs and stocks of associated marine resources. Local communities often support coral-reef conservation in order to raise income potential associated with tourism and/or improved resource levels. Coral reefs create an annual income in S-Florida alone of over $4 billion. Thus, no conflict between development, societal welfare, and coral-reef conservation needs to exist. Despite growing threats, it is not too late for decisive action to protect and save these economically and ecologically high-value ecosystems. Conservation science plays a critical role in designing effective strategies.


Midterm and long-term follow-up of cerebral aneurysms treated with flow diverter devices: a single-center experience.
The introduction of flow diverter devices is revolutionizing the endovascular approach to cerebral aneurysms. Midterm and long-term results of angiographic, cross-sectional imaging and clinical follow-up are still lacking. The authors report their experience with endovascular treatment of intracranial aneurysms using both the Pipeline embolization device and Silk stents. From October 2008 to July 2011 a consecutive series of 104 intracranial aneurysms in 101 patients (79 female, 22 male; average age 53 years) were treated. Three of the 104 aneurysms were ruptured and 101 were unruptured. Silk stents were implanted in 47 of the aneurysms and Pipeline stents in the remaining 57. In 14 cases a combination of flow diverter devices and coils were used to treat larger aneurysms (maximum diameter > 15 mm). Patients underwent angiographic follow-up examination at 6 months after treatment, with or without CT or MRI, and at 1 year using CT or MRI, with or without conventional angiography. In all cases placement of flow diverter stents was technically successful. The mortality and morbidity rates were both 3%. Adverse events without lasting clinical sequelae occurred in 20% of cases. Angiography performed at 6 months after treatment showed complete aneurysm occlusion in 78 of 91 cases (86% of evaluated aneurysms) and subocclusion in 11 (12%); only in 2 cases were the aneurysms unchanged. Fifty-three aneurysms were evaluated at 1 year after treatment. None of these aneurysms showed recanalization, and 1 aneurysm, which was incompletely occluded at the 6-month follow-up examination, was finally occluded. Aneurysmal sac shrinkage was observed in 61% of assessable aneurysms. Parent artery reconstruction using flow diverter devices is a feasible, safe, and successful technique for the treatment of endovascular treatment of cerebral aneurysms.


Does the real-time ultrasound guidance provide safer venipuncture in implantable venous port implantation?
To examine whether the real-time ultrasound-guided venipuncture for implantable venous port placement is safer than the traditional venipuncture. The study analyzed the results of 2153 venous ports placed consecutively from January 2009 to January 2016. A total of 922 patients in group 1 and 1231 patients in group 2 were admitted with venous port placed using the traditional landmark subclavian approach and real-time ultrasound-guided axillary approach, respectively. Sociodemographic characteristics of patients, early (pneumothorax, pinch-off syndrome, arterial puncture, hematoma, and malposition arrhythmia) and late (deep vein thrombosis, obstruction, infection, erosion-dehiscence, and rotation of the port chamber) complications and the association of these complications with the implantation method were evaluated. There were no significant differences in the sociodemographic characteristics of the patients between the two groups. The overall and early complications in group 2 were significantly lower than those in group 1. Pinch-off syndrome only developed in group 1. Seven patients and two patients had pneumothorax in groups 1 and 2, respectively. Puncture number was significantly associated with the development of the overall complications. The ultrasound-guided axillary approach may be preferred as a method to reduce the risk of both early and late complications. Large, randomized, controlled prospective trials will be helpful in determining a safer implantable venous port implantation technique.


