Nucleotide sequence analysis of a 38.5-kilobase-pair region of the genome of human herpesvirus 6 encoding human cytomegalovirus immediate-early gene homologs and transactivating functions.
Human herpesvirus 6 (HHV-6) is prevalent in the human population, with primary infection occurring early in life. Its predominant CD4+ T-lymphocyte tropism, its ability to activate human immunodeficiency virus type 1 (HIV-1) gene expression in vitro, and its upregulation of CD4 expression has led to speculation that HHV-6 may act as a positive cofactor in the progression of HIV infection to AIDS in individuals infected with both viruses. Previous sequencing studies of restricted regions of the 161.5-kbp genome of HHV-6 have demonstrated unequivocally that it is a member of the betaherpesvirus subgroup and have indicated that the HHV-6 genome is generally collinear with the unique long (UL) component of human cytomegalovirus (HCMV). In the work described in this report we have extended these sequencing studies by determining the primary structure of 38.5-kbp of the HHV-6 genome (genomic position 21.0 to 59.5 kbp). Within the sequenced region lie 31 open reading frames, 20 of which are homologous to positional counterparts in HCMV. Of particular significance is the identification of homologs of the HCMV UL36-38 and US22-type genes, which have been shown to encode transactivating proteins. We show that DNA sequences encoding these HHV-6 homologs were able to transactivate HIV-1 long terminal repeat-directed chloramphenicol acetyltransferase expression in cotransfection assays, thus demonstrating functional as well as structural conservation of these betaherpesvirus-specific gene products. Our data therefore confirm the close relationship between HHV-6 and HCMV and identify putative immediate-early regulatory genes of HHV-6 likely to play key roles in lytic replication and possibly also in the interactions between HHV-6 and HIV in dually infected cells.


Imaging of a spinal nephroblastoma in a dog.
An 8-month-old German Shepherd dog was presented for investigation of pelvic limb gait abnormality. Neurolocalization indicated a T3-L3 spinal cord lesion. The myelographic appearance was of an intramedullary lesion at T9/10, but upon subsequent magnetic resonance imaging it was determined that the mass was extramedullary. A diagnosis of nephroblastoma was made on histological examination. The imaging features of this rare tumor and the differentiation of intradural-extramedullary and intramedullary masses are discussed.


Age- and sex-specific effects of obesity, metabolic syndrome and its components on back pain: The English Longitudinal Study of Ageing.
We aimed to investigate age- and sex-specific effects of obesity, metabolic syndrome (MetS) and its components on back pain in middle-aged and older English individuals. We used data from the English Longitudinal Study of Ageing, wave 2 (2004-2005). Body mass index (BMI) expressed the obesity, while MetS was defined according to revised Adult Treatment Panel (ATP) III criteria. We assessed associations between obesity, MetS and its components with presence and severity of back pain and provided estimates per strata, middle-aged (50-64years) and older (65-79years), women and men. The study sample included 3328 participants, 1021 and 835 middle-aged women and men and 773 and 699 older women and men, respectively. We found that BMI (OR=1.07, 95% CI 1.05-1.09), MetS (OR=1.47, 95% CI 1.22-1.77), high waist circumference (WC), high triglycerides (TG), and high fasting blood glucose were associated with the presence of back pain. Effects of BMI were consistent across the strata. However, MetS was associated with back pain only in women, middle-aged (OR=1.59, 95% CI 1.14-2.21) and older (OR=1.43, 95% CI 1.01-2.05). The MetS component driving this association was high WC, supported by high TG in older women. Higher BMI, presence of MetS, high blood pressure and TG were associated with back pain severity. We found that obesity was associated with the presence and severity of back pain, irrespective of age and sex. However, we found women-specific effects of MetS driven by high WC, indicating that metabolic dysregulation contributes to back pain pathophysiology in women.


SparseCT: System concept and design of multislit collimators.
SparseCT, an undersampling scheme for compressed sensing (CS) computed tomography (CT), has been proposed to reduce radiation dose by acquiring undersampled projection data from clinical CT scanners (Koesters et al. in, SparseCT: Interrupted-Beam Acquisition and Sparse Reconstruction for Radiation Dose Reduction; 2017). SparseCT partially blocks the x-ray beam with a multislit collimator (MSC) to perform a multidimensional undersampling along the view and detector row dimensions. SparseCT undersamples the projection data within each view and moves the MSC along the z-direction during gantry rotation to change the undersampling pattern. It enables reconstruction of images from undersampled data using CS algorithms. The purpose of this work is to design the spacing and width of the MSC slits and the MSC motion patterns based on beam separation, undersampling efficiency, and image quality. The development and testing of a SparseCT prototype with the designed MSC will be described in a following paper. We chose a few initial MSC designs based on the guidance from two metrics: beam separation and undersampling efficiency. Both beam separation and undersampling efficiency were measured from numerically simulated photon distribution with MSC taken into consideration. Beam separation measures the separation between x-ray beams from consecutive slits, taking into account penumbra effects on both sides of each slit. Undersampling efficiency measures the dose-weighted similarity between penumbra undersampling and binary undersampling, in other words, the effective contribution of the incident dose to the signal to noise ratio of the projection data. We then compared the initially chosen MSC designs in terms of their reconstruction image quality. SparseCT projections were simulated from fully sampled patient projection data according to the MSC design and motion pattern, reconstructed iteratively using a sparsity-enforcing penalized weighted least squares cost function with ordered subsets/momentum algorithm, and compared visually and quantitatively. Simulated photon distributions indicate that the size of the penumbra is dominated by the size of the focal spot. Therefore, a wider MSC slit and a smaller focal spot lead to increased beam separation and undersampling efficiency. For fourfold undersampling with a 1.2 mm focal spot, a minimum MSC slit width of three detector rows (projected to the detector surface) is needed for beam separation; for threefold undersampling, a minimum slit width of four detector rows is needed. Simulations of SparseCT projection and reconstruction indicate that the motion pattern of the MSC does not have a visible impact on image quality. An MSC slit width of three or four detector rows yields similar image quality. The MSC is the key component of the SparseCT method. Simulations of MSC designs incorporating x-ray beam penumbra effects showed that for threefold and fourfold dose reductions, an MSC slit width of four detector rows provided reasonable beam separation, undersampling efficiency, and image quality.


Critical care nurses' perceptions of stress and stress-related situations in the workplace.
Critical care nurses (CCNs) experience stressful situations in their daily working environments. A qualitative research approach (exploratory, descriptive and contextual) was used to explore and describe the stressful situations experienced by critical care nurses in the Tshwane metropolitan are of South Africa. Focus group interviews were conducted with critical care nurses. Data was generated by means of focus group interviews. The results revealed CCNs' perceptions and experiences about stressful events, factors contributing to stress in the critical care environment, as well as their needs for support systems.Critical care nurses experience stressful situations in their daily working environments. The question arises for nurses: are there adequate support systems in the critical care environment and what are critical care nurses doing to maintain their own health and well-being? Facilitating conscious awareness among critical care nurses could enhance their resiliency and their hardiness, strengthening their coping capacities in stressful working situations. The contextual framework adopted for this research was the Neuman Systems Model. A qualitative research approach (exploratory, descriptive and contextual) was used to explore and describe the stress experienced by critical care nurses. Focus group interviews were conducted with critical care nurses and individual interviews with nurse managers. The results revealed their perceptions and experiences about the effects of stress in the critical care environment, as well as some of their coping strategies. The recommendations include that stress management programmes should be implemented and evaluated; debriefing services should be available to CCNs, in-service education programmes should address raising CCNs' consciousness awareness and enhance their resiliency skills. Effective communication systems should be established between managers and CCNs to address inconsistencies as they arise, including critical shortages of staff and equipment.


Evaluation of potential protective factors against metabolic syndrome in bottlenose dolphins: feeding and activity patterns of dolphins in sarasota bay, Florida.
Free-ranging bottlenose dolphins (Tursiops truncatus) living in Sarasota Bay, Florida appear to have a lower risk of developing insulin resistance and metabolic syndrome compared to a group of dolphins managed under human care. Similar to humans, differences in diet and activity cycles between these groups may explain why Sarasota dolphins have lower insulin, glucose, and lipids. To identify potential protective factors against metabolic syndrome, existing and new data were incorporated to describe feeding and activity patterns of the Sarasota Bay wild dolphin community. Sarasota dolphins eat a wide variety of live fish and spend 10-20% of daylight hours foraging and feeding. Feeding occurs throughout the day, with the dolphins eating small proportions of their total daily intake in brief bouts. The natural pattern of wild dolphins is to feed as necessary and possible at any time of the day or night. Wild dolphins rarely eat dead fish or consume large amounts of prey in concentrated time periods. Wild dolphins are active throughout the day and night; they may engage in bouts of each key activity category at any time during daytime. Dive patterns of radio-tagged dolphins varied only slightly with time of day. Travel rates may be slightly lower at night, suggesting a diurnal rhythm, albeit not one involving complete, extended rest. In comparison, the managed dolphins are older; often fed a smaller variety of frozen-thawed fish types; fed fish species not in their natural diet; feedings and engaged activities are often during the day; and they are fed larger but fewer meals. In summary, potential protective factors against metabolic syndrome in dolphins may include young age, activity, and small meals fed throughout the day and night, and specific fish nutrients. These protective factors against insulin resistance and type 2 diabetes are similar to those reported in humans. Further studies may benefit humans and dolphins.


Adverse effect of ammonium salts on the antibacterial activity of paraformaldehyde solutions.
The antibacterial activity of aqueous solutions of paraformaldehyde in concentrations from 0.1 to 0.4% (w/v) is bacteriostatic rather than bactericidal in the presence or absence of ammonium chloride. The presence of ammonium chloride significantly lengthened the time of exposure to paraformaldehyde necessary for inhibition of growth of the test organism (Staphylococcus aureus FDA 209) when unbuffered solutions were used. Elevation of the pH of the reacting mixture of paraformaldehyde and ammonium chloride by partial buffering lengthened the time of exposure necessary for inhibition of growth of the test organism. Decrease of antibacterial activity was concomitant with the disappearance of paraformaldehyde from the reacting mixture. The reaction of paraformaldehyde with ammonium chloride was rapid at room temperature (25 C) and at pH levels near neutrality. The fate of the reacting paraformaldehyde, including the possibility of the formation of hexamethylenetetramine or methylenimine, is discussed with particular reference to loss of antibacterial activity.


