Ex vivo expanded hematopoietic progenitor cells improve cardiac function after myocardial infarction: role of beta-catenin transduction and cell dose.
Cell-based therapy after myocardial infarction (MI) is a promising therapeutic option but the relevant cell subsets and dosage requirements are poorly defined. We hypothesized that cell therapy for myocardial infarction is improved by ex vivo expansion and high-dose transplantation of defined hematopoietic progenitor cells (HPCs). Since beta-catenin promotes self-renewal of stem cells we evaluated the therapeutic efficacy of beta-catenin-mediated ex vivo expansion of mouse HPCs in a mouse model of myocardial ischemia/reperfusion followed by intraarterial cell delivery. The impact of cell dose was determined by comparing a low-dose (LD, 5 x 10(5) cells) vs. a high-dose (HD, 1 x 10(7) cells) cell transplantation regimen of beta-catenin-HPCs. The impact of beta-catenin modification of HPCs was determined by comparing control-transduced HPCs (GFP-HPCs) vs. transgenic beta-catenin-HPCs. HD beta-catenin-HPCs significantly improved LV function and end-systolic and end-diastolic dimensions as compared to saline and LD beta-catenin-HPCs. Furthermore, while treatment with HD GFP-HPC resulted in a modest cardiac improvement the application of beta-catenin-HPCs was superior, resulting in a significant improvement in EF, FS and LVESD over saline and control GFP-HPC treatment. Although myocardial engraftment of HPCs was only transient, as determined by cell quantification after dye labeling, beta-catenin-HPC treatment significantly decreased infarct size, reduced cardiomyocyte apoptosis and increased capillary angiogenesis in vitro and in vivo. Ex vivo expanded HPCs improve cardiac function and remodeling post MI in a cell number- and beta-catenin-dependent manner.


Learning Based Segmentation of CT Brain Images: Application to Postoperative Hydrocephalic Scans.
Hydrocephalus is a medical condition in which there is an abnormal accumulation of cerebrospinal fluid (CSF) in the brain. Segmentation of brain imagery into brain tissue and CSF [before and after surgery, i.e., preoperative (pre-op) versus postoperative (post-op)] plays a crucial role in evaluating surgical treatment. Segmentation of pre-op images is often a relatively straightforward problem and has been well researched. However, segmenting post-op computational tomographic (CT) scans becomes more challenging due to distorted anatomy and subdural hematoma collections pressing on the brain. Most intensity- and feature-based segmentation methods fail to separate subdurals from brain and CSF as subdural geometry varies greatly across different patients and their intensity varies with time. We combat this problem by a learning approach that treats segmentation as supervised classification at the pixel level, i.e., a training set of CT scans with labeled pixel identities is employed. Our contributions include: 1) a dictionary learning framework that learns class (segment) specific dictionaries that can efficiently represent test samples from the same class while poorly represent corresponding samples from other classes; 2) quantification of associated computation and memory footprint; and 3) a customized training and test procedure for segmenting post-op hydrocephalic CT images. Experiments performed on infant CT brain images acquired from the CURE Children's Hospital of Uganda reveal the success of our method against the state-of-the-art alternatives. We also demonstrate that the proposed algorithm is computationally less burdensome and exhibits a graceful degradation against a number of training samples, enhancing its deployment potential.


A novel murine model of reversible bile duct obstruction demonstrates rapid improvement of cholestatic liver injury.
There are limited murine models of cholestatic liver diseases characterized by chronic biliary obstruction and resumption of bile flow. While murine bile duct ligation (BDL) is a well-established model of obstructive cholestasis, current models of BDL reversal (BDLR) alter biliary anatomy. We aimed to develop a more physiologic model of BDLR to evaluate the time course and mechanism for resolution of hepatic injury after biliary obstruction. In the present study, we restored bile flow into the duodenum without disruption of the gall bladder after murine BDL using biocompatible PE-50 tubing. After establishing the technique, overall survival for BDLR at 7 or 14 days after BDL was 88%. Sham laparotomy was performed in control mice. Laboratory data, liver histology, and hepatic gene expression were compared among BDL, BDLR, and controls. Laboratory evidence of cholestatic liver injury was observed at day 7 after BDL and rapid improvement occurred within 48 hr of BDLR. After BDLR there was also enhanced gene expression for the bile acid transporter Abcb11, however, bile duct proliferation persisted. Assessment of the immune response showed increased gene and protein expression for the general immune cell marker Cd45 in BDLR versus BDL mice suggesting a reparative immune response after BDLR. In summary, we have established a novel murine model of BDLR that allows for the investigation into bile acid and immune pathways responsible for hepatic repair following obstructive cholestasis. Future studies with our model may identify targets for new therapies to improve outcome in pediatric and adult cholestatic liver disease.


Self-reported efficacy of neurofeedback treatment in a clinical randomized controlled study of ADHD children and adolescents.
Many non-pharmacological treatments for children and adolescents with attention-deficit/hyperactivity disorder (ADHD) have been attempted, but reports indicate that most are ineffective. Although neurofeedback (NF) is a treatment approach for children with ADHD that remains promising, a variety of appropriate measures have been used in reporting and evaluating its effect. To report the self-evaluations of NF treatment by children and adolescents with ADHD. Randomized controlled trial in 91 children and adolescents with ADHD, aged less than 18 years (mean, 11.2 years) participated in a 30-session program of intensive NF treatment. Participants were randomized and allocated by sequentially numbered sealed envelopes into three groups: methylphenidate (MPH) as an active control group, and two trial groups NF with MPH, and NF alone. ADHD core symptoms and school performance were given on a scale of 1 to 10 using a self-reporting questionnaire, and the changes in these scores after treatment were used as the self-reported evaluation. Basic statistical methods (descriptive, analyses of variance, exact χ (2) test, and paired t-test) were used to investigate the baseline data. Changes in ADHD core symptoms and treatment effects were investigated using a general linear model for repeated measures. Eighty participants completed the treatment study and 73 (91%) responded sufficiently on the self-reporting questionnaires. The treatment groups were comparable in age, sex, and cognition as well as in the baseline levels of core ADHD symptoms. All treatments resulted in significant improvements regarding attention and hyperactivity (P<0.001), and did not differ from each other in effectiveness. However, a significant treatment effect in school performance was observed (P=0.042), in which only the NF group showed a significant improvement. The self-reported improvements in ADHD core symptoms and school performance shortly after treatment indicate NF treatment being promising in comparison with medication, suggesting NF as an alternative treatment for children and adolescents who do not respond to MPH, or who suffer side effects. Further long-term follow-up is needed.


When is general wariness favored in avoiding multiple predator types?
Adaptive responses to predation are generally studied assuming only one predator type exists, but most prey species are depredated by multiple types. When multiple types occur, the optimal antipredator response level may be determined solely by the probability of attack by the relevant predator: "specific responsiveness." Conversely, an increase in the probability of attack by one predator type might increase responsiveness to an alternative predator type: "general wariness." We formulate a mathematical model in which a prey animal perceives a cue providing information on the probability of two predator types being present. It can perform one of two evasive behaviors that vary in their suitability as a response to the "wrong" predator type. We show that general wariness is optimal when incorrect behavioral decisions have differential fitness costs. Counterintuitively, difficulty in discriminating between predator types does not favor general wariness. We predict that where responses to predator types are mutually exclusive (e.g., referential alarm-calling), specific responsiveness will occur; we suggest that prey generalize their defensive responses based on cue similarity due to an assumption of response utility; and we predict, with relevance to conservation, that habituation to human disturbance should generalize only to predators that elicit the same antipredator response as humans.


Studying the effect of adding growth factors to the autologous melanocyte keratinocyte suspension in segmental vitiligo.
Addition of different growth factors to the medium used in autologous melanocyte-keratinocyte transplantation procedure (MKTP) was reported in the literature. The aim of the current study was comparison of response to MKTP in segmental vitiligo (SV) with and without adding growth factors to the suspension medium. Eighteen cases with SV were randomly divided into two groups. In group A: Ham F12 medium was used for suspension and in group B: 5 ng/mL recombinant basic fibroblast growth factor (bFGF) and 25 mg/500 mL 3'5' cyclic adenosine monophosphate (cAMP) were added to the medium. All cases received NB-UVB twice weekly for 24 weeks. The area of vitiligo lesions was measured before and after therapy by point-counting technique and complications were recorded. Excellent response (90%-100% repigmentation) occurred in 5/9 cases (56%) in group A and 7/9 cases (78%) in group B (with growth factors). A significant decrease in the area of treated lesions before and after therapy was found in both groups A and B (P = .0012 and .0004, respectively), however, a higher percentage of reduction in area of vitiligo was seen in group B cases (70% in group A vs 90% in group B; P value: .028). Marginal halo was seen in five cases in group A and six in group B. In conclusion addition of bFGF and cAMP to MKTP medium improved the results of the procedure. It could be considered if economically feasible.