Sociodemographic disparities in chronic pain, based on 12-year longitudinal data.
Existing estimates of sociodemographic disparities in chronic pain in the United States are based on cross-sectional data, often treat pain as a binary construct, and rarely test for nonresponse or other types of bias. This study uses 7 biennial waves of national data from the Health and Retirement Study (1998-2010; n = 19,776) to describe long-term pain disparities among older (age 51+) American adults. It also investigates whether pain severity, reporting heterogeneity, survey nonresponse, and/or mortality selection might bias estimates of social disparities in pain. In the process, the article clarifies whether 2 unexpected patterns observed cross-sectionally-plateauing of pain above age 60, and lower pain among racial/ethnic minorities-are genuine or artefactual. Findings show high prevalence of chronic pain: 27.3% at baseline, increasing to 36.6% thereafter. Multivariate latent growth curve models reveal extremely large disparities in pain by sex, education, and wealth, which manifest primarily as differences in intercept. Net of these variables, there is no racial/ethnic minority disadvantage in pain scores, and indeed a black advantage vis-à-vis whites. Pain levels are predictive of subsequent death, even a decade in the future. No evidence of pain-related survey attrition is found, but surveys not accounting for pain severity and reporting heterogeneity are likely to underestimate socioeconomic disparities in pain. The lack of minority disadvantage (net of socioeconomic status) appears genuine. However, the age-related plateauing of pain observed cross-sectionally is not replicated longitudinally, and seems partially attributable to mortality selection, as well as to rising pain levels by birth cohort.


Current State of and Problems Related to Cancer of the Intestinal Tract Associated with Crohn's Disease in Japan.
Cancer of the intestinal tract (small and large intestine) associated with Crohn's disease has a low incidence but can be fatal if it develops. Thus, the key question is how to deal with this type of cancer. The current study surveyed major medical facilities that treat inflammatory bowel disease (IBD) surgically in Japan in order to examine the clinical features of cancer of the intestinal tract associated with Crohn's disease and explore ways to deal with this cancer in the future. Sixteen major medical facilities that treat IBD surgically were surveyed regarding cancer of the intestinal tract associated with Crohn's disease. The medical facilities had treated 3,454 patients with Crohn's disease, 122 of whom had developed intestinal cancer. The medical facilities were surveyed regarding those 122 patients. The incidence of intestinal cancer associated with Crohn's disease has increased yearly. Cancer most often developed in the left side of the colon and, particularly, in the rectum and anal canal. Seventy-six percent of cases were diagnosed preoperatively, 4% were diagnosed intraoperatively, while the remaining 20% were diagnosed pathologically after surgery. The most prevalent histological type of cancer was mucinous carcinoma (50%). Forty-two percent of cancers were differentiated, with 4% being poorly differentiated. The surgical procedure performed most often (67%) was abdominoperineal resection. The 5-year survival rate by stage was 88% for Stage I, 68% for Stage II, 71% for Stage IIIa, 25% for Stage IIIb and 0% for Stage IV. Overall, the 5-year survival rate was 52%. Gastrointestinal (GI) cancer associated with Crohn's disease had an incidence of 3.5%, but also involved a poor prognosis with a 5-year survival rate of 52%. Early detection through surveillance is crucial to improving the prognosis for patients. However, surveillance of the intestinal tract with endoscopy or contrast studies is technically and diagnostically hampered by Crohn's disease and intestinal strictures. A biopsy of the anal canal, a common site of cancer, can readily be performed and constitutes the first step in surveillance.