The differentiation process of intestinal epithelial cells is associated with the appearance of statin, a non-proliferation-specific nuclear protein.
The expression of statin, a 57,000 Mr nuclear protein specifically present in non-proliferating cultured fibroblasts, was studied in vivo in the differentiating epithelial cells of the rat intestine. Using immunofluorescence microscopy we found that undifferentiated, proliferating crypt enterocytes are statin negative, whereas the differentiated non-proliferating villus enterocytes are statin positive. The epithelial cells of the intestine were isolated according to different stages of differentiation and the expression of statin was studied biochemically by immunoblotting assays. The prominent band (57,000 Mr) was present in abundance in villus cell fractions but undetectable in crypt cell fractions. These findings were also confirmed by immunofluorescence microscopy on individual intestinal epithelial cells of the different isolated fractions. The results presented here, which are similar to observations made in cell cultures, suggest that statin is a unique protein associated with the non-proliferative state of differentiated cells in tissue.


Specific amino acids of the glycosyltransferase LpsA direct the addition of glucose or galactose to the terminal inner core heptose of Haemophilus influenzae lipopolysaccharide via alternative linkages.
Lipopolysaccharide is the major glycolipid of the cell wall of the bacterium Haemophilus influenzae, a Gram-negative commensal and pathogen of humans. Lipopolysaccharide is both a virulence determinant and a target for host immune responses. Glycosyltransferases have high donor and acceptor substrate specificities that are generally limited to catalysis of one unique glycosidic linkage. The H. influenzae glycosyltransferase LpsA is responsible for the addition of a hexose to the distal heptose of the inner core of the lipopolysaccharide molecule and belongs to the glycosyltransferase family 25. The hexose added can be either glucose or galactose and linkage to the heptose can be either beta1-2 or beta1-3. Each H. influenzae strain uniquely produces only one of the four possible combinations of linked sugar in its lipopolysaccharide. We show that, in any given strain, a specific allelic variant of LpsA directs the anomeric linkage and the added hexose, glucose, or galactose. Site-directed mutagenesis of a single key amino acid at position 151 changed the hexose added in vivo from glucose to galactose or vice versa. By constructing chimeric lpsA gene sequences, it was shown that the 3' end of the gene directs the anomeric linkage (beta1-2 or beta1-3) of the added hexose. The lpsA gene is the first known example where interstrain variation in lipopolysaccharide core structure is directed by the specific sequence of a genetic locus encoding enzymes directing one of four alternative possible sugar additions from the inner core.


Perceived relationship between military service and homelessness among homeless veterans with mental illness.
This study examined the perceived relationship between military service and the risk of homelessness after discharge and identified specific aspects of military service that homeless veterans experience as having increased their risk for becoming homeless. A cross-sectional survey was conducted among 631 homeless veterans enrolled in the VA Therapeutic Employment Placement and Support Program from January 2001 through September 2003. Associations of sociodemographic characteristics, clinical status, and military service characteristics (independent variables) were examined in relation to perceptions of increased risk for homelessness and time to first episode of homelessness after leaving the military (two dependent variables), using analysis of variance, logistic regression, and multiple regression statistical analyses. Fewer than one third (31%) of the homeless veterans in this study reported that military service increased their risk for homelessness--either somewhat (18%) or very much (13%). Among those veterans who perceived military service as increasing their risk for becoming homeless, the three aspects of military service most commonly identified included a) substance abuse problems that began in the military (75%), b) inadequate preparation for civilian employment (68%), and c) loss of a structured lifestyle. The relatively small proportion of homeless veterans who attributed homelessness to their military service, coupled with the long 14-year average lag time between discharge and their first episode of homelessness, is consistent with epidemiological data suggesting that military service itself does not substantially increase the risk for becoming homeless among veterans.


Influences on allergic mechanisms through gut, lung, and skin microbiome exposures.
In industrialized societies the incidence of allergic diseases like atopic dermatitis, food allergies, and asthma has risen alarmingly over the last few decades. This increase has been attributed, in part, to lifestyle changes that alter the composition and function of the microbes that colonize the skin and mucosal surfaces. Strategies that reverse these changes to establish and maintain a healthy microbiome show promise for the prevention and treatment of allergic disease. In this Review, we will discuss evidence from preclinical and clinical studies that gives insights into how the microbiota of skin, intestinal tract, and airways influence immune responses in the context of allergic sensitization.


Pulmonary oedema -- a life threatening disease.
The aim was to describe the health history of patients after pulmonary oedema and investigate how they perceive their condition and treatment. In part one of the study medical records of patients treated for acute pulmonary oedema (n=44) were reviewed regarding social status, health history, medication and cause of the pulmonary oedema. In part two, interviews were performed focusing on the patients' conceptions of the illness, current situation and effects of pulmonary oedema on daily life. One-year mortality was 65% and all but 3 patients had a previous heart diagnosis. Analyses of the interviews yielded five categories: A suffocating feeling; trust in care providers; medication - an annoyance but also a saviour; dealing with existential issues alone or with relatives; concurrent diseases affecting daily life. Patients' who experience a pulmonary oedema have several heart-related conditions and a very poor prognosis. Experiencing pulmonary oedema is an anxiety-provoking situation and patients should be regularly and carefully monitored.


Carbon nanostructure-based saturable absorber mirror for a diode-pumped 500-MHz femtosecond Yb:KLu(WO4)2 laser.
We report a diode-pumped Yb:KLu(WO(4))(2) (Yb:KLuW) laser passively mode-locked by employing a carbon nanostructure-based multi-functional saturable absorber mirror. Two types of carbon nanostructures, single-walled carbon nanotubes (SWCNTs) and graphene, were deposited on a single dielectric mirror and applied both for stable mode-locking of the Yb:KLuW laser near 1050 nm in a compact cavity configuration. The carbon nanostructure mode-locked laser delivers 157-fs pulses with output powers of up to 85 mW at a repetition rate of 500 MHz.


Detection of pathogenic bacteria using a homogeneous immunoassay based on shear alignment of virus particles and linear dichroism.
Biomolecular detection has for a long time depended on a relatively small number of established methodologies. Many of these depend on the detection of a ligand-antibody complex using some kind of optical technique, e.g., chemiluminescence. Before this measurement can be made, the ligand-antibody complex generally has to be separated from bulk contaminants. This process involves the implementation of a heterogeneous assay format involving immobilization of the antibody onto a solid support to enable washing of the unbound ligand. This approach has a number of inherent issues including being slow and complex and requiring the use of expensive reagents. In this paper, we demonstrate how we have harnessed a biologically inspired nanoparticle to provide the basis for a homogeneous assay which requires no immobilization. The method relies on using fluid shear flow to align a fiber-like nanoparticle formed from a filamentous virus, M13, combined with a ligand-specific antibody. This renders the particle visible to linear dichroic spectroscopy, which provides an easily interpretable signal. The addition of the target ligand (in this case Escherichia coli O157) leads to the formation of a nanoparticle-ligand particle that is unable to align, leading to the perturbation of the linear dichroism signal.


Relation of chlorophyll fluorescence sensitive reflectance ratios to carbon flux measurements of montanne grassland and norway spruce forest ecosystems in the temperate zone.
We explored ability of reflectance vegetation indexes (VIs) related to chlorophyll fluorescence emission (R₆₈₆/R₆₃₀, R₇₄₀/R₈₀₀) and de-epoxidation state of xanthophyll cycle pigments (PRI, calculated as (R₅₃₁- R₅₇₀)/(R₅₃₁-R₅₇₀) to track changes in the CO₂ assimilation rate and Light Use Efficiency (LUE) in montane grassland and Norway spruce forest ecosystems, both at leaf and also canopy level. VIs were measured at two research plots using a ground-based high spatial/spectral resolution imaging spectroscopy technique. No significant relationship between VIs and leaf light-saturated CO₂ assimilation (A(MAX)) was detected in instantaneous measurements of grassland under steady-state irradiance conditions. Once the temporal dimension and daily irradiance variation were included into the experimental setup, statistically significant changes in VIs related to tested physiological parameters were revealed. ΔPRI and Δ(R₆₈₆/R₆₃₀) of grassland plant leaves under dark-to-full sunlight transition in the scale of minutes were significantly related to A(MAX) (R² = 0.51). In the daily course, the variation of VIs measured in one-hour intervals correlated well with the variation of Gross Primary Production (GPP), Net Ecosystem Exchange (NEE), and LUE estimated via the eddy-covariance flux tower. Statistical results were weaker in the case of the grassland ecosystem, with the strongest statistical relation of the index R₆₈₆/R₆₃₀ with NEE and GPP.


Avoiding temporal distortions in tilted pulses.
Tilted femtosecond laser pulses, having an intensity front with an angle to the propagation direction, can be generated by a dispersive element and a lens or mirror for imaging. Here we show that conventional geometries, for example with a grating at Littrow's condition, produce significant temporal distortions over the beam profile. The aberrations are the result of a mismatch between the grating's surface and the object plane of the imaging system. This changes the chirp of the pulses over the beam profile and lengthens the pulses to picoseconds for millimeter-sized beams. The distortions can be avoided by choosing a geometry in which the propagation direction of the tilted pulses is perpendicular to the grating's surface.


Depression following traumatic brain injury: epidemiology, risk factors and management.
It is important for clinicians to recognize major depression following traumatic brain injury (TBI) because of its association with poor global and psychosocial outcome, postconcussive symptoms and cognitive deficits. The purpose of this review is to provide an up-to-date selective review of the current understanding of epidemiology, risk factors and management of major depression following TBI. Many studies of prevalence of depression following TBI have not used accepted structured criteria for the diagnoses, but those that did found wide ranges of rates, from 17% to 61%. The risk factors for development of depression following TBI are poorly understood, but past psychiatric history, frontal lesions and atrophy, and family dysfunction have been shown in more than one study to play important roles. There are few controlled trials of the treatment of major depression in patients with TBI using accepted diagnostic criteria for major depression, as well as defined criteria for response and remission. As such, it is important for clinicians to use best practice guidelines for the treatment of major depression in the absence of TBI.