Anatomic suitability of ruptured abdominal aortic aneurysms for endovascular repair.
Mortality from ruptured abdominal aortic aneurysms (rAAAs) remains high despite improvements in anesthesia, postoperative intensive care, and surgical techniques. Recent small series and single-center experiences suggest that endovascular aneurysm repair (EVAR) for rAAAs is feasible and may improve short-term survival. However, the applicability of EVAR to all cases of rAAA is unknown. The purpose of this study was to investigate the anatomical suitability of ruptured aneurysms for EVAR as determined by preoperative cross-sectional imaging. A contemporary consecutive series of rAAAs presenting to a tertiary academic center was retrospectively reviewed. Preoperative radiographic imaging was reviewed and assessed for endovascular compatibility based on currently available EVAR devices. Patients with aneurysm morphology demonstrating neck diameter >32 mm, neck length <10 mm, neck angulation >60 degrees, severe iliac tortuosity, or external iliac diameter <6 mm were deemed noncandidates for EVAR. Forty-seven rAAAs were treated over a 10-year period, with 47% of patients presenting with free rupture and 60% of patients transferred from outside hospitals. Five (11%) patients were treated with EVAR, all over the past 2 years, while the remaining 42 patients underwent open repair. Preoperative imaging was available for review in 43 (91%) patients, and morphological measurements indicated that 49% would have been candidates for EVAR with currently available devices. Criteria precluding EVAR in this cohort were inadequate neck length in 73%, unsuitable iliac access in 23%, large neck diameter in 18%, and severe neck angulation in 14%. Overall 30-day mortality was 34%, and 1-year mortality was 42%. Candidates for EVAR were more likely than non-EVAR candidates to be male (95% vs. 68%, p = 0.046) and to have smaller sac diameters (7.0 vs. 8.5 cm, p = 0.02) and longer neck lengths (24.1 vs. 8.6 mm, p < 0.0001); less likely to have a >60 degree angulated neck (10% vs. 45%, p = 0.0002), larger external iliac diameter (8.9 vs. 7.3 mm, p = 0.015), and less blood loss during surgical repair (2.4 vs. 6.0 L, p = 0.02); and more likely to be discharged home (71% vs. 25%, p = 0.05). There were no differences in 30-day, 1-year, or overall mortality between candidates for EVAR and noncandidates. Only 49% of patients with rAAAs in this consecutive series were found to be candidates for EVAR with conventional stent-graft devices. Differences in demographics, aneurysm morphology, and outcomes between candidates and noncandidates undergoing open repair suggest that differential risks apply to ruptured aneurysm patients. Protocols and future reports of EVAR for rAAAs should be tailored to these results. Device and technique modifications are necessary to increase the applicability of EVAR for rAAAs.


The mechanism of the translocation step in DNA replication by DNA polymerase I: a computer simulation analysis.
High-fidelity DNA polymerases copy DNA rapidly and accurately by adding correct deoxynucleotide triphosphates to a growing primer strand of DNA. Following nucleotide incorporation, a series of conformational changes translocate the DNA substrate by one base pair step, readying the polymerase for the next round of incorporation. Molecular dynamics simulations indicate that the translocation consists globally of a polymerase fingers-opening transition, followed by the DNA displacement and the insertion of the template base into the preinsertion site. They also show that the pyrophosphate release facilitates the opening transition and that the universally conserved Y714 plays a key role in coupling polymerase opening to DNA translocation. The transition involves several metastable intermediates in one of which the O helix is bent in the vicinity of G711. Completion of the translocation appears to require a gating motion of the O1 helix, perhaps facilitated by the presence of G715. These roles are consistent with the high level of conservation of Y714 and the two glycine residues at these positions. It is likely that a corresponding mechanism is applicable to other polymerases.


Linear and nonlinear spatial subunits in Y cat retinal ganglion cells.
1. The mechanism which makes Y cells different from X cells was investigated. 2. Spatial frequency contrast sensitivity functions for the fundamental and second harmonic responses of Y cells to alternating phase gratings were determined. 3. The fundamental spatial frequency response was predicted by the Fourier transform of the sensitivity profile of the Y cell. The high spatial frequency cut-off of a Y cell's fundamental response was in this way related to the centre of the cell's receptive field. 4. The second harmonic response of a Y cell did not cut off at such a low spatial frequency as the fundamental response. This result indicated that the source of the second harmonic was a spatial subunit of the receptive field smaller in spatial extent than the centre. 5. Contrast sensitivity vs. spatial phase for a Y cell was measured under three conditions: a full grating, a grating seen through a centrally located window, a grating partially obscured by a visual shutter. The 2nd/1st harmonic sensitivity ratio went down with the window and up with the shutter. These results implied that the centre of Y cells was linear and also that the nonlinear subunits extended into the receptive field surround. 6. Spatial localization of the nonlinear subunits was determined by means of a spatial dipole stimulus. The nonlinear subunits overlapped the centre and surround of the receptive field and extended beyond both. 7. The nature of the Y cell nonlinearity was found to be rectification, as determined from measurements of the second harmonic response as a function of contrast. 8. Spatial models for the Y cell receptive field are proposed.


Is climate change a threat for water uses in the Mediterranean region? Results from a survey at local scale.
Water scarcity and water security are linked, not only through the direct effects of water shortages on each water users' access to water, but also because of water conflicts generated. Climate change is predicted to raise temperatures in the Mediterranean region and reduce rainfall, leading to a reduction in water yield and possibly worsening the situation of water resource shortages that Mediterranean regions are already experiencing. In its dissemination strategy, the EU FP7 CLIMB project addressed water security threats through an analysis of water uses and water use rivalries within a few target catchments distributed over the Mediterranean region. The present work explores whether climate change is locally perceived by stakeholders (water users and managers) as a key issue for their water uses and water security. Individual interviews, meetings, and compilation of questionnaires were conducted at five sites located in the Mediterranean region. The methodology permitted an analysis of water use and its evolution in the water management context, an identification of the state of awareness of local stakeholders and of the pressures on water use and water use rivalries, and a prioritization of water uses. Currently, the main response to increasing water demand in the Mediterranean region, while not yet considering climate change as a driving force, is a progressive externalization of water resources, with limits represented by national borders and technological possibilities. Overall, 'climate change' was not mentioned by stakeholders during both interviews and in answers to the questionnaires. Even the prospect of decreasing precipitation was not considered a relevant or threatening issue in the coming 20years. This confirms the need to continue all efforts to disseminate the state of knowledge on climate change impacts in the Mediterranean region, such as water scarcity, especially to local water managers, as initiated by various research programs of the European Commission.


Effects of visual and auditory stimuli on median nerve somatosensory evoked potentials in man.
To demonstrate electrophysiological evidence of neural connections of somatosensory with visual and auditory pathways, interactions of median nerve somatosensory evoked potentials (SEPs) with visual evoked potentials (VEPs) and auditory evoked potentials (AEPs) were analyzed in 12 healthy subjects. In Experiment I (SEP vs. VEP), three patterns of stimulation, namely, electric stimulation of left median nerve, binocular LED flash, and simultaneous electric and flash stimulation, were applied with random interstimulus intervals of 2-4 sec until more than 100 responses had been obtained and averaged for each pattern of stimulation. Simultaneous electric and visual responses were subtracted from arithmetical sums of SEPs and VEPs to show interactions between somatosensory and visual responses. In Experiment II (SEP vs. AEP), binaural short-duration tone bursis instead of LED flashes were used in the same manner as in Experiment I, and interactions between somatosensory and auditory responses were analyzed. Results indicated that the effects of both visual and auditory interaction on SEPs were significant around 120-130 msec of latency. In other words, cross-modal sensory interaction occurred in the late phase of sensory processing.


Myosin IB from Entamoeba histolytica is involved in phagocytosis of human erythrocytes.
Entamoeba histolytica is a protozoan parasite that causes amoebic dysentery in humans. The disease is prevalent worldwide. Infection with E. histolytica results in invasion of the intestine by the parasite, followed by tissue damage and inflammation. During this invasive process, parasites kill and phagocytose human epithelial cells, immune cells and erythrocytes. Expression of amoebic pathogenicity requires a dynamic cytoskeleton that allows movement, tissue penetration and changes in parasite morphology. Myosin IB is a member of the myosin I family of motor proteins. Studies conducted both with Dictyostelium discoideum, a non-pathogenic amoeba, and with the yeast Saccharomyces cerevisiae indicate the involvement of myosin IB in cellular processes including movement, phagocytosis and endocytosis. Recently, we isolated the gene encoding myosin IB from E. histolytica. Thus, we decided to analyze the role of myosin IB in pathogenesis of amoeba. Using a specific anti-myosin IB antibody, this protein was localized in cell regions including the pseudopod, vesicles and underneath the plasma membrane. When E. histolytica was activated for erythrophagocytosis, myosin IB was markedly recruited to both the phagocytic cup and around internalized phagosomes. To analyze the role of myosin IB in phagocytosis, a strain overexpressing the myosin IB gene was constructed. This strain synthesizes threefold more myosin IB than the wild-type strain. Challenge of the transfected cell line with erythrocytes showed that these amoebae were deficient in erythrophagocytosis mainly in the uptake step, suggesting a role for myosin IB in the pathogenic activity of a human parasite.


Engaging Fathers in Effective Parenting for Preschool Children Using Shared Book Reading: A Randomized Controlled Trial.
Engaging fathers and improving their parenting and, in turn, outcomes for their children in preventive/promotion-focused parenting interventions has been a notable, but understudied, challenge in the field. This study evaluated the effects of a novel intervention, Fathers Supporting Success in Preschoolers: A Community Parent Education Program, which focuses on integrating behavioral parent training with shared book reading (i.e., Dialogic Reading) using key conceptual models (i.e., common elements, deployment model, task shifting) to engage and improve father (i.e., male guardians) and child outcomes. One hundred twenty-six low-income, Spanish-speaking fathers and their children were recruited across three Head Start centers in urban communities and were randomized to the intervention or to a waitlist control condition. Outcomes were obtained before and immediately postintervention and included observed and father-reported parenting and child behaviors, standardized assessments of language, and father self-reported parental stress and depressive symptoms. Attendance data were also collected as a proxy measure of engagement to the intervention. Parenting behaviors (observed and father-reported), child behaviors (father-reported), and language development of the children in the intervention group improved significantly relative to those in the waitlist control condition. Effect sizes (ESs) were in the small to large range across outcomes. Fathers can be engaged in parenting interventions, resulting in improved parent and child outcomes. Greater attention must be given to methods for maximizing parenting within a family and toward developing effective, engaging, and sustainable intervention models for fathers.


Iterative phase retrieval for digital holography: tutorial.
This paper provides a tutorial of iterative phase retrieval algorithms based on the Gerchberg-Saxton (GS) algorithm applied in digital holography. In addition, a novel GS-based algorithm that allows reconstruction of 3D samples is demonstrated. The GS-based algorithms recover a complex-valued wavefront using wavefront back-and-forth propagation between two planes with constraints superimposed in these two planes. Iterative phase retrieval allows quantitatively correct and twin-image-free reconstructions of object amplitude and phase distributions from its in-line hologram. The present work derives the quantitative criteria on how many holograms are required to reconstruct a complex-valued object distribution, be it a 2D or 3D sample. It is shown that for a sample that can be approximated as a 2D sample, a single-shot in-line hologram is sufficient to reconstruct the absorption and phase distributions of the sample. Previously, the GS-based algorithms have been successfully employed to reconstruct samples that are limited to a 2D plane. However, realistic physical objects always have some finite thickness and therefore are 3D rather than 2D objects. This study demonstrates that 3D samples, including 3D phase objects, can be reconstructed from two or more holograms. It is shown that in principle, two holograms are sufficient to recover the entire wavefront diffracted by a 3D sample distribution. In this method, the reconstruction is performed by applying iterative phase retrieval between the planes where intensity was measured. The recovered complex-valued wavefront is then propagated back to the sample planes, thus reconstructing the 3D distribution of the sample. This method can be applied for 3D samples such as 3D distribution of particles, thick biological samples, and other 3D phase objects. Examples of reconstructions of 3D objects, including phase objects, are provided. Resolution enhancement obtained by iterative extrapolation of holograms is also discussed.