Diruthenium(ii)-capped oligothienylethynyl bridged highly soluble organometallic wires exhibiting long-range electronic coupling.
Organometallic molecular wires with π-conjugation along their molecular backbones are of considerable interest for application in molecular-scale electronics. In this regard, thienylethynyl-based π-conjugated oligomers of three, five and seven thienylethynyl units with -C[triple bond, length as m-dash]C-H termini have been successfully synthesized through stepwise Pd(0)/Cu(i)-catalyzed Sonogashira coupling. The corresponding highly soluble diruthenium(ii) diacetylide complexes (O1-Ru2, O3-Ru2, O5-Ru2 and O7-Ru2, respectively) have been prepared by the reaction of cis-Ru(dppe)2Cl2 and NaPF6 in DCM with the corresponding rigid rod-like thienylethynyl oligomers with one, three, five and seven thienylethynyl π-conjugated segments containing alkynyl termini (O1, O3, O5 and O7). These Ru(ii)-Cl capped diacetylide complexes have been further functionalized by incorporating a phenylacetynyl moiety to afford [Ru(ii)-C[triple bond, length as m-dash]C-Ph]-capped diacetylide organometallic wires (O1-Ru2-Ph, O3-Ru2-Ph, O5-Ru2-Ph and O7-Ru2-Ph). The photophysical properties of the highly soluble thienylethynyl-based oligomers and Ru(ii)-organometallic wires have been explored to understand their electronic properties. Electrochemical studies of the binuclear ruthenium(ii)-alkynyl complexes showed highly interesting results, revealing long-range electrochemical communication between the two remote Ru(ii) termini connected even with five and seven thienylethynyl units. DFT computational studies further support the long range electrochemical communication between the redox active metal termini through heavy participation of the thienylethynyl bridge in the corresponding mono-oxidized mixed valence species of the organometallic wire-like complexes.


Acute hantavirus infection induces galectin-3-binding protein.
Hantaviruses are zoonotic viruses that cause life-threatening diseases when transmitted to humans. Severe hantavirus infection is manifested by impairment of renal function, pulmonary oedema and capillary leakage. Both innate and adaptive immune responses contribute to the pathogenesis, but the underlying mechanisms are not fully understood. Here, we showed that galectin-3-binding protein (Gal-3BP) was upregulated as a result of hantavirus infection both in vitro and in vivo. Gal-3BP is a secreted glycoprotein found in human serum, and increased Gal-3BP levels have been reported in chronic viral infections and in several types of cancer. Our in vitro experiments showed that, whilst Vero E6 cells (an African green monkey kidney cell line) constitutively expressed and secreted Gal-3BP, this protein was detected in primary human cells only as a result of hantavirus infection. Analysis of Gal-3BP levels in serum samples of cynomolgus macaques infected experimentally with hantavirus indicated that hantavirus infection induced Gal-3BP also in vivo. Finally, analysis of plasma samples collected from patients hospitalized because of acute hantavirus infection showed higher Gal-3BP levels during the acute than the convalescent phase. Furthermore, the Gal-3BP levels in patients with haemorrhagic fever with renal syndrome correlated with increased complement activation and with clinical variables reflecting the severity of acute hantavirus infection.


Effects of acute ventricular volume manipulation on in situ cardiomyocyte cell membrane configuration.
Effects of mechanical stimulation on cardiac electrical activity, gene expression, protein synthesis, and tissue remodelling have received increasing attention in recent years, as reviewed in this issue of PBMB. Little is known, though, about how changes in ventricular filling affect the cell configuration of cardiomyocytes in the ventricular wall. Here, we present first electron-microscopic insight into changes in cardiomyocyte cell structure in situ during acute ventricular volume manipulation. Apart from confirming the anticipated ventricular volume-related changes in cardiomyocyte sarcomere length, there is evidence of (i) unfolding of 'slack' membrane, primarily from sarcolemmal invaginations near the Z-lines, and (ii) stretch-induced incorporation of sub-membrane caveolae into the surface membrane. The functional relevance of these changes in cardiomyocyte membrane configuration-other than to cater for the length-dependent modulation of the cell surface to cell volume ratio-remains to be elucidated.