Children's fear and behavior in private pediatric dentistry practices.
This study assessed the proportion of children with dental fear, the proportion of children with negative behavior and the relationship of children's dental fear and children's negative behavior in private pediatric dentistry practices in western Washington state. A total of 421 children seen in 21 private pediatric dentistry practices in western Washington State participated. The average age of the children was 6.8+/-2.8 years (range=0.8-12.8 years). An average of 21 children were studied per practice (range=7-25 children). Dental fear was measured using the parents' version of the Dental Subscale of the Child Fear Survey Schedule (CFS). Behavior of the child during treatment was rated using the Frankl scale. Additional data were collected regarding the child's previous experiences and parental fear. The children's average item score on the 15-item CFS was 2+/-0.7, corresponding to a total score of 29.6 out of 75, where 75 indicates maximum fear. The proportion of children with dental fear, defined as an average item score of > or = 2.5 (corresponding to a total score of > or = 38), was 20% (85/421, 95% CI=16.3, 24%). The proportion of children who displayed negative behavior during treatment was 21% (95% CI=17.5, 24%). A prevalence ratio of 2.4 was calculated to describe the relationship between children's behavior during treatment and children's dental fear prior to dental treatment. Multivariate logistical regression analysis showed children with dental fear, younger children, and children exposed to treatment involving local anesthesia have higher odds of displaying negative behavior. The proportion of children with dental fear in private pediatric dentistry practices was 20%, and the proportion of children with negative behavior during treatment was 21%. Children with negative behavior had greater odds of having dental fear and children with dental fear had greater odds of having negative behavior. Screening for dental fear may allow pediatric dentists to prepare children more adequately for positive treatment experiences.


Triple-bond reactivity of diphosphorus molecules.
We report a mild method for generating the diphosphorus molecule or its synthetic equivalent in homogeneous solution; the P2 allotrope of the element phosphorus is normally obtained only under extreme conditions (for example, from P4 at 1100 kelvin). Diphosphorus is extruded from a niobium complex designed for this purpose and can be trapped efficiently by two equivalents of an organic diene to produce an organodiphosphorus compound. Diphosphorus stabilized by coordination to tungsten pentacarbonyl can be generated similarly at 25 degrees C, and in this stabilized form it still efficiently consumes two organic diene molecules for every diphosphorus unit.


Increased door to admission time is associated with prolonged throughput for ED patients discharged home.
Emergency Department (ED) service evaluations are typically based on surveys of discharged patients. Physicians/administrators benefit from data that quantifies system-based factors that adversely impact the experience of those who represent the survey cohort. While investigators have established that admitted patient boarding impacts overall ED throughput times, we sought to specifically quantify the relationship between throughput times for patients admitted (EDLOS) versus discharged home from the ED (DCLOS). We performed a prospective analysis of consecutive patient encounters at an inner-city ED. Variables collected: median daily DCLOS for ED patients, ED daily census, left without being seen (LWBS), median door to doctor, median room to doctor, and daily number admitted. Admitted patients divided into 2 groups based on daily median EDLOS for admits (<6 hours, ≥6 hours). Continuous variables analyzed by t-tests. Multivariate regression utilized to identify independent effects of the co-variants on median daily DCLOS. We analyzed 24,127 patient visits. ED patient DCLOS was longer for patients seen on days with prolonged EDLOS (193.7 minutes, 95%CI 186.7-200.7 vs. 152.8, 144.9-160.5, P< .0001). Variables that were associated with increased daily median EDLOS for admits included: daily admits (P= 0.01), room to doctor time (P< .01), number of patients that left without being seen (P< .01). When controlling for the covariate daily census, differences in DCLOS remained significant for the ≥6 hours group (189.4 minutes, 95%CI 184.1-194.7 vs. 164.8, 155.7-173.9 (P< .0001). Prolonged ED stays for admitted patients were associated with prolonged throughput times for patients discharged home from the ED.


Preserving fertility in female patients with hematological malignancies: a multidisciplinary oncofertility approach.
Oncofertility is a new interdisciplinary field at the intersection of oncology and reproductive medicine that expands fertility options for young cancer patients. The most common forms of hematological malignancies that occur in girls and young women and therefore necessitate oncofertility care are acute lymphocytic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, and Hodgkin's lymphoma. Aggressive gonadotoxic anticancer regimens including alkylating chemotherapy and total body irradiation are used often in treating girls and young women with hematological malignancies. The risks of gonadotoxicity and subsequent iatrogenic premature ovarian insufficiency and fertility loss depend mainly on the type and stage of the disease, dose of anticancer therapy as well as the age of the patient at the beginning of treatment. To avoid or at least mitigate the devastating complications of anticancer therapy-induced gonadotoxicity, effective and comprehensive strategies that integrate different options for preserving and restoring fertility ranging from established to experimental strategies should be offered before, during, and after chemotherapy or radiotherapy. A multidisciplinary approach that involves strong coordination and collaboration between hemato-oncologists, gynecologists, reproductive biologists, research scientists, and patient navigators is essential to guarantee high standard of care.


Lead precipitation by Vibrio harveyi: evidence for novel quorum-sensing interactions.
Three pleiotropic, quorum sensing-defective Vibrio harveyi mutants were observed to precipitate soluble Pb2+ as an insoluble compound. The compound was purified and subjected to X-ray diffraction and elemental analyses. These assays identified the precipitated compound as Pb9(PO4)6, an unusual and complex lead phosphate salt that is produced synthetically at temperatures of ca. 200 degrees C. Regulation of the precipitation phenotype was also examined. Introduction of a luxO::kan allele into one of the mutants abolished lead precipitation, indicating that the well-characterized autoinducer 1 (AI1)-AI2 quorum-sensing system can block lead precipitation in dense cell populations. Interestingly, the V. harveyi D1 mutant, a strain defective for secretion of both AI1 and AI2, was shown to be an effective trans inhibitor of lead precipitation. This suggests that a previously undescribed V. harveyi autoinducer, referred to as AI3, can also negatively regulate lead precipitation. Experiments with heterologous bacterial populations demonstrated that many different species are capable of trans regulating the V. harveyi lead precipitation phenotype. Moreover, one of the V. harveyi mutants in this study exhibited little or no response to intercellular signals from other V. harveyi inocula but was quite responsive to some of the heterologous bacteria. Based on these observations, we propose that V. harveyi carries at least one quorum sensor that is specifically dedicated to receiving cross-species communication.


Imaging of single organic molecules in motion.
High-resolution transmission electron microscopy revealed nearly atomically precise images of stepping conformational change and translational motion of single hydrocarbon molecules confined in carbon nanotubes. One or two C12 or C22 alkyl chains were tethered to a carborane end group and then embedded in the nanotubes. Images of the hydrocarbon chains interacting with each other and with a graphitic surface provide information on three-dimensional structures and dynamic molecular interactions that cannot be obtained by other analytical methods.


The International Network for Evaluating Outcomes of very low birth weight, very preterm neonates (iNeo): a protocol for collaborative comparisons of international health services for quality improvement in neonatal care.
The International Network for Evaluating Outcomes in Neonates (iNeo) is a collaboration of population-based national neonatal networks including Australia and New Zealand, Canada, Israel, Japan, Spain, Sweden, Switzerland, and the UK. The aim of iNeo is to provide a platform for comparative evaluation of outcomes of very preterm and very low birth weight neonates at the national, site, and individual level to generate evidence for improvement of outcomes in these infants. Individual-level data from each iNeo network will be used for comparative analysis of neonatal outcomes between networks. Variations in outcomes will be identified and disseminated to generate hypotheses regarding factors impacting outcome variation. Detailed information on physical and environmental factors, human and resource factors, and processes of care will be collected from network sites, and tested for association with neonatal outcomes. Subsequently, changes in identified practices that may influence the variations in outcomes will be implemented and evaluated using quality improvement methods. The evidence obtained using the iNeo platform will enable clinical teams from member networks to identify, implement, and evaluate practice and service provision changes aimed at improving the care and outcomes of very low birth weight and very preterm infants within their respective countries. The knowledge generated will be available worldwide with a likely global impact.


Massage therapy for fibromyalgia symptoms.
Massage therapy is widely used by patients with fibromyalgia seeking symptom relief. We performed a review of all available studies with an emphasis on randomized controlled trials to determine whether massage therapy can be a viable treatment of fibromyalgia symptoms. Extensive narrative review. PubMed, PsychInfo, CINAHL, PEDro, ISI Web of Science, and Google Scholar databases (inception-December 2009) were searched for the key words "massage", "massotherapy", "self-massage", "soft tissue manipulation", "soft tissue mobilization", "complementary medicine", "fibromyalgia" "fibrositis", and "myofascial pain". No language restrictions were imposed. The reference lists of all articles retrieved in full were also searched. The effects of massage on fibromyalgia symptoms have been examined in two single-arm studies and six randomized controlled trials. All reviewed studies showed short-term benefits of massage, and only one single-arm study demonstrated long-term benefits. All reviewed studies had methodological problems. The existing literature provides modest support for use of massage therapy in treating fibromyalgia. Additional rigorous research is needed in order to establish massage therapy as a safe and effective intervention for fibromyalgia. In massage therapy of fibromyalgia, we suggest that massage will be painless, its intensity should be increased gradually from session to session, in accordance with patient's symptoms; and the sessions should be performed at least 1-2 times a week.


SadA, a trimeric autotransporter from Salmonella enterica serovar Typhimurium, can promote biofilm formation and provides limited protection against infection.
Salmonella enterica is a major cause of morbidity worldwide and mortality in children and immunocompromised individuals in sub-Saharan Africa. Outer membrane proteins of Salmonella are of significance because they are at the interface between the pathogen and the host, they can contribute to adherence, colonization, and virulence, and they are frequently targets of antibody-mediated immunity. In this study, the properties of SadA, a purported trimeric autotransporter adhesin of Salmonella enterica serovar Typhimurium, were examined. We demonstrated that SadA is exposed on the Salmonella cell surface in vitro and in vivo during infection of mice. Expression of SadA resulted in cell aggregation, biofilm formation, and increased adhesion to human intestinal Caco-2 epithelial cells. Immunization of mice with folded, full-length, purified SadA elicited an IgG response which provided limited protection against bacterial challenge. When anti-SadA IgG titers were enhanced by administering alum-precipitated protein, a modest additional protection was afforded. Therefore, despite SadA having pleiotropic functions, it is not a dominant, protective antigen for antibody-mediated protection against Salmonella.