Maturation of Esophageal Motility and Esophagogastric Junction in Preterm Infants.
Preterm infants commonly present with oral feeding problems. The role of maturation of esophageal bolus transport mechanisms herein remains unclear. To characterize esophageal motility and function of esophagogastric junction (EGJ) during deglutitive swallowing in healthy preterm infants and to describe maturational changes. Four consecutive high-resolution manometry studies with impedance studies were performed weekly to investigate esophageal motility and EGJ function. Esophageal pressure topography and pressure-impedance metrics were derived. Mixed models with repeated measures were used for statistical analysis. We analyzed 137 nutritive swallows from 36 motility studies in 10 preterm infants. The mean gestational age was 30.17 ± 0.94 weeks; the mean postmenstrual age at time point 1 and 4 was 34.42 ± 0.86 and 37.45 ± 1.16 weeks, respectively. Esophageal peristaltic wave patterns in response to nutritive swallows were observed in all patients. At later time points, esophageal body peristalsis became more rapid, evidenced by a faster distal contractile velocity and shorter distal latency (p = 0.002 and p < 0.0001, respectively). In addition, 4-s integrated relaxation pressures increased and distal contractile integral decreased at later time points (p = 0.003 and p = 0.021, respectively). Bolus clearance also improved at later age (p = 0.008). Preterm infants demonstrate peristaltic esophageal motility following nutritive swallows. However, alterations in esophageal bolus transport in relation to peristalsis are demonstrated. Peristaltic progression becomes more rapid, while deglutitive relaxation pressures increase with increasing age. These maturational changes may suggest further development of the enteric nervous system after birth in former preterm neonates.


Ranking of Production Animal Welfare and Ethics Issues in Australia and New Zealand by Veterinary Students.
The importance of animal welfare and ethics (AWE) within the veterinary education should reflect community concerns and expectations about AWE, and the professional demands of veterinary accreditation on the first day of practice (or 'Day One' competences). Currently, much interest and debate surrounds the treatment of production animals, particularly around live export. To explore the attitudes to AWE of veterinary students in Australia and New Zealand, a survey was undertaken to (i) understand what students consider important AWE topics for initial production animal competence; and (ii) ascertain how these priorities correlated with gender, area of intended practice and stage-of-study. The results from 575 veterinary students showed that all students ranked strategies to address painful husbandry procedures as the most important issues on their first day in production animal practice. Additionally, it was found that the importance students assigned to an understanding of human⁻animal interactions declined as they progressed through the veterinary course. In contrast, the importance of an understanding of euthanasia issues for production animals increased for male students as they progressed through the course, and remained consistently high in females. Females also gave higher ranking to the importance of understanding production animal stress associated with transport, and ranked strategies to address painful husbandry procedures more important than did males. These findings should help the development of AWE teaching resources that address students' attitudes and competence and that can be delivered when students are most receptive.


Dietary Choices and Habits during COVID-19 Lockdown: Experience from Poland.
The outbreak of coronavirus disease (COVID-19) in late December 2019 in China, which later developed into a pandemic, has forced different countries to implement strict sanitary regimes and social distancing measures. Globally, at least four billion people were under lockdown, working remotely, homeschooling children, and facing challenges coping with quarantine and the stressful events. The present cross-sectional online survey of adult Poles (n = 1097), conducted during a nationwide quarantine, aimed to assess whether nutritional and consumer habits have been affected under these conditions. Over 43.0% and nearly 52% reported eating and snacking more, respectively, and these tendencies were more frequent in overweight and obese individuals. Almost 30% and over 18% experienced weight gain (mean ± SD 3.0 ± 1.6 kg) and loss (-2.9 ± 1.5 kg), respectively. Overweight, obese, and older subjects (aged 36-45 and >45) tended to gain weight more frequently, whereas those with underweight tended to lose it further. Increased BMI was associated with less frequent consumption of vegetables, fruit, and legumes during quarantine, and higher adherence to meat, dairy, and fast-foods. An increase in alcohol consumption was seen in 14.6%, with a higher tendency to drink more found among alcohol addicts. Over 45% of smokers experienced a rise in smoking frequency during the quarantine. The study highlights that lockdown imposed to contain an infectious agent may affect eating behaviors and dietary habits, and advocates for organized nutritional support during future epidemic-related quarantines, particularly for the most vulnerable groups, including overweight and obese subjects.


The Gut Microbiome of Adults with Allergic Rhinitis Is Characterised by Reduced Diversity and an Altered Abundance of Key Microbial Taxa Compared to Controls.
Unique gut microbial colonisation patterns are associated with the onset of allergic disease in infants; however, there is insufficient evidence to determine if aberrant microbial composition patterns persist in adult allergic rhinitis (AR) sufferers. To compare the gut microbiome composition between adult AR sufferers and controls. Gut microbial composition in stool samples was compared between 57 adult AR sufferers (39.06 ± 13.29 years) and 23 controls (CG; 36.55 ± 10.51 years) via next-generation sequencing of the V3-V4 hypervariable regions of the 16S rRNA gene. Taxonomic classification and identity assignment was performed using a reference-based approach with the NCBI database of 16S rRNA gene sequences. Species richness determined via the Shannon index was significantly reduced in the AR cohort compared to the CG (4.35 ± 0.59 in AR vs. 4.65 ± 0.55 in CG, p = 0.037); trends for reductions in operational taxonomic unit (OTU) counts, inverse Simpson, and CHAO1 diversity indices were also noted. Bacteroidetes (p = 0.014) was significantly more abundant in the AR group than in the CG. In contrast, the Firmicutes phylum was significantly less abundant in the AR group than in the CG (p = 0.006). An increased abundance of Parabacteroides (p = 0.008) and a reduced abundance of Oxalobacter (p = 0.001) and Clostridiales (p = 0.005) were also observed in the AR cohort compared to the CG. Adult AR sufferers have a distinct gut microbiome profile, marked by a reduced microbial diversity and altered abundance of certain microbes compared to controls. The results of this study provide evidence that unique gut microbial patterns occur in AR sufferers in adulthood and warrant further examination in the form of mechanistic studies.


Stressed mycobacteria use the chaperone ClpB to sequester irreversibly oxidized proteins asymmetrically within and between cells.
Mycobacterium tuberculosis (Mtb) defends itself against host immunity and chemotherapy at several levels, including the repair or degradation of irreversibly oxidized proteins (IOPs). To investigate how Mtb deals with IOPs that can neither be repaired nor degraded, we used new chemical and biochemical probes and improved image analysis algorithms for time-lapse microscopy to reveal a defense against stationary phase stress, oxidants, and antibiotics--the sequestration of IOPs into aggregates in association with the chaperone ClpB, followed by the asymmetric distribution of aggregates within bacteria and between their progeny. Progeny born with minimal IOPs grew faster and better survived a subsequent antibiotic stress than their IOP-burdened sibs. ClpB-deficient Mtb had a marked recovery defect from stationary phase or antibiotic exposure and survived poorly in mice. Treatment of tuberculosis might be assisted by drugs that cripple the pathway by which Mtb buffers, sequesters, and asymmetrically distributes IOPs.


Charge storage properties of biopolymer electrodes with (sub)tropical lignins.
The electrochemical and charge storage properties of different lignins inside biopolymer electrodes were studied and correlated with the chemical variations of the lignins as indicated from the nuclear magnetic resonance (NMR) spectroscopic data. The varying fractions of monolignols were found to correlate with charge storage properties. It was found that as the sinapyl to guaiacyl (S/G) ratio increased both the specific capacitance and charge capacity increased considerably. This indicates that quinones generated on S-units can contribute more to charge storage in the biopolymer electrodes.


InterProScan: protein domains identifier.
InterProScan [E. M. Zdobnov and R. Apweiler (2001) Bioinformatics, 17, 847-848] is a tool that combines different protein signature recognition methods from the InterPro [N. J. Mulder, R. Apweiler, T. K. Attwood, A. Bairoch, A. Bateman, D. Binns, P. Bradley, P. Bork, P. Bucher, L. Cerutti et al. (2005) Nucleic Acids Res., 33, D201-D205] consortium member databases into one resource. At the time of writing there are 10 distinct publicly available databases in the application. Protein as well as DNA sequences can be analysed. A web-based version is accessible for academic and commercial organizations from the EBI (http://www.ebi.ac.uk/InterProScan/). In addition, a standalone Perl version and a SOAP Web Service [J. Snell, D. Tidwell and P. Kulchenko (2001) Programming Web Services with SOAP, 1st edn. O'Reilly Publishers, Sebastopol, CA, http://www.w3.org/TR/soap/] are also available to the users. Various output formats are supported and include text tables, XML documents, as well as various graphs to help interpret the results.