When can listeners detect disfluency in spontaneous speech?
Three experiments investigated listeners' ability to detect disfluency in spontaneous speech. All employed gated word recognition with judgments of disfluency for spontaneous utterances containing disfluencies and for three kinds of fluent control utterances from the same six speakers: repetitions of corrected recordings of original disfluent items, spontaneous fluent utterances loosely matched in structure to the disfluent items, and repetitions of those spontaneous fluent items. In Experiment 1, 120 stimuli were word-level gated and presented to 20 subjects for word identification and for judgments on whether the utterance was about to become disfluent. Listeners were unable to predict disfluency reliably. New subjects (N = 20, 43) judged whether the same utterances had already become disfluent at each word gate in Experiment 2 or at each 35 ms gate in Experiment 3. Subjects reliably detected existing disfluencies during the first word gate after the interruption and before they recognized the word. Though more common around disfluencies than at similar points in controls, failures of word identification were not reliably associated with detection. Results are discussed in the light of computational models of disfluency detection.


Tea derived galloylated polyphenols cross-link purified gastrointestinal mucins.
Polyphenols derived from tea are thought to be important for human health. We show using a combination of particle tracking microrheology and small-angle neutron scattering that polyphenols acts as cross-linkers for purified gastrointestinal mucin, derived from the stomach and the duodenum. Both naturally derived purified polyphenols, and green and black tea extracts are shown to act as cross-linkers. The main active cross-linking component is found to be the galloylated forms of catechins. The viscosity, elasticity and relaxation time of the mucin solutions experience an order of magnitude change in value upon addition of the polyphenol cross-linkers. Similarly small-angle neutron scattering experiments demonstrate a sol-gel transition with the addition of polyphenols, with a large increase in the scattering at low angles, which is attributed to the formation of large scale (>10 nm) heterogeneities during gelation. Cross-linking of mucins by polyphenols is thus expected to have an impact on the physicochemical environment of both the stomach and duodenum; polyphenols are expected to modulate the barrier properties of mucus, nutrient absorption through mucus and the viscoelastic microenvironments of intestinal bacteria.


Influence of leaf size, orientation, and arrangement on temperature and transpiration in three high-elevation, large-leafed herbs.
The temperature and water relations of the largleafed, high-elevation species Frasera speciosa, Balsamorhiza sagittata, and Rumex densiflorus were evaluated in the Medicine Bow Mountains of southeast Wyoming (USA) to determine the influence of leaf size, orientation, and arrangement on transpiration. These species characteristically have low minimum stomatal resistances (<60 s m-1) and high maximum transpiration rates (>260 mg m-2s-1 for F. speciosa). Field measurements of leaf and microclimatic parameters were incorporated into a computer simulation using standard energy balance equations which predicted leaf temperature (T leaf) and transpiration for various leaf sizes. Whole-plant transpiration during a day was simulated using field measurements for plants with natural leaf sizes and compared to transpiration rates simulated for plants having identical, but hypothetically smaller (0.5 cm) leaves during a clear day and a typically cloudy day. Although clear-day transpiration for F. speciosa plants with natural size leaves was only 2.0% less per unit leaf area than that predicted for plants with much smaller leaves, daily transpiration of B. sagittata and R. densiflorus plants with natural leaf sizes was 16.1% and 21.1% less, respectively. The predicted influence of a larger leaf size on transpiration for the cloudy day was similar to clear-day results except that F. speciosa had much greater decreases in transpiration (12.7%). The different influences of leaf size on transpiration between the three species was primarily due to major differences in leaf absorptance to solar radiation, orientation, and arrangement which caused large differences in T leaf. Also, simulated increases in leaf size above natural sizes measured in the field resulted in only small additional decreases in predicted transpiration, indicating a leaf size that was nearly optimal for reducing transpiration. These results are discussed in terms of the possible evolution of a larger leaf size in combination with specific leaf absorptances, orientations and arrangements which could act to reduce transpiration for species growing in short-season habitats where the requirement for rapid carbon fixation might necessitate low stomatal resistances.