Retarded growth of the medial septum: a major gene effect in acallosal mice.
Absence of the corpus callosum is a hereditary brain defect that appears with varying severity in four inbred mouse strains and is the result of more than one major genetic locus. If relatively few, perhaps two or three, loci are involved in the prenatal ontogeny of the abnormal corpus callosum, it should be possible to identify a distinct morphological process which shows a major gene effect. Because available evidence suggests the source of callosal agenesis occurs in the substrates of axon guidance near the midsagittal plane rather than in the axons themselves, morphometric analysis was done for sagittal sections of the medial septal region in embryos of normal hybrids and four acallosal strains. The anterodorsal zone of the medial septum subadjacent to the cavum septi grew much slower in acallosal BALB/c and I/LnJ mice whereas the ventral septal region was apparently normal. In the Bailey recombinant inbred strains derived from an acallosal BALB/c progenitor, one recombinant (CXBG/By) closely resembled BALB/c whereas the others resembled the normal C57BL/6 parent strain. This pattern of results supports a major gene influence on fusion of the cerebral hemispheres near the region where the corpus callosum first crosses midplane over the dorsal septum.


Oral diamorphine: lack of effect on dyspnoea and exercise tolerance in the "pink puffer" syndrome.
The aim of this study was to assess the effects of diamorphine on breathlessness and exercise tolerance in patients with severe chronic airflow obstruction and normal arterial carbon dioxide tension (PCO2) levels ("pink puffer" syndrome). In this double-blind, cross-over, randomized study we examined both acute and chronic effects of single and multiple doses of oral diamorphine in 14 "pink puffer" patients. Their mean resting forced expiratory volume in one second (FEV1) was 36% predicted normal, mean arterial oxygen tension (PaO2) was 9.2 kPa and mean PaCO2 was 5.2 kPa. Ten patients took either diamorphine 2.5 or 5 mg or placebo elixir 6 hourly for 2 weeks, recording on a diary card dyspnoea, sleepiness and well-being on a visual analogue scale (VAS). The final treatment was given 30 min before measuring spirometry, arterial blood gases, plasma morphine levels, 6 min walking distances, time walked on treadmill and self-assessment of dyspnoea on a VAS scale after exercise. On two further days, eight patients took two doses, 4 h apart, of either diamorphine 7.5 mg or placebo elixir. Spirometry, 6 min walking distance with a VAS score for dyspnoea were measured before and at 1 h after each dose. Morphine levels and blood gases were also measured. Whether given in single or repeated doses, oral diamorphine had no significant effect on exercise tolerance and breathlessness when compared with placebo. Diamorphine 2.5-7.5 mg produced neither sleepiness nor a deterioration in blood gases. However, plasma levels associated with analgesic efficacy were not achieved with these doses. Thus, as given in this study, oral diamorphine is unlikely to have therapeutic potential in the treatment of dyspnoea in the "pink puffer" syndrome.


Acidic pH increases airway surface liquid viscosity in cystic fibrosis.
Cystic fibrosis (CF) disrupts respiratory host defenses, allowing bacterial infection, inflammation, and mucus accumulation to progressively destroy the lungs. Our previous studies revealed that mucus with abnormal behavior impaired mucociliary transport in newborn CF piglets prior to the onset of secondary manifestations. To further investigate mucus abnormalities, here we studied airway surface liquid (ASL) collected from newborn piglets and ASL on cultured airway epithelia. Fluorescence recovery after photobleaching revealed that the viscosity of CF ASL was increased relative to that of non-CF ASL. CF ASL had a reduced pH, which was necessary and sufficient for genotype-dependent viscosity differences. The increased viscosity of CF ASL was not explained by pH-independent changes in HCO3- concentration, altered glycosylation, additional pH-induced disulfide bond formation, increased percentage of nonvolatile material, or increased sulfation. Treating acidic ASL with hypertonic saline or heparin largely reversed the increased viscosity, suggesting that acidic pH influences mucin electrostatic interactions. These findings link loss of cystic fibrosis transmembrane conductance regulator-dependent alkalinization to abnormal CF ASL. In addition, we found that increasing Ca2+ concentrations elevated ASL viscosity, in part, independently of pH. The results suggest that increasing pH, reducing Ca2+ concentration, and/or altering electrostatic interactions in ASL might benefit early CF.


Effects of Single-Drop Impactions and Natural and Simulated Rains on the Dispersal of Botryosphaeria dothidea Conidia.
ABSTRACT Laboratory and field experiments were conducted to study the dispersal of Botryosphaeria dothidea conidia using single-drop impactions and natural and simulated precipitations. For laboratory studies, 200 single drops were released from a height of 1 m on infected pistachio nuts. On pieces of photographic film, 50% of the droplets were collected within 20 mm (average droplet travel distance) of the target area, and the droplets ranged from 0.041 to 3.19 mm in diameter, with an average of 0.3 mm. Each droplet carried an average of 23 B. dothidea conidia. In 3 years of field experiments, rainwater was collected in funnels connected to bottles positioned at different heights inside the tree canopy and at different distances away from the edge of tree canopy in three commercial pistachio orchards in San Joaquin, Yolo, and Glenn counties in California. Numbers of conidia in rainwater varied among and within sampling seasons by sampling dates and orchards. Up to 67,000 conidia/ml were obtained in rainwater samples collected from an orchard in Yolo County. Rainwater from orchards in Yolo and Glenn counties contained a consistently higher number of conidia than rainwater collected from the orchard in San Joaquin County. Variation in numbers of conidia also existed among heights where bottles were located. There were significantly more conidia in rainwater collected inside than outside tree canopies. Inside tree canopies, bottles located at 100 and 150 cm above ground collected more B. dothidea conidia than those placed at 50 and 200 cm. Conidia were collected as far as 1 m from the tree canopy edge. Based on data from the Glenn County orchard, a linear relationship between number of conidia (Y) and rainfall amount (X) in millimeters was determined as Y = 240X - 3,867, with r(2) = 0.91, which meant that a minimum of 16.1 mm of rain was needed to disperse conidia of B. dothidea. The power law model best described the dispersal gradients of B. dothidea propagules in the 1999-2000 and 2001-02 sampling seasons, with r(2) values of >/=0.73, whereas the exponential law model fit best for the 2000-01 data, with r(2) values of >/=0.81. In a rain simulation experiment, the intensity of the rain generated by a nozzle at 138 kPa of pressure inside the tree canopy was approximately five times higher than rain recorded outside the tree canopy. Rain removed up to 65% of conidia from infected fruit. These results confirmed that B. dothidea is a splash-dispersed pathogen with relatively short distances of spore dispersal within pistachio orchards. Only pycnidia are present in pistachio orchards; therefore, the results also indicate that inoculum of B. dothidea should be entirely splashed dispersed.


Concussion symptomology and recovery in children and adolescents with pre-existing anxiety.
To examine pre-existing anxiety disorders as a risk factor for increased concussion symptomology and prolonged recovery in children and adolescents. In this retrospective cohort study, we abstracted medical record data for 637 children/adolescents (5-17 years) presenting to three tertiary concussion clinics between April 2018 and March 2019. Primary outcomes were mean concussion symptom and vision symptom severity scores measured at clinic visits. Linear mixed-effects regression models were employed to investigate differences in average symptom load, vision symptom score and symptom recovery trajectories across anxiety strata, adjusted for random effects (time), age and sex. Secondary outcomes, time to concussion symptom recovery and time to return to academics and sports, respectively, were examined via log-rank tests and multivariable Cox regression. Among 637 eligible concussion patients, 155 (24%) reported pre-existing anxiety. On average, patients with anxiety reported an additional 2.64 (95% CI 1.84 to 3.44) concussion symptoms and 7.45 (95% CI 5.22 to 9.68) higher vision symptom severity scores throughout recovery versus those without, after adjusting for age and sex. There was no evidence that concussion or vision symptom trajectories varied over time between those with/without anxiety after accounting for baseline dissimilarities in symptom scores (all pinteraction >0.05). Anxiety was significantly associated with delayed symptom recovery (adjusted HR 3.34, 95% CI 2.18 to 5.12), return to school (adjusted HR 2.01, 95% CI 1.59 to 2.53) and return to physical activity (adjusted HR 1.88, 95% CI 1.49 to 2.37). Pre-existing anxiety disorders were associated with more severe symptomology and prolonged recovery after concussion in children and adolescents. These results can be referenced by providers to manage patients' recovery expectations.


Behavioural assessment of flicker fusion frequency in chicken Gallus gallus domesticus.
To interact with its visual environment, an organism needs to perceive objects in both space and time. High temporal resolution is hence important to the fitness of diurnally active animals, not least highly active aerial species such as birds. However, temporal resolution, as assessed by flicker fusion frequency (FFF; the stimulus frequency at which a flickering light stimulus can no longer be resolved and appears continuous) or critical flicker fusion frequency (CFF; the highest flicker fusion frequency at any light intensity) has rarely been assessed in birds. In order to further our understanding of temporal resolution as a function of light intensity in birds we used behavioural experiments with domestic chickens (Gallus gallus domesticus) from an old game breed 'Gammalsvensk dvärghöna' (which is morphologically and behaviourally similar to the wildtype ancestor, the red jungle fowl, G. gallus), to generate an 'Intensity/FFF curve' (I/FFF curve) across full spectrum light intensities ranging from 0.2 to 2812 cd m⁻². The I/FFF curve is double-branched, resembling that of other chordates with a duplex retina of both rods and cones. Assuming that the branches represent rod and cone mediated responses respectively, the break point between them places the transition between scotopic and photopic vision at between 0.8 and 1.9 cd m⁻². Average FFF ranged from 19.8 Hz at the lowest light intensity to a CFF 87.0 Hz at 1375 cd m⁻². FFF dropped slightly at the highest light intensity. There was some individual variation with certain birds displaying CFFs of 90-100 Hz. The FFF values demonstrated by this non-selected breed appear to be considerably higher than other behaviourally derived FFF values for similar stimuli reported for white and brown commercial laying hens, indicating that the domestication process might have influenced temporal resolution in chicken.