Modulation of 5-fluorouracil with high-dose leucovorin calcium: activity in ovarian cancer and correlation with CA-125 levels.
The purpose of this study was to estimate the response rate, response duration, and survival of patients with advanced ovarian cancer treated with a 132-hr continuous infusion of high-dose calcium leucovorin in combination with five consecutive daily bolus doses of 5-fluorouracil (5-FU) and to correlate changes in CA-125 levels with clinical and radiologic assessment of disease progression. Forty-six heavily pretreated patients [median number of previous chemotherapy regimens, 2.5 (range 1-7)] with advanced ovarian cancer received 132-hr continuous infusions of calcium leucovorin (500 mg/m2/day) for 5 1/2 days, with daily bolus doses of 5-FU (370 mg/m2/day) for 5 days beginning 24 hr after initiation of the calcium leucovorin. Twenty-three patients had clinically measurable disease and 23 had evaluable disease; CA-125 levels were performed prior to each treatment course and after the final course of therapy. One of 42 patients had a partial response to combination chemotherapy (duration, 8.9 months); 16/42 had stable disease [median duration, 4.9 months (range, 2.4-9.0 months)]. Toxicity of combination therapy included mild myelosuppression and stomatitis, similar to previously reported toxicity profiles for the 5-FU and calcium leucovorin combinations. Sensitivity of CA-125 levels as a single indicator of disease progression was 55%. The combination of infusional high-dose calcium leucovorin and 5-FU has little activity in refractory ovarian cancer. CA-125 levels incorrectly predict clinical disease activity in about one-third of cases and should not be the sole criterion for determination of clinical response when evaluating chemotherapeutic efficacy in heavily pretreated patients.


Bacterial Pathogens Hijack the Innate Immune Response by Activation of the Reverse Transsulfuration Pathway.
The reverse transsulfuration pathway is the major route for the metabolism of sulfur-containing amino acids. The role of this metabolic pathway in macrophage response and function is unknown. We show that the enzyme cystathionine γ-lyase (CTH) is induced in macrophages infected with pathogenic bacteria through signaling involving phosphatidylinositol 3-kinase (PI3K)/MTOR and the transcription factor SP1. This results in the synthesis of cystathionine, which facilitates the survival of pathogens within myeloid cells. Our data demonstrate that the expression of CTH leads to defective macrophage activation by (i) dysregulation of polyamine metabolism by depletion of S-adenosylmethionine, resulting in immunosuppressive putrescine accumulation and inhibition of spermidine and spermine synthesis, and (ii) increased histone H3K9, H3K27, and H3K36 di/trimethylation, which is associated with gene expression silencing. Thus, CTH is a pivotal enzyme of the innate immune response that disrupts host defense. The induction of the reverse transsulfuration pathway by bacterial pathogens can be considered an unrecognized mechanism for immune escape.IMPORTANCE Macrophages are professional immune cells that ingest and kill microbes. In this study, we show that different pathogenic bacteria induce the expression of cystathionine γ-lyase (CTH) in macrophages. This enzyme is involved in a metabolic pathway called the reverse transsulfuration pathway, which leads to the production of numerous metabolites, including cystathionine. Phagocytized bacteria use cystathionine to better survive in macrophages. In addition, the induction of CTH results in dysregulation of the metabolism of polyamines, which in turn dampens the proinflammatory response of macrophages. In conclusion, pathogenic bacteria can evade the host immune response by inducing CTH in macrophages.


Distally based anterolateral thigh flap: an underutilized option for peri-patellar wound coverage.
Wound coverage in the supra-patellar area presents a significant challenge for orthopaedic and reconstructive surgeons due to the need for preservation of knee joint function but the paucity of regional soft tissue flaps available. While many orthopaedic and reconstructive surgeons make use of the rotational gastrocnemius flap for coverage of peri-patellar defects, this flap has certain limitations. The goal of this study was to report a single-centre experience with the use of the distally based anterolateral thigh flap (ALT) and review the current literature on the use of the ALT for peri-patellar defects. In this report, both a single-centre experience using distally based anterolateral thigh (ALT) island flaps for supra-patellar wound coverage and the existing literature on this topic were reviewed. A systematic literature review was performed to assess the use of the ALT for peri-patellar wounds. Five patients with a mean age of 69 underwent a distally based ALT flap for coverage of peri-patellar defects. Four out of 5 flaps survived at the end of their respective follow-up. Based on this combined experience, the distally based reverse-flow anterolateral thigh island flap represents a useful but relatively underutilized option for appropriately selected supra-patellar wounds due to minimal donor site morbidity, multiple flap components, and predictable pedicle anatomy. The flap's major weakness is its potentially unreliable venous drainage, requiring delay or secondary venous outflow anastomosis. Given the ALT flap's favourable profile, the authors recommend consideration for its use when managing a peri-patellar coverage wound issue.


Mammalian cyclin/PCNA (DNA polymerase delta auxiliary protein) stimulates processive DNA synthesis by yeast DNA polymerase III.
Human cyclin/PCNA (proliferating cell nuclear antigen) is structurally, functionally, and immunologically homologous to the calf thymus auxiliary protein for DNA polymerase delta. This auxiliary protein has been investigated as a stimulatory factor for the nuclear DNA polymerases from S. cerevisiae. Calf cyclin/PCNA enhances by more than ten-fold the ability of DNA polymerase III to replicate templates with high template/primer ratios, e.g. poly(dA).oligo(dT) (40:1). The degree of stimulation increases with the template/primer ratio. At a high template/primer ratio, i.e. low primer density, cyclin/PCNA greatly increases processive DNA synthesis by DNA polymerase III. At low template/primer ratios (e.g. poly(dA).oligo(dT) (2.5:1), where addition of cyclin/PCNA only minimally increases the processivity of DNA polymerase III, a several-fold stimulation of total DNA synthesis is still observed. This indicates that cyclin/PCNA may also increase productive binding of DNA polymerase III to the template-primer and stabilize the template-primer-polymerase complex. The activity of yeast DNA polymerases I and II is not affected by addition of cyclin/PCNA. These results strengthen the hypothesis that yeast DNA polymerase III is functionally analogous to the mammalian DNA polymerase delta.


Material thickness optimization for transmission-mode terahertz time-domain spectroscopy.
The thickness of a sample material for a transmission-mode terahertz time-domain spectroscopy (THz-TDS) measurement is the subject of interest in this paper. A sample that is too thick or too thin can raise the problem of measurement uncertainty. Although greater thickness allows the terahertz radiation--or T-rays--to interact more with bulk material, the SNR rolls off with thickness due to signal attenuation. A sample that is too thin renders itself nearly invisible to T-rays, in such a way that the system can hardly sense the difference between the sample and a free space path. The optimal trade-off is analyzed and revealed in this paper, where our approach is to find the optimal thickness that results in the minimal uncertainty of measured optical constants. The derived model for optimal thickness is supported by the results from experiments performed with polyvinyl chloride (PVC), high-density polyethylene (HDPE), and lactose samples.


Random amplified polymorphic DNA and amplified fragment length polymorphism analyses of Pasteurella multocida isolates from fatal fowl cholera infections.
Fowl cholera, a disease caused by Pasteurella multocida, continues to be a major problem for the poultry industry. The sources of pathogenic organisms responsible for most sporadic epidemics remain unconfirmed, although attenuated vaccines that retain a low level of virulence have occasionally been implicated in outbreaks of the disease. One of the vaccines most commonly used to prevent fowl cholera is the M-9 strain. In the present study, 61 clinical isolates from turkeys that died of fowl cholera from 1997 to 1999 on 36 Utah farms were analyzed and compared to the M-9 vaccine strain. Genetic analyses of the isolates were done by random amplified polymorphic DNA (RAPD) analysis and amplified fragment length polymorphism (AFLP) fingerprinting. The results of these genetic analyses were correlated with the vaccination status of the flock, isolate serotype, and geographic location. Although both genetic techniques effectively identified similar subtle genomic differences, RAPD analysis provided only 77% of the detail provided by AFLP analysis. While a relationship between genetic profile and serotype was evident, no significant relationship indicating geographic influence was found (P = 0.351). Interestingly, organisms isolated from vaccinated flocks were significantly closer genetically to the M-9 vaccine strain than isolates from unvaccinated birds were (P = 0.020). Statistical analyses revealed that this relationship could not have been determined by serotyping alone (P = 0.320), demonstrating the value of AFLP and RAPD analyses in the characterization of disease-causing strains.


Tuberculosis in Staff and Students of Patan Hospital.
There is a high risk of occupational exposure to tuberculosis among healthcare workers in endemic countries. Regular screening for tuberculosis among healthcare workers is not carried out in Nepal. Infection control measures are also not routinely implemented. The aim of this study was to determine the prevalence of active tuberculosis among staff/students at Patan Hospital. Participants were given a self-administered questionnaire and invited to undergo chest radiography. Cases were scored and reviewed based on predetermined criteria, and presumptive tuberculosis cases were invited to undergo sputum smear and culture. Participants were categorized according to the extent of patient contact and asked about history of tuberculosis medication. Among 560 participants, 76.8% had direct contact with patients. Fifty-eight (10.4%) gave history of cough >2 weeks. Based on symptom history and chest radiography, 20.0% (n=112) cases were reviewed, and 12.5% (n=14) of those reviewed had sputum tested for acid-fast bacilli. One participant had culture-positive tuberculosis. Fifty participants (8.9%) reported tuberculosis in the past, among which 42.0% (n=21) occurred after employment at Patan Hospital and 42.0% before joining Patan Hospital. Security staff, radiology technicians and ward cleaning staff had the highest proportion of cases with a history of tuberculosis.History of tuberculosis medication had no relation with age, sex, education, body mass index and smoking.The incidence rate of tuberculosis at Patan Hospital was 3.6 per 1000 person-years. Overall incidence of tuberculosis among healthcare workers is noteworthy. However, this study suggests when symptomatic tuberculosis occurs in healthcare worker at Patan Hospital, it is diagnosed and there is not a large pool of undiagnosed tuberculosis.


Infusion port dislodgement of bilateral breast tissue expanders after MRI.
Tissue expanders are placed routinely for breast reconstruction, and magnetic resonance imaging (MRI) is a common diagnostic procedure. Many studies have reported on the safety of MRI in patients with nonferromagnetic implants; however, many tissue expanders contain ferromagnetic components. The authors present a case of bilateral tissue expander infusion port dislodgment after MRI. A 56-year-old woman underwent bilateral mastectomy and immediate reconstruction with McGhan BIOSPAN tissue expanders. These implants contain integral nonferromagnetic infusion ports, as well as small, powerful Magna-Site magnets. Several weeks postoperatively the patient underwent MRI of her spine, which was ordered by her primary physician for back pain. Subsequently, the infusion ports could not be located with the finder magnet. A chest radiograph was obtained, which demonstrated bilateral dislodgment of the infusion ports. Surgical removal and replacement of the tissue expanders were required. Safety considerations of MRI have been discussed extensively in the literature, and data on MRI with various implanted devices have been obtained. The potential risks of performing MRI on patients with metallic implants include conduction of electrical currents, heating of the implant, misinterpretation resulting from artifact, and the possibility of movement or dislodgment of the implant. The small magnet integral to many tissue expanders may be overlooked by patients and physicians during pre-MRI screening. All patients undergoing tissue expansion with implants that contain integral ports should be thoroughly warned about the potential hazards of MRI.