The small non-coding RNA profile of mouse oocytes is modified during aging.
Oocytes are reliant on messenger RNA (mRNA) stores to support their survival and integrity during a protracted period of transcriptional dormancy as they await ovulation. Oocytes are, however, known to experience an age-associated alteration in mRNA transcript abundance, a phenomenon that contributes to reduced developmental potential. Here we have investigated whether the expression profile of small non-protein-coding RNAs (sRNAs) is similarly altered in aged mouse oocytes. The application of high throughput sequencing revealed substantial changes to the global sRNA profile of germinal vesicle stage oocytes from young (4-6 weeks) and aged mice (14-16 months). Among these, 160 endogenous small-interfering RNAs (endo-siRNAs) and 10 microRNAs (miRNAs) were determined to differentially accumulate within young and aged oocytes. Further, we revealed decreased expression of two members of the kinesin protein family, Kifc1 and Kifc5b, in aged oocytes; family members selectively targeted for expression regulation by endo-siRNAs of elevated abundance. The implications of reduced Kifc1 and Kifc5b expression were explored using complementary siRNA-mediated knockdown and pharmacological inhibition strategies, both of which led to increased rates of aneuploidy in otherwise healthy young oocytes. Collectively, our data raise the prospect that altered sRNA abundance, specifically endo-siRNA abundance, could influence the quality of the aged oocyte.


Open Stomata 1 Kinase is Essential for Yeast Elicitor-Induced Stomatal Closure in Arabidopsis.
We recently demonstrated that yeast elicitor (YEL)-induced stomatal closure requires a Ca(2+)-dependent kinase, CPK6. A Ca(2+)-independent kinase, Open Stomata 1 (OST1), is involved in stomatal closure induced by various stimuli including ABA. In the present study, we investigated the role of OST1 in YEL-induced stomatal closure in Arabidopsis using a knock-out mutant, ost1-3, and a kinase-deficient mutant, ost1-2. YEL did not induce stomatal closure or activation of guard cell S-type anion channels in the ost1 mutants unlike in wild-type plants. However, YEL did not increase OST1 kinase activity in wild-type guard cells. The YEL-induced stomatal closure and activation of S-type anion channels were also impaired in a gain-of-function mutant of a clade A type 2C protein phosphatase (ABA INSENSITIVE 1), abi1-1C. In the ost1 mutants like in the wild type, YEL induced H2O2 accumulation, activation of non-selective Ca(2+)-permeable cation (ICa) channels and transient elevations in cytosolic free Ca(2+) concentration ([Ca(2+)]cyt) in guard cells. These results suggest that OST1 kinase is essential for stomatal closure and activation of S-type anion channels induced by YEL and that OST1 is not involved in H2O2 accumulation, ICa channel activation or [Ca(2+)]cyt elevations in guard cells induced by YEL.


Matrix metalloproteinases and their inhibitors in the nasal mucosa of patients with perennial allergic rhinitis.
Allergic rhinitis and asthma show many similarities in their epithelial and inflammatory responses to allergens. However, one notable difference is that disruption and desquamation of the epithelium is a characteristic feature of asthma, whereas in perennial allergic rhinitis the epithelium is intact and thickened. One reason for this might be differing expression of matrix metalloproteinases (MMPs) or their inhibitors (TIMPs). There are few published data on the presence of MMPs or TIMPs in the nasal mucosa in rhinitis. The purpose of this study was to investigate MMP and TIMP mRNA and protein in nasal mucosa from subjects with perennial allergic rhinitis and from nonrhinitic control subjects. Biopsy specimens of nasal mucosa were taken from 10 well-characterized subjects with perennial allergic rhinitis and 10 nonrhinitic control subjects. MMP and TIMP mRNA was quantified through use of competitive RT-PCR, and protein was detected by means of Western blotting and ELISA. TIMP-1 mRNA and TIMP-2 mRNA were present in nasal samples, but there was no significant difference between the 2 groups. Only small amounts of MMP-1, -2, -3, and -9 mRNA were detected in the same samples. The corresponding proteins were detected by means of Western blotting. TIMP-1 protein and TIMP-2 protein were quantified in tissue homogenates; there was no significant difference between the 2 groups. Our studies have demonstrated the presence of large amounts of TIMP-1 and TIMP-2 mRNA and protein in nasal mucosa. There is no upregulation of MMPs or changes in TIMP expression in the nasal mucosa of patients with allergic rhinitis.