Caregiving burden of children with chronic diseases.
The care demands of children with chronic diseases can affect caregivers' health by imposing caregiving burden to them. The health status of caregivers plays a vital role in the quality of care provided to such children and in their quality of life. To determine caregiving burden in caregivers and to identify relevant influential factors. In this cross-sectional study, a total number of 249 caregivers of children with chronic diseases who referred to hospitalization and ambulatory departments of Bandar Abbas, Iran in 2016 were selected using convenience sampling method. The main caregivers who were older than 18 years and provided care to a sick child for at least three months consecutively were included. Caregiving burden was measured using the Caregiver Burden Scale. Data was analyzed SPSS 16 using descriptive statistics, Spearman's correlation coefficient and Mann-Whitney U test. Mean score of caregiving burden was 1.98 which was close to moderate level. The highest caregiving burden was observed in general strain dimension (2.35), and cerebral palsy imposed the maximum burden to caregivers (2.24). Correlation coefficient revealed that perceived caregiving burden was in connection with children's and caregivers' age, duration of disease and caregiving, child's level of disability, number of family members and income level (p<0.05). Mann-Whitney U test showed that female caregivers, villagers, and caregivers dealing with more than one patient experienced higher burden (p<0.05). Different variables can increase caregiving burden. Therefore, planning for holistic and family-centered interventions to decrease caregiving burden is necessary for health care providers.


Neural representations and mechanisms for the performance of simple speech sequences.
Speakers plan the phonological content of their utterances before their release as speech motor acts. Using a finite alphabet of learned phonemes and a relatively small number of syllable structures, speakers are able to rapidly plan and produce arbitrary syllable sequences that fall within the rules of their language. The class of computational models of sequence planning and performance termed competitive queuing models have followed K. S. Lashley [The problem of serial order in behavior. In L. A. Jeffress (Ed.), Cerebral mechanisms in behavior (pp. 112-136). New York: Wiley, 1951] in assuming that inherently parallel neural representations underlie serial action, and this idea is increasingly supported by experimental evidence. In this article, we developed a neural model that extends the existing DIVA model of speech production in two complementary ways. The new model includes paired structure and content subsystems [cf. MacNeilage, P. F. The frame/content theory of evolution of speech production. Behavioral and Brain Sciences, 21, 499-511, 1998 ] that provide parallel representations of a forthcoming speech plan as well as mechanisms for interfacing these phonological planning representations with learned sensorimotor programs to enable stepping through multisyllabic speech plans. On the basis of previous reports, the model's components are hypothesized to be localized to specific cortical and subcortical structures, including the left inferior frontal sulcus, the medial premotor cortex, the basal ganglia, and the thalamus. The new model, called gradient order DIVA, thus fills a void in current speech research by providing formal mechanistic hypotheses about both phonological and phonetic processes that are grounded by neuroanatomy and physiology. This framework also generates predictions that can be tested in future neuroimaging and clinical case studies.


Type 6 secretion dynamics within and between bacterial cells.
The bacterial type 6 secretion system (T6SS) functions as a virulence factor capable of attacking both eukaryotic and prokaryotic target cells by a process that involves protein transport through a contractile bacteriophage tail-like structure. The T6SS apparatus is composed, in part, of an exterior sheath wrapped around an interior tube. Here, we report that in living cells the cytoplasmic adenosine triphosphatase called ClpV specifically recognizes the contracted T6SS sheath structure, causing its disassembly within seconds. ClpV imaging allowed spatial and temporal documentation of cell-cell interactions (termed T6SS dueling) that likely mark the location of repeated T6SS-mediated protein translocation events between bacterial cells.


Formation and metabolism of inositol 1,4,5-trisphosphate in human platelets.
1. myo-[3H]Inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], when added to lysed platelets, was rapidly converted into [3H]inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4], which was in turn converted into [3H]inositol 1,3,4-trisphosphate [Ins(1,3,4)P3]. This result demonstrates that platelets have the same metabolic pathways for interconversion of inositol polyphosphates that are found in other cells. 2. Labelling of platelets with [32P]Pi, followed by h.p.l.c., was used to measure thrombin-induced changes in the three inositol polyphosphates. Interfering compounds were removed by a combination of enzymic and non-enzymic techniques. 3. Ins(1,4,5)P3 was formed rapidly, and reached a maximum at about 4 s. It was also rapidly degraded, and was no longer detectable after 30-60 s. 4. Formation of Ins(1,3,4,5)P4 was almost as rapid as that of Ins(1,4,5)P3, and it remained detectable for a longer time. 5. Ins(1,3,4)P3 was formed after an initial lag, and this isomer reached its maximum, which was 10-fold higher than that of Ins(1,4,5)P3, at 30 s. 6. Comparison of the intracellular Ca2+ concentration as measured with fura-2 indicates that agents other than Ins(1,4,5)P3 are responsible for the sustained maintenance of a high concentration of intracellular Ca2+. It is proposed that either Ins(1,3,4)P3 or Ins(1,3,4,5)P4 may also be Ca2+-mobilizing agents.


Trends in colorectal cancer testing among Medicare subpopulations.
In 1998, Medicare initiated universal coverage for colorectal cancer (CRC) screening via fecal occult blood testing (FOBT) and sigmoidoscopy. In mid-2001, universal coverage was advanced to screening colonoscopy. This study sought to determine whether trends in CRC testing differed among racial/ethnic, age, or gender subgroups of the Medicare population. In 2006, claims from 1995 to 2003 were analyzed for annual 5% random samples of fee-for-service Medicare enrollees living in Surveillance, Epidemiology, and End Results (SEER) regions to calculate the annual, age-standardized percentages of subjects who received FOBT, sigmoidoscopy, or colonoscopy. Logistic regression then modeled trends in annual test use within racial/ethnic, age, and gender subgroups across three Medicare coverage periods (precoverage [1995-1997]; limited coverage [1998-mid-2001]; and full coverage [mid-2001-2003]). The annual use of FOBT and sigmoidoscopy declined from 1995 to 2003 in all racial/ethnic groups, but the relative decline in sigmoidoscopy use was greater among whites compared to nonwhites. In contrast, colonoscopy use increased substantially in all racial/ethnic groups. However, relative to the precoverage period among whites, the full-coverage period was associated with significantly greater colonoscopy use among whites (OR=2.14; 95% CI=2.09, 2.19) than blacks (OR=1.86; 95% CI=1.75, 1.96); Asian/Pacific Islanders (OR=1.73; 95% CI=1.62, 1.86); or Hispanics (OR=1.65; 95% CI=1.49, 1.81). The use of colonoscopy during the full-coverage period was also differentially greater among enrollees aged <80 years. CRC testing trends were similar among male and female enrollees. Colonoscopy is supplanting sigmoidoscopy as a CRC test among Medicare enrollees, while FOBT use is in decline. The transition from sigmoidoscopy to colonoscopy has occurred more quickly among white than nonwhite Medicare enrollees.


Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson's disease: a large-scale international study.
A genome-wide association study identified 13 single-nucleotide polymorphisms (SNPs) significantly associated with Parkinson's disease. Small-scale replication studies were largely non-confirmatory, but a meta-analysis that included data from the original study could not exclude all SNP associations, leaving relevance of several markers uncertain. Investigators from three Michael J Fox Foundation for Parkinson's Research-funded genetics consortia-comprising 14 teams-contributed DNA samples from 5526 patients with Parkinson's disease and 6682 controls, which were genotyped for the 13 SNPs. Most (88%) participants were of white, non-Hispanic descent. We assessed log-additive genetic effects using fixed and random effects models stratified by team and ethnic origin, and tested for heterogeneity across strata. A meta-analysis was undertaken that incorporated data from the original genome-wide study as well as subsequent replication studies. In fixed and random-effects models no associations with any of the 13 SNPs were identified (odds ratios 0.89 to 1.09). Heterogeneity between studies and between ethnic groups was low for all SNPs. Subgroup analyses by age at study entry, ethnic origin, sex, and family history did not show any consistent associations. In our meta-analysis, no SNP showed significant association (summary odds ratios 0.95 to 1.08); there was little heterogeneity except for SNP rs7520966. Our results do not lend support to the finding that the 13 SNPs reported in the original genome-wide association study are genetic susceptibility factors for Parkinson's disease.


Contribution of Pretomanid to Novel Regimens Containing Bedaquiline with either Linezolid or Moxifloxacin and Pyrazinamide in Murine Models of Tuberculosis.
Novel regimens combining bedaquiline and pretomanid with either linezolid (BPaL regimen) or moxifloxacin and pyrazinamide (BPaMZ regimen) shorten the treatment duration needed to cure tuberculosis (TB) in BALB/c mice compared to that of the first-line regimen and have yielded promising results in initial clinical trials. However, the independent contribution of the investigational new drug pretomanid to the efficacy of BPaMZ has not been examined, and its contribution to BPaL has been examined only over the first 2 months of treatment. In the present study, the addition of pretomanid to BL increased bactericidal activity, prevented emergence of bedaquiline resistance, and shortened the duration needed to prevent relapse with drug-susceptible isolates by at least 2 months in BALB/c mice. Addition of pretomanid to bedaquiline, moxifloxacin, and pyrazinamide (BMZ) resulted in a 1-log10 greater CFU reduction after 1 month of treatment and/or reduced the number of mice relapsing in each of 2 experiments in BALB/c mice and in immunocompromised nude mice. Bedaquiline-resistant isolates were found at relapse in only one BMZ-treated nude mouse. Treatment of infection with a pyrazinamide-resistant mutant in BALB/c mice with BPaMZ prevented selection of bedaquiline-resistant mutants and reduced the proportion of mice relapsing compared to that for BMZ treatment alone. Among severely ill C3HeB/FeJ mice with caseous pneumonia and cavitation, BPaMZ increased median survival (≥60 versus 21 days) and reduced median lung CFU by 2.4 log10 at 1 month compared to the level for BMZ. In conclusion, in 3 different mouse models, pretomanid contributed significantly to the efficacy of the BPaMZ and BPaL regimens, including restricting the selection of bedaquiline-resistant mutants.