Classifying fractures of the distal radius: impossible or unnecessary? Review of the literature and proposal of a grouping system.
Reviewing the literature it was found that no classification of fractures of the distal radius is universally accepted regarding reproducibility, treatment orientation, and ability to predict outcome. The authors find the use of the existing classifications extremely difficult in practice, especially when trying to communicate, and believe that classification, treatment, and prognosis cannot be directly connected because of the complexity of fracture patterns and treatment options. Five hundred fractures of the distal radius were studied and a grouping system was developed in which fractures are positioned according to the direction of displacement of the distal part and the existence of an intra-articular extension. Nine special parameters are also defined that characterize the personality of each fracture of the distal radius. According to this personality, a fracture can be finally connected to treatment, which is presented in a special protocol also developed after a wide review of the literature. An easily reproduced and remembered grouping system of fractures of the distal radius is offered. This, when combined with the special parameters, leads to a complete description of the fracture and is directly connected to the treatment guidelines presented here as a special protocol.


A comparison of the contribution of various gases to the greenhouse effect.
The current concern about an anthropogenic impact on global climate has made it of interest to compare the potential effect of various human activities. A case in point is the comparison between the emission of greenhouse gases from the use of natural gas and that from other fossil fuels. This comparison requires an evaluation of the effect of methane emissions relative to that of carbon dioxide emissions. A rough analysis based on the use of currently accepted values shows that natural gas is preferable to other fossil fuels in consideration of the greenhouse effect as long as its leakage can be limited to 3 to 6 percent.


Peripheral mitochondrial function correlates with clinical severity in idiopathic Parkinson's disease.
Parkinson's disease is an intractable disorder with heterogeneous clinical presentation that may reflect different underlying pathogenic mechanisms. Surrogate indicators of pathogenic processes correlating with clinical measures may assist in better patient stratification. Mitochondrial function, which is impaired in and central to PD pathogenesis, may represent one such surrogate indicator. Mitochondrial function was assessed by respirometry experiment in fibroblasts derived from idiopathic patients (n = 47) in normal conditions and in experimental settings that do not permit glycolysis and therefore force energy production through mitochondrial function. Respiratory parameters and clinical measures were correlated with bivariate analysis. Machine-learning-based classification and regression trees were used to classify patients on the basis of biochemical and clinical measures. The effects of mitochondrial respiration on α-synuclein stress were assessed monitoring the protein phosphorylation in permitting versus restrictive glycolysis conditions. Bioenergetic properties in peripheral fibroblasts correlate with clinical measures in idiopathic patients, and the correlation is stronger with predominantly nondopaminergic signs. Bioenergetic analysis under metabolic stress, in which energy is produced solely by mitochondria, shows that patients' fibroblasts can augment respiration, therefore indicating that mitochondrial defects are reversible. Forcing energy production through mitochondria, however, favors α-synuclein stress in different cellular experimental systems. Machine-learning-based classification identified different groups of patients in which increasing disease severity parallels higher mitochondrial respiration. The suppression of mitochondrial activity in PD may be an adaptive strategy to cope with concomitant pathogenic factors. Moreover, mitochondrial measures in fibroblasts are potential peripheral biomarkers to follow disease progression. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


[The effect of Ginkgo biloba extract in patients with intermittent claudication].
Eighteen patients with stable intermittent claudication were randomized in a double blind cross-over study comparing the effects of the Ginkgo biloba extract GB-8 at a dose of 120 mg o.d. with placebo. All patients were treated for three months with the active extract and three months with placebo. The effects of treatment on arterial insufficiency were quantified by measurements of systemic and peripheral systolic blood pressures, and pain-free and maximal walking distances on a tread-mill. Questionnaires based on visual analogue scales were used to quantify the severity of leg pain, impairment of concentration, and inability to remember. Short-term memory was objectively assessed. We did not find any significant changes in either peripheral blood pressures, walking distances or the severity of leg pain. Systemic blood pressure was reduced both by placebo and GB-8. The impairment of concentration and the inability to remember were both reduced, when comparing results during active treatment to placebo. Short-term memory did not change significantly. In conclusion, our study has shown that treatment with the Ginkgo biloba extract GB-8 improves some cognitive functions in elderly patients with moderate arterial insufficiency, whereas the extract did not change signs and symptoms of vascular disease in the patients.


Hepatitis C infection in patients with hereditary bleeding disorders: epidemiology, natural history, and management.
Hereditary bleeding disorders include a group of diseases with abnormalities of coagulation. Prior to 1990, infection with hepatitis C virus (HCV) was mainly transmitted via pooled plasma products as a treatment for hereditary bleeding disorders. Anti-HCV positivity in these patients may be as high as >70% in some areas, while some of them have also been coinfected with human immunodeficiency virus. Since about 20% of HCV-infected patients clear the infection naturally, chronic HCV infection represents a significant health problem in this group of patients. Mortality due to chronic HCV infection is estimated to be >10 times higher in patients with hemophilia than in the general population, and is mainly due to liver cirrhosis and hepatocellular carcinoma. The antiviral treatment of HCV in patients with hereditary bleeding disorders is not different from that of any other infected patients. Nevertheless, many patients with hereditary bleeding disorders have declined (Peg)interferon-based treatment because of side effects. In recent years, multiple orally administrated direct-acting antivirals (DAAs) have been approved for HCV treatment. Unfortunately, there is not much experience from treating these patients with DAA regimens, as major studies and real-life data did not include adequate numbers of patients with inherited hemorrhagic disorders. However, the available data indicate that DAAs have an excellent safety profile with a sustained virological response rate of >90%.


Hemisynthetic alkaloids derived from trilobine are antimalarials with sustained activity in multidrug-resistant Plasmodium falciparum.
Malaria eradication requires the development of new drugs to combat drug-resistant parasites. We identified bisbenzylisoquinoline alkaloids isolated from Cocculus hirsutus that are active against Plasmodium falciparum blood stages. Synthesis of a library of 94 hemi-synthetic derivatives allowed to identify compound 84 that kills multi-drug resistant clinical isolates in the nanomolar range (median IC50 ranging from 35 to 88 nM). Chemical optimization led to compound 125 with significantly improved preclinical properties. 125 delays the onset of parasitemia in Plasmodium berghei infected mice and inhibits P. falciparum transmission stages in vitro (culture assays), and in vivo using membrane feeding assay in the Anopheles stephensi vector. Compound 125 also impairs P. falciparum development in sporozoite-infected hepatocytes, in the low micromolar range. Finally, by chemical pull-down strategy, we characterized the parasite interactome with trilobine derivatives, identifying protein partners belonging to metabolic pathways that are not targeted by the actual antimalarial drugs or implicated in drug-resistance mechanisms.


Epileptic seizure-induced structural and functional changes in rat femur and tibia bone tissues: a Fourier transform infrared imaging study.
The disease- and drug-related bone disorders are rapidly increasing in the population. It is previously reported that anti-epileptic drugs (AEDs) may cause osteopenia, osteoporosis, and fractures in epilepsy patients. However, it cannot be determined whether the bone disorders in epileptic patients are due to AED therapy and/or to epilepsy and epileptic seizures. There is no study in the literature which investigates the sole effects of epilepsy and epileptic seizures on bone tissues. The current study provides the first report on determination of the possible effects of epilepsy and epileptic seizures on long bone tissues. Wistar Albino Glaxo/Rijswijk rats, which are accepted as genetic rat models for human absence epilepsy, were compared with the healthy Wistar rats to get information about the sole effects of epilepsy and epileptic seizures on bones. Cortical regions of tibia and femur bones were studied by Fourier transform infrared microspectroscopy (FTIRM). According to FTIRM parameters, variation on bone mineral and matrix composition, including decreased mineral content, decreased collagen cross-links, increased carbonate substitution, and larger crystals in epileptic group compared to the healthy one, show severe effects of epilepsy and seizures on bone tissues for the first time.


Swedish midwives' perception of their practice environment - A cross sectional study.
There is a shortage of midwives in Sweden. Evidence suggests that the work environment is likely to play a part in retention and attrition rates. To explore the practice environment of Swedish midwives and factors associated with the perception of an unfavorable work environment. 475/1000 (48.6%) members of the Swedish Midwifery association completed a questionnaire including the Practice Environment Scale (PES). Differences in mean scores were calculated for the subscales of PES and midwives' background characteristics. Logistic regression was used to investigate factors most strongly associated with unfavorable working environment. The two domains that showed significant differences in terms of participant characteristics were the Staffing and resources adequacy subscale and the Foundations of quality care subscale. Midwives younger than 40 years, those with less than 10 years' experience and those with an additional academic degree rated these two domains more unfavorably. Protective factors for assessing the work environment unfavorable were mainly internal such as high quality of life and high self-efficacy. Swedish midwives were most satisfied with the midwife-doctor relationship and least satisfied with their participation in work place or hospital affairs. Midwives suffering from burnout, those who provided hospital based care and those without leadership position were more likely to assess their work environment as unfavorable. This study identified personal factors as well as work related factors to be associated with midwives' assessment of their practice work environment. Establishing healthy work places where midwives feel recognized and valued could prevent midwives from leaving the profession.