MR-guided laser-induced interstitial thermotherapy of recurrent glioblastoma multiforme: preliminary results in 16 patients.
We investigated the survival after laser-induced interstitial thermotherapy in 16 patients suffering from recurrent glioblastoma multiforme. The concept underlying the intervention is the cytoreduction of the tumor tissue by local thermocoagulation. All patients received standard chemotherapy (temozolomide). The median overall survival time after the first relapse was 9.4 months, corresponding to a median overall survival time after laser irradiation of 6.9 months. During the study, however, the median survival after laser coagulation increased to 11.2 months. This survival time is substantially longer than those reported for the natural history (<5 months) or after chemotherapy (temozolomide: 5.4-7.1 months). We conclude that cytoreduction by laser irradiation might be a promising option for patients suffering from recurrent glioblastoma multiforme. In addition, the data indicate the presence of a substantial learning curve. Future work should optimize the therapeutic regimen and evaluate this treatment approach in controlled clinical trials.


Osteoporosis and cognitive impairment interwoven warning signs: community-based study on older adults-Bushehr Elderly Health (BEH) Program.
Cognitive impairment and osteoporosis are frequently seen to coincide in clinical practice. Osteoporosis was higher in elderly populations with cognitive impairment, especially in postmenopausal women. Thus, prophylaxis for osteoporosis, falls, and fractures should be considered as part of the treatment of patients with cognitive impairment. Cognitive impairment and osteoporosis are two important health concerns among older adults that their possible relationship, concurrent occurrence, and linking mechanism have recently been highlighted. The purpose of this study was to assess the sex-independent association of these two conditions. From among 2331 individuals aged ≥ 60 years selected in Bushehr Elderly Health (BEH) Program, Iran; data of 1508 participants were analyzed. Cognitive status was assessed using Category Fluency Test and Mini-cog assessment instrument. Association between osteopenia-osteoporosis and cognitive impairment were assessed using uni- and multivariable logistic regression models. Osteoporosis was diagnosed in 598 (39.6%) of the participants (58.3% female and 21.9% male, P < 0.001). From among them, 677 (44.9%) had evidence of cognitive impairment (64.5% female and 31.0% male, P < 0.001). Multivariate logistic regressions showed spinal and total hip osteoporosis was associated with 1.83 (CI 95% 1.13-2.96) and 2.24-fold (CI 95% 1.28-3.89) increase in the risk of cognitive impairment among female subjects, respectively. Ordinal logistic regression, on the other hand, revealed cognitive impairment to be associated with 1.42-fold (CI 95% 1.04-1.92) increase in the risk of spinal osteopenia-osteoporosis, 1.5-fold increase in total hip osteoporosis (CI 95% 1.09-2.05), and 1.48-fold increase in general osteoporosis (CI 95% 1.06-2.0). Different degrees of bone loss and cognitive impairment may be a risk factor for each other among women but not in men. It is suggested that the screening, adopting preventive measures for the other condition and regular follow-ups, if needed, could be of utmost importance.