A new 440-kD isoform is the major ankyrin in neonatal rat brain.
This report describes initial characterization of a 440-kD isoform of brain ankyrin (ankyrinB) representing an alternatively spliced mRNA product of the gene encoding the major isoform of ankyrin in adult human brain (Otto, E., M. Kunimoto, T. McLaughlin, V. Bennett, J. Cell Biology. 114:241-253). Northern and immunoblot analyses indicate that 440-kD ankyrinB includes the spectrin and membrane-binding domains as well as a regulatory domain of the major 220-kD isoform. 440-kD ankyrinB contains, in addition, a sequence of a predicted size of 220 kD which is inserted between the regulatory domain and spectrin/membrane-binding domains. 440-kD ankyrinB has properties expected of a peripherally associated membrane-skeletal protein: it is exclusively present in the particulate fraction of brain homogenates, is extracted with NaOH, and remains associated with Triton-X-100-resistant structures. Expression of 440-kD ankyrinB in rat brain began at birth before other ankyrins could be detected, peaked 10 d after birth, and then decreased progressively to 30% of the maximum in adults. Expression of the 220-kD ankyrinB and ankyrinR (erythroid ankyrin) began approximately 10 d after the 440-kD isoform, increased rapidly between 10 and 15 d after birth, and finally achieved their maximal levels in adults. 440-kD ankyrinB is present in approximately equivalent amounts in all regions of neonatal brain while in adult brain it is present in highest levels in cerebellum and lowest in brain stem. 440-kD ankyrinB was localized by immunofluorescence in regions of neonatal and adult brain containing primarily dendrites and unmyelinated axons. 440-kD ankyrinB thus may play a specialized role in neuronal processes.


Some mathematical and representational aspects of solid modeling.
An approach is presented to the tripartite problem of modeling physical solids mathematically, representing the models in a computer, and using representations in geometric algorithms. Examples are primarily from the domain of manufacturing and design of discrete goods, but the results reported here have wider significance. Mathematical definitions can formalize many of our intuitions about three-dimensional (3-D) objects and operations on them. Representation-free (mathematical) models and functions allow formal properties to be defined for characterizing geometric representations. Three common representation schemes for 3-D objects are described briefly, along with some of their formal and informal properties. A rigorous, as opposed to ad hoc, approach to modeling has several advantages. Broadly, the conceptual complications and ambiguities which are endemic to ad hoc problem statements and solutions may be avoided by appealing to a precise mathematical semantics. Mathematical rigor is mandatory in applications such as automatic manufacturing in which correctness must be guaranteed and consistency and validity maintained.


Relative role of genes and environment on BP: twin studies in Madras, India.
This study was conducted to test the feasibility of the twin research model in a developing country with diverse cultures and to understand the relative influence of genetic and environmental factors on BP variation among South Indians. This was a cross-sectional twin study of volunteers using a two-by-two factorial design for the analysis of quantitative traits. The factors were twin type (monozygotic and dizygotic) and sex (male and female). The study was conducted in Madras. Twenty-four pairs of twins were contacted for participation in the project. Of the 24 pairs we contacted, 91% (20) actually participated in our study. Among 20 sets we studied, 10 (50%) are males and 10 (50%) are females with an average age of 23 years. The mean SBP of this volunteer twin population was 115.18 +/- 1.27 mmHg and DBP was 68.53 +/- 1.41 mmHg. Analysis of dietary habits (vegetarian/nonvegetarian) showed that BP was greater (118.26 +/- 2.29/71.88 +/- 2.34 mmHg) in vegetarian twins than nonvegetarians (112.28 +/- 1.42/66.2 +/- 1.90 mmHg). Also a positive correlation between urinary excretion of calcium and BP was observed. The present study demonstrates that epidemiological research in a developing country like India is feasible and economical, using the twin research methodology. As observed in other populations, the major source of BP variation in the population appears to be predominantly under genetic control.


A tool for functional plant genomics: chimeric RNA/DNA oligonucleotides cause in vivo gene-specific mutations.
Self-complementary chimeric oligonucleotides (COs) composed of DNA and modified RNA residues were evaluated as a means to (i) create stable, site-specific base substitutions in a nuclear gene and (ii) introduce a frameshift in a nuclear transgene in plant cells. To demonstrate the creation of allele-specific mutations in a member of a gene family, COs were designed to target the codon for Pro-196 of SuRA, a tobacco acetolactate synthase (ALS) gene. An amino acid substitution at Pro-196 of ALS confers a herbicide-resistance phenotype that can be used as a selectable marker in plant cells. COs were designed to contain a 25-nt homology domain comprised of a five-deoxyribonucleotide region (harboring a single base mismatch to the native ALS sequence) flanked by regions each composed of 10 ribonucleotides. After recovery of herbicide-resistant tobacco cells on selective medium, DNA sequence analyses identified base conversions in the ALS gene at the codon for Pro-196. To demonstrate a site-specific insertion of a single base into a targeted gene, COs were used to restore expression of an inactive green fluorescent protein transgene that had been designed to contain a single base deletion. Recovery of fluorescent cells confirmed the deletion correction. Our results demonstrate the application of a technology to modify individual genetic loci by catalyzing either a base substitution or a base addition to specific nuclear genes; this approach should have great utility in the area of plant functional genomics.


The Importance of Being a 'Lark' in Post-Menopausal Women with Obesity: A Ploy to Prevent Type 2 Diabetes Mellitus?
Chronotype is defined as the behavioral manifestation of circadian rhythms related to the external light-dark cycle. Evening chronotype has been associated with an increased risk of developing cardiometabolic diseases in obesity. Menopause is a lifestage associated with an increased risk of developing cardiometabolic diseases and a change in circadian rhythmicity compared to pre-menopause. However, the prevalence of chronotype categories in menopause and their role in determining menopause-related cardiometabolic risk, mostly in obesity, have not been investigated. Thus, we aimed to investigate the prevalence of chronotype categories in post-menopausal women with obesity and their role in menopause-related cardiometabolic risk. In this cross-sectional study we enrolled 49 pre-menopausal and 74 post-menopausal women with obesity. Anthropometric parameters, lifestyle habits, adherence to the Mediterranean Diet (MD), sleep quality, chronotype and the presence of type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) were studied. No significance differences were detected in terms of lifestyle and adherence to the MD between pre- and post-menopausal women. Chronotype was classified as morning in 66 (53.6%), evening in 20 (16.3%) and intermediate in 37 (30.1%) women. In addition, pre-menopausal women with obesity showed a significantly higher chance to have an intermediate chronotype (OR = 2.21, 95% CI 1.28-3.83; p = 0.004), whereas post-menopausal women with obesity showed a trend to have a higher morning chronotype (OR = 1.42, 95% CI 0.98-2.06; p = 0.051), although this did not reach statistical significance. No significant differences were detected in terms of prevalence of evening chronotype between the two groups. However, the evening chronotype had a significantly higher risk to have T2DM compared to the morning (OR = 17.29, 95% CI 2.40-124.27; p = 0.005) and intermediate chronotypes (OR = 30.86, 95% CI 2.05-464.32; p = 0.013) in both pre- and post-menopausal women with obesity. In conclusion, the intermediate chronotype was significantly more prevalent in pre-menopausal women with obesity compared to post-menopausal women. Evening chronotype was associated to T2DM in both pre- and post-menopause. These results support the importance of including the assessment of chronotype in the management of women with obesity in post-menopause.


Portable Electronic Tongue Based on Microsensors for the Analysis of Cava Wines.
Cava is a quality sparkling wine produced in Spain. As a product with a designation of origin, Cava wine has to meet certain quality requirements throughout its production process; therefore, the analysis of several parameters is of great interest. In this work, a portable electronic tongue for the analysis of Cava wine is described. The system is comprised of compact and low-power-consumption electronic equipment and an array of microsensors formed by six ion-selective field effect transistors sensitive to pH, Na⁺, K⁺, Ca2+, Cl-, and CO₃2-, one conductivity sensor, one redox potential sensor, and two amperometric gold microelectrodes. This system, combined with chemometric tools, has been applied to the analysis of 78 Cava wine samples. Results demonstrate that the electronic tongue is able to classify the samples according to the aging time, with a percentage of correct prediction between 80% and 96%, by using linear discriminant analysis, as well as to quantify the total acidity, pH, volumetric alcoholic degree, potassium, conductivity, glycerol, and methanol parameters, with mean relative errors between 2.3% and 6.0%, by using partial least squares regressions.


[Primary biliary cholangitis. Part 2. State of the art, diagnosis, associated diseases, treatment and prognosis].
Primary biliary cholangitis (PBC) is a chronic autoimmune cholangiopathy characterized by a selective destruction of biliary epithelial cells of small and medium caliber hepatic ducts, which mainly affects women. The main symptoms are fatigue and pruritus, however, a large proportion of patients may be asymptomatic. The diagnosis is based on AMA titers >1:40, alkaline phosphatase >1.5 times the upper limit for more than 24 weeks and compatible liver histology. It is associated with multiple autoimmune diseases mainly extrahepatic, thyroid diseases, bone diseases, among others. The first line treatment is ursodeoxycholic acid (UDCA), that improves liver function tests and delay the progression to cirrhosis. Currently, there are new treatments and adjuvant therapies on study. The purpose of this review is to offer an update in this topic, which is very important in gastroenterology and internal medicine. We formed an interdisciplinary team to search in the data base Medline thorough PubMed with the keywords describe below, we made a critical lecture of the titles and abstracts of each article to write this paper.