Effects of altering initial position on movement direction and extent.
The purpose of this study was to examine the relative influence of initial hand location on the direction and extent of planar reaching movements. Subjects performed a horizontal-plane reaching task with the dominant arm supported above a table top by a frictionless air-jet system. A start circle and a target were reflected from a horizontal projection screen onto a horizontally positioned mirror, which blocked the subject's view of the arm. A cursor, representing either actual or virtual finger location, was only displayed between each trial to allow subjects to position the cursor in the start circle. Prior to occasional "probe trials," we changed the start location of the finger relative to the cursor. Subjects reported being unaware of the discrepancy between cursor and finger. Our results indicate that regardless of initial hand location, subjects did not alter the direction of movement. However, movement distance was systematically adjusted in accord with the baseline target position. Thus when the hand start position was perpendicularly displaced relative to the target direction, neither the direction nor the extent of movement varied relative to that of baseline. However, when the hand was displaced along the target direction, either anterior or posterior, movements were made in the same direction as baseline trials but were shortened or lengthened, respectively. This effect was asymmetrical such that movements from anterior displaced positions showed greater distance adjustment than those from posterior displaced positions. Inverse dynamic analysis revealed substantial changes in elbow and shoulder muscle torque strategies for both right/left and anterior/posterior pairs of displacements. In the case of right/left displacements, such changes in muscle torque compensated changes in limb configuration such that movements were made in the same direction and to the same extent as baseline trials. Our results support the hypothesis that movement direction is specified relative to an origin at the current location of the hand. Movement extent, on the other hand, appears to be affected by the workspace learned during baseline movement experience.


The occurrence of antibiotic resistance genes in a Mediterranean river and their persistence in the riverbed sediment.
The spread of antibiotic resistance genes (ARGs) in the environment is a serious concern. Bacterial ARGs can spread via different mobile genetic elements as phage particles, which thereby emerge as novel vectors for environmental dissemination. To assess how climate events, such as heavy rains or water scarcity, could affect the spread of ARGs, it is necessary to know their prevalence and abundance in aquatic environments as well as the potential reservoirs from which they could become mobile. This study evaluates the occurrence of ARGs in the water and sediment of a Mediterranean river. Six clinically relevant ARGs (blaTEM, blaCTX-M, qnrA, qnrS, mecA and sul1) were quantified by qPCR in the bacterial and phage fractions of 69 water and 70 sediment samples from the River Llobregat (NE Spain), collected during both dry and rainy periods. blaTEM and sul1 were the most prevalent and abundant ARGs; the others were more variable. Significant seasonal differences in ARG prevalences and abundances were observed. Since ARGs were detected in the sediment, the persistence of the most abundant ARGs naturally occurring in that sediment (blaTEM and sul1) was evaluated under three conditions. No ARG inactivation occurred in fresh sediment over 14 days; while the ARGs declined by less than 2 log10 units over 35 days in semi-dry and dry sediment. The occurrence of ARGs in water and sediment is influenced by seasonal conditions and they can be mobilized by bacteria and phage particles. In sediment, ARGs persist for long periods and hence sediment can be a natural reservoir of ARGs, from where they can spread and cause the emergence of new resistant strains.


Causes of pneumonia presenting to a district general hospital.
The incidence of bacterial, viral, mycoplasma, and rickettsial infections has been assessed prospectively in 210 adult patients with pneumonia who presented to a district hospital over a six-year period. One hundred and thirteen infective agents were detected in 103 patients. The agent most frequently detected was Mycoplasma pneumoniae which accounted for 30 infections. A bacterial pathogen was found in 43 patients. Streptococcus pneumoniae was the most common of these (24 patients); Staphylococcus aureus (eight), Haemophilus influenzae (four), Klebsiella spp (three), and Legionella pneumophila (three) were all less common. Chlamydial or rickettsial infections (Psittacosis or Q fever) were detected in nine patients. Viral infections were found in 31 patients (22 influenza A, four influenza B, two parainfluenza, and three respiratory syncytial virus). There were 10 patients in whom more than one pathogen was identified. In 107 patients no pathogens could be identified. Seventy-five per cent of these patients had either received antibiotics before entering hospital, or were unable to produce any sputum for culture. The incidence of bacterial pneumonia has probably therefore been underestimated. Nevertheless this survey does emphasise the importance of M pneumoniae as a pathogen in patients with pneumonia presenting to hospital.


Pathology of periportal fibrosis involution in human schistosomiasis.
Optical and electron microscopical evidences of focal matrix degradation were frequently seen in liver sections of periportal fibrosis caused by schistosomiasis mansoni in man. The material came from 14 wedge hepatic biopsies taken from patients with chronic advanced hepatosplenic disease and undergoing operations for the relief of portal hypertension. Besides the presence of focal areas of rarefaction, fragmentation and dispersion of collagen fibers, the enlarged portal spaces also showed hyperplasia of elastic tissue and disarray of smooth muscle fibers following destruction of portal vein branches. Eggs were scanty in the tissue sections, and matrix degradation probably represented involuting changes related to the progressive diminution of parasite-related aggression, which occurs spontaneously with age or after cure by chemotherapy. The changes indicative of matrix degradation now described are probably the basic morphological counterpart of periportal fibrosis involution currently being documented by ultrasonography in hepatosplenic patients submitted to curative chemotherapy.


SuperDCA for genome-wide epistasis analysis.
The potential for genome-wide modelling of epistasis has recently surfaced given the possibility of sequencing densely sampled populations and the emerging families of statistical interaction models. Direct coupling analysis (DCA) has previously been shown to yield valuable predictions for single protein structures, and has recently been extended to genome-wide analysis of bacteria, identifying novel interactions in the co-evolution between resistance, virulence and core genome elements. However, earlier computational DCA methods have not been scalable to enable model fitting simultaneously to 104-105 polymorphisms, representing the amount of core genomic variation observed in analyses of many bacterial species. Here, we introduce a novel inference method (SuperDCA) that employs a new scoring principle, efficient parallelization, optimization and filtering on phylogenetic information to achieve scalability for up to 105 polymorphisms. Using two large population samples of Streptococcus pneumoniae, we demonstrate the ability of SuperDCA to make additional significant biological findings about this major human pathogen. We also show that our method can uncover signals of selection that are not detectable by genome-wide association analysis, even though our analysis does not require phenotypic measurements. SuperDCA, thus, holds considerable potential in building understanding about numerous organisms at a systems biological level.


A phase II study of pazopanib in patients with recurrent or metastatic invasive breast carcinoma: a trial of the Princess Margaret Hospital phase II consortium.
Angiogenesis is an important hallmark of breast cancer growth and progression. Pazopanib, an oral small molecule inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and KIT, has activity across a range of solid tumors. We evaluated the activity of single-agent pazopanib in recurrent or metastatic breast cancer (MBC). Patients with recurrent breast cancer or MBC, treated with up to two prior lines of chemotherapy, were eligible to receive pazopanib, 800 mg daily until progression. The primary endpoint was the objective response rate as measured by Response Evaluation Criteria in Solid Tumors. Secondary endpoints included time to progression, the stable disease rate, and toxicity. Using a two-stage design, confirmed response in three of 18 patients was required to proceed to stage 2. Twenty evaluable patients were treated, with a median age of 56 years; 70% were estrogen receptor positive, all were human epidermal growth factor receptor 2 negative. The majority had one or two prior lines of chemotherapy. One patient (5%) had a partial response, 11 (55%) had stable disease (SD) [four (20%) with SD > or = 6 months], and seven (35%) had progressive disease as their best response. One (5%) was not evaluable. The median time to progression was 5.3 months. Pazopanib did not cause significant severe toxicity aside from grade 3-4 transaminitis, hypertension, and neutropenia in three patients each (14% each) and grade 3 gastrointestinal hemorrhage in one patient (5%). Pazopanib provides disease stability in advanced breast cancer. The activity seen is comparable with that of other antiangiogenic agents in this setting. Pazopanib may be of interest for future studies in breast cancer, including in combination with other systemic agents.


Changes in chronic respiratory symptoms in two populations of adults studied longitudinally over 13 years.
Data from two longitudinal studies conducted in Cracow, Poland, and Tucson, Arizona, USA, were used to evaluate the differences in period prevalence, incidence and remission rates of respiratory symptoms between two populations, as well as to assess the between-cities similarities in the relationships of the symptoms to age and smoking habit. The analysis was based on data from 3,082 adult Cracow residents, interviewed twice 13 yrs apart, and from 1,452 Tucson adults, with mean period between initial and final survey of 12.2 yrs. Log-linear models were used to consider possible interactions of the symptoms, age, smoking, gender and city. The relationship of the symptoms to smoking was similar in both cities, after adjustment for age and gender, with at least doubled incidence rates of most symptoms in continuous smokers compared to lifetime nonsmokers. The between-population differences in the symptoms were related to age, indicating onset of bronchitic symptoms occurring earlier in life in Cracow, and of asthmatic symptoms in Tucson. These differences were due to factors other than tobacco smoking e.g. various types of ambient air pollution.


Songbird cheaters pay a retaliation cost: evidence for auditory conventional signals.
Conventional signals impose costs on senders through receiver retaliation rather than through investment in signal production. While several visual conventional signals have been described (mainly 'badges of status'), acoustic examples are rare; however, several aspects of repertoire use in songbirds are potential candidates. We performed interactive playback experiments to determine whether song-type matches (responding to a song with the same song type), repertoire matches (responding to a song with a different song type, but one in the repertoires of both singers) and unshared song types serve as conventional signals during male-male territorial interactions in banded wrens, Thryothorus pleurostictus. Our results demonstrate that these three signals incite varying levels of receiver aggression: song-type matches induce faster approach than do repertoire matches, and repertoire matches induce faster approach than do unshared song types. Production costs do not differ, while the receiver response does. Because territorial banded wrens approach opponents who signal aggressively, such opponents risk attack. This system will punish and prevent cheaters, as weak males signalling aggression will be subject to escalation by stronger or more-motivated opponents.


Exercise preserves muscle mass and force in a prostate cancer mouse model.
The purpose of this study was to examine the effects of exercise in modulating biomarkers of sarcopenia in a treatment naïve transgenic adenocardinoma of the mouse prostate (TRAMP) model. Thirty TRAMP mice were randomized to either exercise (voluntary wheel running) or no-treatment control group for a period of 20 weeks. During necropsy, gastrocnemius muscles and prostate tumors were harvested and weighed. Gastrocnemius concentrations of myostatin, insulin-like growth factor (IGF)-1 and tumor necrosis factor (TNF)-α were quantified. Exercise mice had greater muscle mass than controls (p=0.04). Myostatin was significantly lower in the exercise group compared to controls (p=0.01). Exercise mice maintained forelimb grip force while control mice had a significaint decrease (p=0.01). No significant difference was observed in pre-post all limb grip strength. Further, forelimb and all limb grip strength was negatively associated with tumor mass (p<0.01).