ETS factors are required but not sufficient for specific patterns of enhancer activity in different endothelial subtypes.
Correct vascular differentiation requires distinct patterns of gene expression in different subtypes of endothelial cells. Members of the ETS transcription factor family are essential for the transcriptional activation of arterial and angiogenesis-specific gene regulatory elements, leading to the hypothesis that they play lineage-defining roles in arterial and angiogenic differentiation directly downstream of VEGFA signalling. However, an alternative explanation is that ETS binding at enhancers and promoters is a general requirement for activation of many endothelial genes regardless of expression pattern, with subtype-specificity provided by additional factors. Here we use analysis of Ephb4 and Coup-TFII (Nr2f2) vein-specific enhancers to demonstrate that ETS factors are equally essential for vein, arterial and angiogenic-specific enhancer activity patterns. Further, we show that ETS factor binding at these vein-specific enhancers is enriched by VEGFA signalling, similar to that seen at arterial and angiogenic enhancers. However, while arterial and angiogenic enhancers can be activated by VEGFA in vivo, the Ephb4 and Coup-TFII venous enhancers are not, suggesting that the specificity of VEGFA-induced arterial and angiogenic enhancer activity occurs via non-ETS transcription factors. These results support a model in which ETS factors are not the primary regulators of specific patterns of gene expression in different endothelial subtypes.


Second messengers and divergent HD-GYP phosphodiesterases regulate 3',3'-cGAMP signaling.
3',3'-cyclic GMP-AMP (cGAMP) is the third cyclic dinucleotide (CDN) to be discovered in bacteria. No activators of cGAMP signaling have yet been identified, and the signaling pathways for cGAMP have been inferred to display a narrow distribution based upon the characterized synthases, DncV and Hypr GGDEFs. Here, we report that the ubiquitous second messenger cyclic AMP (cAMP) is an activator of the Hypr GGDEF enzyme GacB from Myxococcus xanthus. Furthermore, we show that GacB is inhibited directly by cyclic di-GMP, which provides evidence for cross-regulation between different CDN pathways. Finally, we reveal that the HD-GYP enzyme PmxA is a cGAMP-specific phosphodiesterase (GAP) that promotes resistance to osmotic stress in M. xanthus. A signature amino acid change in PmxA was found to reprogram substrate specificity and was applied to predict the presence of non-canonical HD-GYP phosphodiesterases in many bacterial species, including phyla previously not known to utilize cGAMP signaling.


Directions in abusive language training data, a systematic review: Garbage in, garbage out.
Data-driven and machine learning based approaches for detecting, categorising and measuring abusive content such as hate speech and harassment have gained traction due to their scalability, robustness and increasingly high performance. Making effective detection systems for abusive content relies on having the right training datasets, reflecting a widely accepted mantra in computer science: Garbage In, Garbage Out. However, creating training datasets which are large, varied, theoretically-informed and that minimize biases is difficult, laborious and requires deep expertise. This paper systematically reviews 63 publicly available training datasets which have been created to train abusive language classifiers. It also reports on creation of a dedicated website for cataloguing abusive language data hatespeechdata.com. We discuss the challenges and opportunities of open science in this field, and argue that although more dataset sharing would bring many benefits it also poses social and ethical risks which need careful consideration. Finally, we provide evidence-based recommendations for practitioners creating new abusive content training datasets.


Characterization of polymorphic solid-state changes using variable temperature X-ray powder diffraction.
The aim of this study was to use variable temperature X-ray powder diffraction (VT-XRPD) to understand the solid-state changes in the pharmaceutical materials during heating. The model compounds studied were sulfathiazole, theophylline and nitrofurantoin. This study showed that the polymorph form of sulfathiazole SUTHAZ01 was very stable and SUTHAZ02 changed as a function of temperature to SUTHAZ01. Theophylline monohydrate changed via its metastable form to its anhydrous form during heating and nitrofurantoin monohydrate changed via amorphous form to its anhydrous form during heating. The crystallinity of SUTHAZ01, SUTHAZ02 and theophylline monohydrate were very high and stable. Nitrofurantoin monohydrate was also very crystalline at room temperature but during heating at lower temperatures the crystallinity decreased and started to increase strongly at the temperature where the sample had changed to the anhydrous form. The average crystallite size of sulfathiazole samples varied only a little during heating. The average crystallite size of both theophylline and nitrofurantoin monohydrate decreased during heating. However, the average crystallite size of nitrofurantoin monohydrate returned back to starting size at higher temperatures. These analyses showed that VT-XRPD can be used to effectively characterize polymorphic changes during heating.