Association between SARS-CoV-2 infection and self-harm: Danish nationwide register-based cohort study.
Case studies have linked SARS-CoV-2 infection to suicidal behaviour. However, conclusive evidence is lacking. To examine whether a history of SARS-CoV-2 infection or SARS-CoV-2-related hospital admission was associated with self-harm in the general population and in high-risk groups. A cohort design was applied to nationwide data on all people aged ≥15 years and living in Denmark between 27 February 2020 and 15 October 2021. Exposure was identified as having had a positive SARS-CoV-2 PCR test, and further assessed as SARS-CoV-2-related hospital admission. Rates of probable self-harm were examined using adjusted incidence rate ratios (aIRRs). The following subgroups were identified: (a) lower educational level, (b) chronic medical conditions, (c) disability pension, (d) mental disorders, (e) substance use disorders, and history of (f) homelessness and (g) imprisonment. Among 4 412 248 included individuals, 260 663 (5.9%) had tested positive for SARS-CoV-2. Out of 5453 individuals presenting with self-harm, 131 (2.4%) had been infected. Individuals with a history of a positive SARS-CoV-2 test result had an aIRR for self-harm of 0.86 (95% CI 0.72-1.03) compared with those without. High rates were found after a SARS-CoV-2-related hospital admission (aIRR = 7.68; 95% CI 5.61-10.51) or a non-SARS-CoV-2-related admission (aIRR = 10.27; 95% CI 9.65-10.93) versus non-infected and not admitted. In sensitivity analyses with a more restrictive definition of self-harm, a positive PCR test was associated with lower rates of self-harm. Individuals with a PCR-confirmed SARS-CoV-2 infection did not have higher rates of self-harm than those without. Hospital admission in general, rather than being SARS-CoV-2 positive. seemed to be linked to elevated rates of self-harm.


Activation of Nrf2/ARE signaling pathway attenuates lanthanum chloride induced injuries in primary rat astrocytes.
Lanthanum (La) exposure can lead to learning and memory disorder in animals; however, the underlying mechanism of La induced neurotoxicity is still unknown. It has been demonstrated that Nrf2 activation by tert-butylhydroquinone (tBHQ) results in neuroprotection against brain injuries. However, little study has been done with respect to its effect on La induced neurotoxicity. Herein, experiments are undertaken to determine if there is a correlation between La damaged astrocytes and the Nrf2/ARE signalling pathway. Primary rat astrocytes are exposed to 0 mmol L-1, 0.125 mmol L-1, 0.25 mmol L-1 and 0.5 mmol L-1 lanthanum chloride (LaCl3) for 24 hours. The results reveal that LaCl3 increases the apoptosis/necrosis rate of astrocytes, decreases the glutathione (GSH) content, increases reactive oxygen species (ROS) levels and significantly down-regulates Nrf2 as well as the mRNA and protein expression of Nrf2-regulated genes, including NADP(H): dehydrogenase quinone 1 (NQO1), hemeoxygenase-1 (HO-1), superoxide dismutase 2 (SOD2), glutathione peroxidase 1 (GSH-Px1), glutathione-s-transferase (GST) and γ-glutamine cysteine synthase (γ-GCS) in astrocytes. In addition, it is found that tBHQ displays an antagonistic effect on astrocytes damaged by LaCl3. Therefore, La damaged astrocytes are possibly related to the down-regulated Nrf2/ARE pathway, and treatment with tBHQ clearly activates the Nrf2/ARE signalling pathway, which exerts protection against oxidative stress.


Prospective mental imagery in patients with major depressive disorder or anxiety disorders.
Prospective negative cognitions are suggested to play an important role in maintaining anxiety disorders and major depressive disorder (MDD). However, little is known about positive prospective mental imagery. This study investigated differences in prospective mental imagery among 27 patients with anxiety disorders, 24 patients with MDD, and 32 control participants. Measures of both deliberately generated and intrusive imagery were completed. Results indicated that both patients with anxiety disorders and those with MDD provided poorer vividness ratings for deliberately generated prospective positive scenarios compared to the control group. Patients with anxiety disorders showed a greater ability to vividly generate imagery for prospective negative scenarios than both patients with MDD and control participants. Finally, both clinical groups reported greater levels of intrusive prospective imagery of personally-relevant events as compared to the control group. The current findings underline the necessity to target prospective positive mental imagery in treating MDD and anxiety disorders.


Gαo is required for L-canavanine detection in Drosophila.
Taste is an essential sense for the survival of most organisms. In insects, taste is particularly important as it allows to detect and avoid ingesting many plant toxins, such as L-canavanine. We previously showed that L-canavanine is toxic for Drosophila melanogaster and that flies are able to detect this toxin in the food. L-canavanine is a ligand of DmXR, a variant G-protein coupled receptor (GPCR) belonging to the metabotropic glutamate receptor subfamily that is expressed in bitter-sensitive taste neurons of Drosophila. To transduce the signal intracellularly, GPCR activate heterotrimeric G proteins constituted of α, β and γ subunits. The aim of this study was to identify which Gα protein was required for L-canavanine detection in Drosophila. By using a pharmacological approach, we first demonstrated that DmXR has the best coupling with Gαo protein subtype. Then, by using genetic, behavioral assays and electrophysiology, we found that Gαo47A is required in bitter-sensitive taste neurons for L-canavanine sensitivity. In conclusion, our study revealed that Gαo47A plays a crucial role in L-canavanine detection.


Version Correction via Eccentric Reaming Compromises Remaining Bone Quality in B2 Glenoids: A Computational Study.
Version correction via eccentric reaming reduces clinically important retroversion in Walch type B2 glenoids (those with substantial glenoid retroversion and a second, sclerotic neoglenoid cavity) before total shoulder arthroplasty (TSA). Clinically, an increased risk of glenoid component loosening in B2 glenoids was hypothesized to be the result of compromised glenoid bone quality attributable to eccentric reaming. However, no established guidelines exist regarding how much version correction can be applied without compromising the quality of glenoid bone. (1) How does version correction correlate to the reaming depth and the volume of resected bone during eccentric reaming of B2 glenoids? (2) How does version correction affect the density of the remaining glenoid bone? (3) How does version correction affect the spatial distribution of high-quality bone in the remaining glenoid? CT scans of 25 patients identified with Walch type B2 glenoids (age, 68 ± 9 years; 14 males, 11 females) were selected from a cohort of 111 patients (age, 69 ± 10 years; 50 males, 61 females) with primary shoulder osteoarthritis who underwent TSA. Virtual TSA with version corrections of 0°, 5°, 10°, and 15° was performed on 25 CT-reconstructed three-dimensional models of B2 scapulae. After simulated eccentric reaming at each version correction angle, bone density (Hounsfield units [HUs]) was analyzed in five adjacent 1-mm layers under the reamed glenoid surface. Remaining high-quality bone (> 650 HUs) distribution in each 1-mm layer at different version corrections was observed on spatial distribution maps. Larger version corrections required more bone resection, especially from the anterior glenoid. Mean bone densities in the first 1-mm bone bed under the reamed surface were lower with 10° (523.3 ± 79.9 HUs) and 15° (479.5 ± 81.0 HUs) version corrections relative to 0° (0°, 609.0 ± 103.9 HUs; mean difference between 0° and 15°, 129.5 HUs [95% CI, 46.3-212.8 HUs], p < 0.001; mean difference between 0° and 10°, 85.7 HUs [95% CI, 8.6-162.9 HUs], p = 0.021) version correction. Similar results were observed for the second 1-mm bone bed. Spatial distribution maps qualitatively showed a decreased frequency of high-quality bone in the anterior glenoid as version correction increased. A version correction as low as 10° was shown to reduce the density of the glenoid bone bed for TSA glenoid fixation in our computational study that simulated reaming on CT-reconstructed B2 glenoid models. Increased version correction resulted in gradual depletion of high-quality bone from the anterior region of B2 glenoids. This computational study of eccentric reaming of the glenoid before TSA quantitatively showed glenoid bone quality is sensitive to version correction via simulated eccentric reaming. The bone density results of our study may benefit surgeons to better plan TSA on B2 glenoids needing durable bone support, and help to clarify goals for development of precision surgical tools.


Morphological features of the ovaries during oogenesis of the Oriental fruit fly, Bactrocera dorsalis, in relation to the physiological state.
Determination of physiological state in insects is useful in furthering the understanding of how insect behavior changes with age. Central to this determination is the identification of characters that allow assessment of physiological age. While non-destructive measures produce the most desired outcomes, internal markers may be more diagnostic and reliable. In this study, key morphological characters during previtellogenesis through vitellogenesis and ovulation were assessed as markers to determine physiological states of the oriental fruit fly, Bactrocera dorsalis (Hendel) (Diptera: Tephritidae). Ovary length and width, ovarian index (length × width), and egg load of laboratory-reared B. dorsalis females recorded daily from eclosion up to 80 days old suggested significant differences in the ovarian index and egg load between females from each oogenesis stage. Parity status determined by the presence of follicular relics was found to provide high-accuracy classifications for B. dorsalis females. The presence of follicular relics with distinct morphological features provides a reliable identification tool to determine the physiological state of wild female oriental fruit fly. The potential applications of this technique to identify the physiological age of female fruit flies to study behavioral attributes in their natural habitat, and also the potential applications in relation to field control, are discussed.


Glass surface evolution following gas adsorption and particle deposition from indoor cooking events as probed by microspectroscopic analysis.
Indoor surfaces are extremely diverse and their interactions with airborne compounds and aerosols influence the lifetime and reactivity of indoor emissions. Direct measurements of the physical and chemical state of these surfaces provide insights into the underlying physical and chemical processes involving surface adsorption, surface partitioning and particle deposition. Window glass, a ubiquitous indoor surface, was placed vertically during indoor activities throughout the House Observations of Microbial and Environmental Chemistry (HOMEChem) campaign and then analyzed to measure changes in surface morphology and surface composition. Atomic force microscopy-infrared (AFM-IR) spectroscopic analyses reveal that deposition of submicron particles from cooking events is a contributor to modifying the chemical and physical state of glass surfaces. These results demonstrate that the deposition of glass surfaces can be an important sink for organic rich particles material indoors. These findings also show that particle deposition contributes enough organic matter from a single day of exposure equivalent to a uniform film up to two nanometers in thickness, and that the chemical distinctness of different indoor activities is reflective of the chemical and morphological changes seen in these indoor surfaces. Comparison of the experimental results to physical deposition models shows variable agreement, suggesting that processes not captured in physical deposition models may play a role in the sticking of particles on indoor surfaces.