The gross motor function measure: a means to evaluate the effects of physical therapy.
This paper reports the results of a study to validate a measure of gross motor function in detecting change in the motor function of disabled children. Physiotherapists used this instrument to assess 111 patients with cerebral palsy, 25 with head injury and 34 non-disabled preschool children on two occasions, the second after an interval of four to six months. Parents and therapists independently rated the children's function within two weeks of each assessment, and a sample of paired assessments was videotaped for 'blind' evaluation by therapists. Correlations between scores for change on this measure and the judgments of change by parents, therapists and 'blind' evaluators supported the hypothesis that the instrument would be responsive to both negative and positive changes.


Sro7 and Sro77, the yeast homologues of the Drosophila lethal giant larvae (Lgl), regulate cell proliferation via the Rho1-Tor1 pathway.
Saccharomyces cerevisiae Sro7 and Sro77 are homologues of the Drosophila tumour suppressor lethal giant larvae (Lgl), which regulates cell polarity in Drosophila epithelial cells. Here, we showed that double mutation of SRO7/SRO77 was defective in colony growth. The colony of the SRO7/SRO77 double deletion was much smaller than the WT and appeared to be round with a smooth surface, compared with the WT. Analysis using transmission electron microscopy revealed multiple defects of the colony cells, including multiple budding, multiple nuclei, cell lysis and dead cells, suggesting that the double deletion caused defects in cell polarity and cell wall integrity (CWI). Overexpression of RHO1, one of the central regulators of cell polarity and CWI, fully recovered the sro7Δ/sro77Δ phenotype. We further demonstrated that sro7Δ/sro77Δ caused a decrease of the GTP-bound, active Rho1, which in turn caused an upregulation of TOR1. Deletion of TOR1 in sro7Δ/sro77Δ (sro7Δ/sro77Δ/tor1Δ) recovered the cell growth and colony morphology, similar to WT. Our results suggested that the tumour suppressor homologue SRO7/SRO77 regulated cell proliferation and yeast colony development via the Rho1-Tor1 pathway.


Uncoupling of substrate-level phosphorylation in Escherichia coli during glucose-limited growth.
The respiratory chain of Escherichia coli contains three different cytochrome oxidases. Whereas the cytochrome bo oxidase and the cytochrome bd-I oxidase are well characterized and have been shown to contribute to proton translocation, physiological data suggested a nonelectrogenic functioning of the cytochrome bd-II oxidase. Recently, however, this view was challenged by an in vitro biochemical analysis that showed that the activity of cytochrome bd-II oxidase does contribute to proton translocation with an H(+)/e(-) stoichiometry of 1. Here, we propose that this apparent discrepancy is due to the activities of two alternative catabolic pathways: the pyruvate oxidase pathway for acetate production and a pathway with methylglyoxal as an intermediate for the production of lactate. The ATP yields of these pathways are lower than those of the pathways that have so far always been assumed to catalyze the main catabolic flux under energy-limited growth conditions (i.e., pyruvate dehydrogenase and lactate dehydrogenase). Inclusion of these alternative pathways in the flux analysis of growing E. coli strains for the calculation of the catabolic ATP synthesis rate indicates an electrogenic function of the cytochrome bd-II oxidase, compatible with an H(+)/e(-) ratio of 1. This analysis shows for the first time the extent of bypassing of substrate-level phosphorylation in E. coli under energy-limited growth conditions.


The Ai project: historical and ecological contexts.
This paper aims to review a long-term research project exploring the chimpanzee mind within historical and ecological contexts. The Ai project began in 1978 and was directly inspired by preceding ape-language studies conducted in Western countries. However, in contrast with the latter, it has focused on the perceptual and cognitive capabilities of chimpanzees rather than communicative skills between humans and chimpanzees. In the original setting, a single chimpanzee faced a computer-controlled apparatus and performed various kinds of matching-to-sample discrimination tasks. Questions regarding the chimpanzee mind can be traced back to Wolfgang Koehler's work in the early part of the 20th century. Yet, Japan has its unique natural and cultural background: it is home to an indigenous primate species, the Japanese snow monkey. This fact has contributed to the emergence of two previous projects in the wild led by the late Kinji Imanishi and his students. First, the Koshima monkey project began in 1948 and became famous for its discovery of the cultural propagation of sweet-potato washing behavior. Second, pioneering work in Africa, starting in 1958, aimed to study great apes in their natural habitat. Thanks to the influence of these intellectual ancestors, the present author also undertook the field study of chimpanzees in the wild, focusing on tool manufacture and use. This work has demonstrated the importance of social and ecological perspectives even for the study of the mind. Combining experimental approaches with a field setting, the Ai project continues to explore cognition and behavior in chimpanzees, while its focus has shifted from the study of a single subject toward that of the community as a whole.


Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis.
Although cyclophosphamide and prednisolone are effective in treating systemic vasculitis, the optimum treatment regimes and duration of treatment are unknown. We randomized 54 patients aged 15-70 years (median 57.5 years) with systemic vasculitis (classical polyarteritis n = 8, microscopic polyarteritis n = 17, Wegener's granulomatosis n = 29) to treatment with either pulse cyclophosphamide and prednisolone (PCYP) (n = 24) or continuous oral and prednisolone and cyclophosphamide, with the latter followed after a median of 3 months (range 1.5-10 months) by azathioprine (CCAZP) (n = 30). Patients on CCAZP were more likely to develop leucopenia (13/30) than patients on PCYP, (7/24) although the difference was not significant. The numbers of infective episodes during follow up were comparable in the two groups at 1.7/patient for PCYP and 1.66/patient for CCAZP. Overall, 26/30 patients (87%) treated with CCAZP developed treatment-related toxicity, as did 17/24 patients (71%) treated with PCYP. After a median follow-up of 40.4 months (range 0.7-64.8), there was no difference in the frequency of deaths (PCYP 5, CCAZP 4), relapses (PCCYP 7, CCAZP 8), treatment failures (PCYP 4, CCAZP 4), improvement in disease activity scores or renal function. Survival at three years was 77% in patients treated with PCYP, and 90% in patients on CCAZP (p = 0.38). There was a tendency towards increased toxicity in patients treated with the continuous regimen.


Estrogen receptor-beta prevents cardiac fibrosis.
Development of cardiac fibrosis portends the transition and deterioration from hypertrophy to dilation and heart failure. Here we examined how estrogen blocks this important development. Angiotensin II (AngII) and endothelin-1 induce cardiac hypertrophy and fibrosis in humans. and we find that these agents directly stimulate the transition of the cardiac fibroblast to a myofibroblast. AngII and endothelin-1 stimulated TGFβ1 synthesis in the fibroblast, an inducer of fibrosis that signaled via c-jun kinase to Sma- and Mad-related protein 3 phosphorylation and nuclear translocation in myofibroblasts. As a result, mesenchymal proteins fibronectin and vimentin were produced, as were collagens I and III, the major forms found in fibrotic hearts. 17β-Estradiol (E2) or dipropylnitrile, an estrogen receptor (ER)β agonist, comparably blocked all these events, reversed by estrogen receptor (ER)β small interfering RNA. E2 and dipropylnitrile signaling through cAMP and protein kinase A prevented myofibroblast formation and blocked activation of c-jun kinase and important events of fibrosis. In the hearts of ovariectomized female mice, cardiac hypertrophy and fibrosis were induced by AngII infusion and prevented by E2 administration to wild type but not ERβ knockout rodents. Our results establish the cardiac fibroblast as an important target for hypertrophic/fibrosis-inducing peptides the actions of which were mitigated by E2/ERβ acting in these stromal cells.


Herpes simplex virus membrane proteins gE/gI and US9 act cooperatively to promote transport of capsids and glycoproteins from neuron cell bodies into initial axon segments.
Herpes simplex virus (HSV) and other alphaherpesviruses must move from sites of latency in ganglia to peripheral epithelial cells. How HSV navigates in neuronal axons is not well understood. Two HSV membrane proteins, gE/gI and US9, are key to understanding the processes by which viral glycoproteins, unenveloped capsids, and enveloped virions are transported toward axon tips. Whether gE/gI and US9 function to promote the loading of viral proteins onto microtubule motors in neuron cell bodies or to tether viral proteins onto microtubule motors within axons is not clear. One impediment to understanding how HSV gE/gI and US9 function in axonal transport relates to observations that gE(-), gI(-), or US9(-) mutants are not absolutely blocked in axonal transport. Mutants are significantly reduced in numbers of capsids and glycoproteins in distal axons, but there are less extensive effects in proximal axons. We constructed HSV recombinants lacking both gE and US9 that transported no detectable capsids and glycoproteins to distal axons and failed to spread from axon tips to adjacent cells. Live-cell imaging of a gE(-)/US9(-) double mutant that expressed fluorescent capsids and gB demonstrated >90% diminished capsids and gB in medial axons and no evidence for decreased rates of transport, stalling, or increased retrograde transport. Instead, capsids, gB, and enveloped virions failed to enter proximal axons. We concluded that gE/gI and US9 function in neuron cell bodies, in a cooperative fashion, to promote the loading of HSV capsids and vesicles containing glycoproteins and enveloped virions onto microtubule motors or their transport into proximal axons.


Localisation of proteins of iron metabolism in the human placenta and liver.
Two anatomical sites that are important in human iron metabolism are the liver and placenta. Liver macrophages recycle iron from erythrocytes, and the placenta transfers iron from the mother to the fetus. The cellular distribution of proteins involved in iron transport in these two sites was studied. Transferrin receptor-1 (TfR1) and Ferroportin (FPN) expression was found on the placental syncytiotrophoblast (STB) and were polarised such that TfR1 was on the apical maternal-facing membrane and FPN was on the basal fetal-facing membrane, consistent with unidirectional iron transport from mother to fetus. Ferritin was strongly expressed in the stroma, suggesting that fetal tissue can store and accumulate iron. HFE was on some parts of the basal STB and, where present, HFE clearly colocalised with FPN but not TfR1. In the stroma, both HFE and FPN were present on CD68+ Hofbauer macrophage cells. In liver, the location of HFE is controversial. Using four mouse monoclonals and two polyclonal sera we showed that the pattern of HFE expression mirrored the distribution of CD68+ macrophage Kupffer cells. FPN was also most strongly expressed by CD68+ Kupffer cells. These findings contribute to understanding how iron is transported and stored in the human placenta and liver.