Intracellular location of BRCA2 protein expression and prostate cancer progression in the Swedish Watchful Waiting Cohort.
Prostate cancer patients with inherited BRCA2 mutations have a survival disadvantage. However, it is unknown whether progression is associated with BRCA2 protein expression in diagnostic prostate cancer tissue, among men without inherited mutations. We conducted a nested case-control study within the Swedish Watchful Waiting cohort. The case group included all 71 patients who died from prostate cancer within 5 years from diagnosis and controls were all patients (n = 165) who lived at least 7 years after diagnosis. Tissue microarrays were stained using antibodies for C- and N-terminal domains of the BRCA2 protein. Location (nuclear, cytoplasmic and membranous) and magnitude (intensity and percentage) of expression were assessed. Logistic regression models produced odds ratios (OR) and 95% confidence intervals (CI) adjusted for age, year of diagnosis and Gleason score. Positive BRCA2 staining at the cell membrane was associated with reduced risk of death within 5 years (N-terminal: OR = 0.47, 95% CI = 0.21-1.04, P = 0.06; C-terminal: OR = 0.41, 95% CI = 0.18-0.91, P = 0.03) and low Gleason scores (P = 0.006). Positive cytoplasmic C-terminal staining was associated with higher Gleason scores and increased lethality (OR = 3.61, 95% CI = 1.61-8.07, P = 0.002). BRCA2 protein expression at the cell membrane and lack of C-terminal expression in the cytoplasm were associated with a reduced risk of rapidly fatal prostate cancer. BRCA2 protein expression in prostate cancer tissue may have independent prognostic value. The potential biological significance of BRCA2 expression at the cell membrane warrants further investigation.


Mitogen activated protein kinases SakA(HOG1) and MpkC collaborate for Aspergillus fumigatus virulence.
Here, we investigated which stress responses were influenced by the MpkC and SakA mitogen-activated protein kinases of the high-osmolarity glycerol (HOG) pathway in the fungal pathogen Aspergillus fumigatus. The ΔsakA and the double ΔmpkC ΔsakA mutants were more sensitive to osmotic and oxidative stresses, and to cell wall damaging agents. Both MpkC::GFP and SakA::GFP translocated to the nucleus upon osmotic stress and cell wall damage, with SakA::GFP showing a quicker response. The phosphorylation state of MpkA was determined post exposure to high concentrations of congo red and Sorbitol. In the wild-type strain, MpkA phosphorylation levels progressively increased in both treatments. In contrast, the ΔsakA mutant had reduced MpkA phosphorylation, and surprisingly, the double ΔmpkC ΔsakA had no detectable MpkA phosphorylation. A. fumigatus ΔsakA and ΔmpkC were virulent in mouse survival experiments, but they had a 40% reduction in fungal burden. In contrast, the ΔmpkC ΔsakA double mutant showed highly attenuated virulence, with approximately 50% mice surviving and a 75% reduction in fungal burden. We propose that both cell wall integrity (CWI) and HOG pathways collaborate, and that MpkC could act by modulating SakA activity upon exposure to several types of stresses and during CW biosynthesis.


Transfusion-related acute lung injury management in a pediatric intensive care unit.
Transfusion-related acute lung injury (TRALI) constitutes a life threatening complication of blood transfusion. In severe TRALI cases supportive care with mechanical ventilation in intensive care unit is needed. We present two severe TRALI cases caused by leukocyte depleted, ABO compatible, packed red blood cell transfusions, coming from multiparous women donors. In the first case diagnosis was based on clinical findings and established by the identification of leukocyte antibodies in donor's unit and recipient's serum and she deal with invasive mechanical ventilation. In the second case, diagnosis was based on clinical criteria and chest radiograph findings and non-invasive mechanical ventilation was used. Both cases were treated in a Pediatric Intensive Care Unit and they had a favorable outcome.