Tanshinone IIA Inhibits VEGF Secretion and HIF-1α Expression in Cultured Human Retinal Pigment Epithelial Cells under Hypoxia.
The current work intends to study the activity of tanshinone IIA on secretion of vascular endothelial growth factor (VEGF) and expression of hypoxia inducible factor 1α (HIF-1α) in human retinal pigment epithelial cells (ARPE-19 cells) under hypoxic condition. The cytotoxicity of tanshinone IIA was tested in ARPE-19 cells by MTT assay. ARPE-19 cells were incubated with different concentrations of cobalt chloride (100, 150, and 200 µM) for 12 h, and levels of expressed HIF-1α and secreted VEGF were quantified through Western blot and ELISA, respectively. Further, ARPE-19 cells were pretreated for 1 h with different concentrations of tanshinone IIA (5, 10, 15, and 18 µM). After 1 h, the cells were subjected to hypoxic condition using 150 µM cobalt chloride for 12 h in the presence and absence of tanshinone IIA. The cells were then harvested, and the secreted VEGF and expressed HIF-1α was studied. Tanshinone IIA at concentrations of 5, 10, 15, and 18 μM did not show cytotoxicity in ARPE-19 cells. Chemical hypoxia induced by cobalt chloride caused a significant increase in VEGF level in a dose-dependent manner, and HIF-1α expression peaked at 150 µM. Based on the data, cobalt chloride concentration was maintained at 150 μM for further studies. Tanshinone IIA decreased the level of HIF-1α and VEGF secretion in a dose-dependent manner under hypoxic condition. Tanshinone IIA could be explored as a new potential candidate for treating wet AMD.


Optimizing the Distribution of Leg Muscles for Vertical Jumping.
A goal of biomechanics and motor control is to understand the design of the human musculoskeletal system. Here we investigated human functional morphology by making predictions about the muscle volume distribution that is optimal for a specific motor task. We examined a well-studied and relatively simple human movement, vertical jumping. We investigated how high a human could jump if muscle volume were optimized for jumping, and determined how the optimal parameters improve performance. We used a four-link inverted pendulum model of human vertical jumping actuated by Hill-type muscles, that well-approximates skilled human performance. We optimized muscle volume by allowing the cross-sectional area and muscle fiber optimum length to be changed for each muscle, while maintaining constant total muscle volume. We observed, perhaps surprisingly, that the reference model, based on human anthropometric data, is relatively good for vertical jumping; it achieves 90% of the jump height predicted by a model with muscles designed specifically for jumping. Alteration of cross-sectional areas-which determine the maximum force deliverable by the muscles-constitutes the majority of improvement to jump height. The optimal distribution results in large vastus, gastrocnemius and hamstrings muscles that deliver more work, while producing a kinematic pattern essentially identical to the reference model. Work output is increased by removing muscle from rectus femoris, which cannot do work on the skeleton given its moment arm at the hip and the joint excursions during push-off. The gluteus composes a disproportionate amount of muscle volume and jump height is improved by moving it to other muscles. This approach represents a way to test hypotheses about optimal human functional morphology. Future studies may extend this approach to address other morphological questions in ethological tasks such as locomotion, and feature other sets of parameters such as properties of the skeletal segments.


The Role of Kv1.2 Channel in Electrotaxis Cell Migration.
Voltage-gated potassium Kv1.2 channels play pivotal role in maintaining of resting membrane potential and, consequently, regulation of cellular excitability of neurons. Endogenously generated electric field (EF) have been proven as an important regulator for cell migration and tissue repair. The mechanisms of ion channel involvement in EF-induced cell responses are extensively studied but largely are poorly understood. In this study we generated three COS-7 clones with different expression levels of Kv1.2 channel, and confirmed their functional variations with patch clamp analysis. Time-lapse imaging analysis showed that EF-induced cell migration response was Kv1.2 channel expression level depended. Inhibition of Kv1.2 channels with charybdotoxin (ChTX) constrained the sensitivity of COS-7 cells to EF stimulation more than their motility. Immunocytochemistry and pull-down analyses demonstrated association of Kv1.2 channels with actin-binding protein cortactin and its re-localization to the cathode-facing membrane at EF stimulation, which confirms the mechanism of EF-induced directional migration. This study displays that Kv1.2 channels represent an important physiological link in EF-induced cell migration. The described mechanism suggests a potential application of EF which may improve therapeutic performance in curing injuries of neuronal and/or cardiac tissue repair, post operational therapy, and various degenerative syndromes.


Transcriptomic profiling of proteases and antiproteases in the liver of sexually mature hens in relation to vitellogenesis.
Most egg yolk precursors are synthesized by the liver, secreted into the blood and transferred into oocytes, to provide nutrients and bioactive molecules for the avian embryo. Three hundred and sixteen distinct proteins have been identified in egg yolk. These include 37 proteases and antiproteases, which are likely to play a role in the formation of the yolk (vitellogenesis), as regulators of protein metabolism. We used a transcriptomic approach to define the protease and antiprotease genes specifically expressed in the hen liver in relation to vitellogenesis by comparing sexually mature and pre-laying chickens showing different steroid milieu. Using a 20 K chicken oligoarray, a total of 582 genes were shown to be over-expressed in the liver of sexually mature hens (1.2 to 67 fold-differences). Eight of the top ten over-expressed genes are known components of the egg yolk or perivitelline membrane. This list of 582 genes contains 12 proteases and 3 antiproteases. We found that "uncharacterized protein LOC419301/similar to porin" (GeneID:419301), an antiprotease and "cathepsin E-A-like/similar to nothepsin" (GeneID:417848), a protease, were the only over-expressed candidates (21-fold and 35-fold difference, respectively) that are present in the egg yolk. Additionally, we showed the 4-fold over-expression of "ovochymase-2/similar to oviductin" (GeneID:769290), a vitelline membrane-specific protease. Our approach revealed that three proteases and antiproteases are likely to participate in the formation of the yolk. The role of the other 12 proteases and antiproteases which are over-expressed in our model remains unclear. At least 1/3 of proteases and antiproteases identified in egg yolk and vitelline membrane proteomes are expressed similarly in the liver regardless of the maturity of hens, and have been initially identified as regulators of haemostasis and inflammatory events. The lack of effect of sex steroids on these genes expressed in the liver but the products of which are found in the yolk suggests that these may be passively incorporated into the yolk rather than actively produced for that purpose. These results raise the question of the biological significance of egg yolk proteases and antiproteases, and more generally of all minor proteins that have been identified in egg yolk.


Large-Scale Gradients in Human Cortical Organization.
Recent advances in mapping cortical areas in the human brain provide a basis for investigating the significance of their spatial arrangement. Here we describe a dominant gradient in cortical features that spans between sensorimotor and transmodal areas. We propose that this gradient constitutes a core organizing axis of the human cerebral cortex, and describe an intrinsic coordinate system on its basis. Studying the cortex with respect to these intrinsic dimensions can inform our understanding of how the spectrum of cortical function emerges from structural constraints.


Child care centre adherence to infant physical activity and screen time recommendations in Australia, Canada and the United States: An observational study.
The aim of this study was to compare adherence to physical activity and sedentary behaviour recommendations within the 2011 Institute of Medicine Early Childhood Obesity Prevention Policies as well as screen time recommendations from the 2013 American Academy of Pediatrics for samples of infants in child care centres in Australia, Canada, and the United States (US). This cross-sectional study used data from: the Australian 2013 Standing Preschools (N=9) and the 2014-2017 Early Start Baseline (N=22) studies; the 2011 Canadian Healthy Living Habits in Pre-School Children study (N=14); and the American 2008 (N=31) and 2013-2017 (N=31) Baby Nutrition and Physical Activity Self-Assessment for Child Care (NAP SACC) trials. Data were compared on the above infant recommendations. Percentages were used to describe compliance to the recommendations and chi-square tests to determine whether compliance differed by country. Child care centres were most compliant (74%-95%) with recommendations to: provide daily indoor opportunities for infants to move freely under adult supervision, daily tummy time for infants less than 6 months of age, indoor and outdoor recreation areas that encourage infants to be physically active, and discourage screen time. Centres were least compliant (38%-41%) with adhering to recommendations to: limit the use of equipment that restricts an infant's movement and provide education about physical activity to families. Compared with Canadian and US centres, Australian centres were less compliant (46%) with the recommendation to engage with infants on the ground each day, to optimize adult-infant interactions and to limit the use of equipment that restricts the infant's movement. Canadian centres were less compliant (39%) with the recommendation to provide training to staff and education to parents about children's physical activity. US centres were less compliant (25%-41%) with the recommendations to provide daily opportunities for infants to explore their outdoor environment, limit the use of equipment that restricts the infant's movement and provide education to families about children's physical activity. Assisting child care centres on limiting the use of equipment that restricts an infant's movement, and providing education about children's physical activity to families may be important targets for future interventions.


Hand preferences for coordinated bimanual actions in 777 great apes: implications for the evolution of handedness in hominins.
Whether or not nonhuman primates exhibit population-level handedness remains a topic of considerable scientific debate. Here, we examined handedness for coordinated bimanual actions in a sample of 777 great apes including chimpanzees, bonobos, gorillas, and orangutans. We found population-level right-handedness in chimpanzees, bonobos and gorillas, but left-handedness in orangutans. Directional biases in handedness were consistent across independent samples of apes within each genus. We suggest that, contrary to previous claims, population-level handedness is evident in great apes but differs among species as a result of ecological adaptations associated with posture and locomotion. We further suggest that historical views of nonhuman primate handedness have been too anthropocentric, and we advocate for a larger evolutionary framework for the consideration of handedness and other aspects of hemispheric specialization among primates.


UKCP: a collaborative network of cerebral palsy registers in the United Kingdom.
Cerebral palsy (CP) is a relatively rare condition with enormous social and financial impact. Information about CP is not routinely collected in the United Kingdom. We have pooled non-identifiable data from the five currently active UK CP registers to form the UKCP database: birth years 1960-1997. This article describes the rationale behind this collaboration and the creation of the database. Data about 6910 children with CP are currently held. The mean annual prevalence rate was 2.1 [corrected] per 1000 live births for birth years 1986-1996. Where type is known, 91 per cent have spastic CP. Where data are available, nearly one-third of children have severely impaired lower limb function, and nearly a quarter have severely impaired upper limb function. As well as describing the range and complexity of motor and associated impairments, the pooled data from the UKCP database provide a platform for studies of aetiology, long-term outcomes, participation and service needs. The UKCP database is an important national resource for the surveillance of CP and the study of its epidemiology in the United Kingdom.