Concordant epigenetic silencing of transforming growth factor-beta signaling pathway genes occurs early in breast carcinogenesis.
Human mammary epithelial cells (HMEC) grown under standard cell culture conditions enter a growth phase referred to as selection, but a subpopulation is able to escape from arrest and continue to proliferate. These cells, called post-selection or variant HMECs, may be derived from progenitor cells found in normal mammary epithelium that subsequently acquire premalignant lesions, including p16(INK4A) promoter hypermethylation. Epigenetic silencing of tumor suppressor genes through DNA methylation and histone modification is an early event in tumorigenesis. A major challenge is to find genes or gene pathways that are commonly silenced to provide early epigenetic diagnostic and therapeutic cancer targets. To identify very early epigenetic events that occur in breast cancer, we used microarrays to screen for gene pathways that were suppressed in post-selection HMECs but reactivated after treatment with the demethylation agent 5-aza-2'-deoxycytidine. We found that several members of the transforming growth factor beta (TGF-beta) signaling pathway were consistently down-regulated in the post-selection HMEC populations, and this was associated with a marked decrease in Smad4 nuclear staining. Gene suppression was not associated with DNA methylation but with chromatin remodeling, involving a decrease in histone H3 lysine 27 trimethylation and an increase in histone H3 lysine 9 dimethylation and deacetylation. These results show for the first time that TGF-beta2, its receptors TGF-beta R1 and TGF-beta R2, and activator thrombospondin-1 are concordantly suppressed early in breast carcinogenesis by histone modifications and indicate that the TGF-beta signaling pathway is a novel target for gene activation by epigenetic therapy.


Prognostic radiology: quantitative assessment of tumor oxygen dynamics by MRI.
It is generally recognized that tumor hypoxia has a strong influence over therapeutic outcome in the clinic. The authors have developed an oximetry approach using 19F echo planar magnetic resonance imaging-FREDOM (Fluorocarbon Relaxometry using Echoplanar imaging for Dynamic Oxygen Mapping), which reveals dynamic changes based on sequential maps of regional tumor PO2. Preclinical investigations focused on diverse sublines of the Dunning prostate R3327 tumor. As expected, intratumoral heterogeneity was considerable. However, large tumors (>3.5 cm3) were significantly less well oxygenated than smaller tumors (<2 cm3). Faster growing, less differentiated tumors were less well oxygenated than size-matched tumors of slower growing sublines. The greatest potential of this technique is the ability to follow the fate of individual tumor regions with respect to interventions. For each subline, there was a significant response to respiratory challenge with oxygen for initially well-oxygenated regions (baseline PO2 > 10 mm Hg). More interestingly, subline dependent behavior was found for initially hypoxic regions that correlated with rate of growth. The authors believe the FREDOM approach is essentially ripe for translation to the clinic. This approach could help to identify patients with hypoxic tumors and indicate the feasibility of manipulating tumor characteristics through adjuvant interventions to improve therapeutic response.


Association of KIBRA rs17070145 polymorphism with episodic memory in the early stages of a human neurodevelopmental disorder.
A common T/C polymorphism within the ninth intron of the KIBRA gene (rs17070145) is thought to influence memory in humans. Since cognitive impairment, including memory, is a core feature of schizophrenia, we attempted to investigate this association in an independent sample of adolescent patients with early-onset schizophrenia (EOS; onset before age 18) probands and their healthy siblings. In a sample of 25 pairs of EOS proband-healthy full sibling, we sought to investigate the association of KIBRA with memory performance. Episodic memory was measured using immediate and delayed recall measures of the California Verbal Learning Test. EOS underperformed at immediate and delayed recall compared with siblings. In a combined analysis (TT vs. TC/CC) assuming a C dominant model of inheritance, we found a main effect of genotype where individuals with TT genotype outperformed non-TT-carriers at immediate and delayed recall. A genotype by group interaction showed that EOS with TT genotype did not show a memory advantage over siblings with TT or non-TT-carriers at immediate or delayed recall. Siblings with TT genotype showed enhanced immediate recall (not delayed recall) compared with non-TT-carriers. This study demonstrates an association between the KIBRA gene and episodic memory (immediate free recall) and suggests a differential effect of this genetic variant in EOS and healthy siblings.


Exhaustive percolation on random networks.
We consider propagation models that describe the spreading of an attribute, called "damage," through the nodes of a random network. In some systems, the average fraction of nodes that remain undamaged vanishes in the large system limit, a phenomenon we refer to as exhaustive percolation. We derive scaling law exponents and exact results for the distribution of the number of undamaged nodes, valid for a broad class of random networks at the exhaustive percolation transition and in the exhaustive percolation regime. This class includes processes that determine the set of frozen nodes in random Boolean networks with in-degree distributions that decay sufficiently rapidly with the number of inputs. Connections between our calculational methods and previous studies of percolation beginning from a single initial node are also pointed out. Central to our approach is the observation that key aspects of damage spreading on a random network are fully characterized by a single function, specifying the probability that a given node will be damaged as a function of the fraction of damaged nodes. In addition to our analytical investigations of random networks, we present a numerical example of exhaustive percolation on a directed lattice.


CDK-dependent nuclear localization of B-cyclin Clb1 promotes FEAR activation during meiosis I in budding yeast.
Cyclin-dependent kinases (CDK) are master regulators of the cell cycle in eukaryotes. CDK activity is regulated by the presence, post-translational modification and spatial localization of its regulatory subunit cyclin. In budding yeast, the B-cyclin Clb1 is phosphorylated and localizes to the nucleus during meiosis I. However the functional significance of Clb1's phosphorylation and nuclear localization and their mutual dependency is unknown. In this paper, we demonstrate that meiosis-specific phosphorylation of Clb1 requires its import to the nucleus but not vice versa. While Clb1 phosphorylation is dependent on activity of both CDK and polo-like kinase Cdc5, its nuclear localization requires CDK but not Cdc5 activity. Furthermore we show that increased nuclear localization of Clb1 during meiosis enhances activation of FEAR (Cdc Fourteen Early Anaphase Release) pathway. We discuss the significance of our results in relation to regulation of exit from meiosis I.


Scanning tunneling microscopy of freeze-fracture replicas of biomembranes.
The high resolution of the scanning tunneling microscope (STM) makes it a potentially important tool for the study of biomaterials. Biological materials can be imaged with the STM by a procedure in which fluid, nonconductive biomaterials are replaced by rigid and highly conductive freeze-fracture replicas. The three-dimensional contours of the ripple phase of dimyristoylphosphatidylcholine bilayers were imaged with unprecedented resolution with commercial STMs and standard freeze-fracture techniques. Details of the ripple amplitude, asymmetry, and configuration unobtainable by electron microscopy or x-ray diffraction can be observed relatively easily with the STM.


Embryonic origin and lineage hierarchies of the neural progenitor subtypes building the zebrafish adult midbrain.
Neurogenesis in the post-embryonic vertebrate brain varies in extent and efficiency between species and brain territories. Distinct neurogenesis modes may account for this diversity, and several neural progenitor subtypes, radial glial cells (RG) and neuroepithelial progenitors (NE), have been identified in the adult zebrafish brain. The neurogenic sequences issued from these progenitors, and their contribution to brain construction, remain incompletely understood. Here we use genetic tracing techniques based on conditional Cre recombination and Tet-On neuronal birthdating to unravel the neurogenic sequence operating from NE progenitors in the zebrafish post-embryonic optic tectum. We reveal that a subpopulation of her5-positive NE cells of the posterior midbrain layer stands at the top of a neurogenic hierarchy involving, in order, the amplification pool of the tectal proliferation zone (TPZ), followed by her4-positive RG cells with transient neurogenic activity. We further demonstrate that the adult her5-positive NE pool is issued in lineage from an identically located NE pool expressing the same gene in the embryonic neural tube. Finally, we show that these features are reminiscent of the neurogenic sequence and embryonic origin of the her9-positive progenitor NE pool involved in the construction of the lateral pallium at post-embryonic stages. Together, our results highlight the shared recruitment of an identical neurogenic strategy by two remote brain territories, where long-lasting NE pools serve both as a growth zone and as the life-long source of young neurogenic RG cells.


The influence of marketing on the sports betting attitudes and consumption behaviours of young men: implications for harm reduction and prevention strategies.
Gambling can cause significant health and social harms for individuals, their families, and communities. While many studies have explored the individual factors that may lead to and minimise harmful gambling, there is still limited knowledge about the broader range of factors that may contribute to gambling harm. There are significant regulations to prevent the marketing of some forms of gambling but comparatively limited regulations relating to the marketing of newer forms of online gambling such as sports betting. There is a need for better information about how marketing strategies may be shaping betting attitudes and behaviours and the range of policy and regulatory responses that may help to prevent the risky or harmful consumption of these products. We conducted qualitative, semi-structured interviews with 50 Australian men (aged 20-37 years) who gambled on sports. We explored their attitudes and opinions regarding sports betting marketing, the embedding of marketing within sports and other non-gambling community environments, and the implications this had for the normalisation of betting. Our findings indicate that most of the environments in which participants reported seeing or hearing betting advertisements were not in environments specifically designed for betting. Participants described that the saturation of marketing for betting products, including through sports-based commentary and sports programming, normalised betting. Participants described that the inducements offered by the industry were effective marketing strategies in getting themselves and other young men to bet on sports. Inducements were also linked with feelings of greater control over betting outcomes and stimulated some individuals to sign up with more than one betting provider. This research suggests that marketing plays a strong role in the normalisation of gambling in sports. This has the potential to increase the risks and subsequent harms associated with these products. Legislators must begin to consider the cultural lag between an evolving gambling landscape, which supports sophisticated marketing strategies, and effective policies and practices which aim to reduce and prevent gambling harm.