Astrophysics. The exceptionally powerful TeV γ-ray emitters in the Large Magellanic Cloud.
The Large Magellanic Cloud, a satellite galaxy of the Milky Way, has been observed with the High Energy Stereoscopic System (H.E.S.S.) above an energy of 100 billion electron volts for a deep exposure of 210 hours. Three sources of different types were detected: the pulsar wind nebula of the most energetic pulsar known, N 157B; the radio-loud supernova remnant N 132D; and the largest nonthermal x-ray shell, the superbubble 30 Dor C. The unique object SN 1987A is, unexpectedly, not detected, which constrains the theoretical framework of particle acceleration in very young supernova remnants. These detections reveal the most energetic tip of a γ-ray source population in an external galaxy and provide via 30 Dor C the unambiguous detection of γ-ray emission from a superbubble.


Iron deficiency is uncommon among lactating women in urban Nepal, despite a high risk of inadequate dietary iron intake.
The main objective of the present study was to examine the association between dietary Fe intake and dietary predictors of Fe status and Hb concentration among lactating women in Bhaktapur, Nepal. We included 500 randomly selected lactating women in a cross-sectional survey. Dietary information was obtained through three interactive 24 h recall interviews including personal recipes. Concentrations of Hb and plasma ferritin and soluble transferrin receptors were measured. The daily median Fe intake from food was 17·5 mg, and 70% of the women were found to be at the risk of inadequate dietary Fe intake. Approximately 90% of the women had taken Fe supplements in pregnancy. The prevalence of anaemia was 20% (Hb levels < 123 g/l) and that of Fe deficiency was 5% (plasma ferritin levels < 15 μg/l). In multiple regression analyses, there was a weak positive association between dietary Fe intake and body Fe (β 0·03, 95% CI 0·014, 0·045). Among the women with children aged < 6 months, but not those with older infants, intake of Fe supplements in pregnancy for at least 6 months was positively associated with body Fe (P for interaction < 0·01). Due to a relatively high dietary intake of non-haem Fe combined with low bioavailability, a high proportion of the women in the present study were at the risk of inadequate intake of Fe. The low prevalence of anaemia and Fe deficiency may be explained by the majority of the women consuming Fe supplements in pregnancy.


STAT3 inhibition enhances CDN-induced STING signaling and antitumor immunity.
Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a key regulator in innate immunity and has emerged as a promising drug target in cancer treatment, but the utility of this pathway in therapeutic development is complicated by its dichotomous roles in tumor development and immunity. The activation of the STING pathway and the induced antitumor immunity could be attenuated by the feedback activation of IL-6/STAT3 pathway. Here we reported that STAT3 inhibition significantly enhanced the intensity and duration of STING signaling induced by the STING agonist c-diAM(PS)2. Such sensitization effect of STAT3 inhibition on STING signaling depended on STING rather than cGAS, which was mediated by simultaneously upregulating the positive modulators and downregulating the negative modulators of the STING pathway. Furthermore, the combination treatment with the STAT3 inhibitor and STING agonist markedly regressed tumor growth in syngeneic mice by increasing CD8+ T cells and reducing regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Our work provides a rationale for the combination of STAT3 inhibitors and STING agonists in cancer immunotherapy.


Involvement of phage phi29 DNA polymerase and terminal protein subdomains in conferring specificity during initiation of protein-primed DNA replication.
To initiate phi29 DNA replication, the DNA polymerase has to form a complex with the homologous primer terminal protein (TP) that further recognizes the replication origins of the homologous TP-DNA placed at both ends of the linear genome. By means of chimerical proteins, constructed by swapping the priming domain of the related phi29 and GA-1 TPs, we show that DNA polymerase can form catalytically active heterodimers exclusively with that chimerical TP containing the N-terminal part of the homologous TP, suggesting that the interaction between the polymerase TPR-1 subdomain and the TP N-terminal part is the one mainly responsible for the specificity between both proteins. We also show that the TP N-terminal part assists the proper binding of the priming domain at the polymerase active site. Additionally, a chimerical 29 DNA polymerase containing the GA-1 TPR-1 subdomain could use GA-1 TP, but only in the presence of phi29 TP-DNA as template, indicating that parental TP recognition is mainly accomplished by the DNA polymerase. The sequential events occurring during initiation of bacteriophage protein-primed DNA replication are proposed.


Gender differences in early accommodation and vergence development.
A remote haploscopic photorefractor was used to assess objective binocular vergence and accommodation responses in 157 full-term healthy infants aged 1-6 months while fixating a brightly coloured target moving between fixation distances at 2, 1, 0.5 and 0.33 m. Vergence and accommodation response gain matured rapidly from 'flat' neonatal responses at an intercept of approximately 2 dioptres (D) for accommodation and 2.5 metre angles(MA) for vergence, reaching adult-like values at 4 months. Vergence gain was marginally higher in females (p = 0.064), but accommodation gain (p = 0.034) was higher and accommodative intercept closer to zero (p = 0.004) in males in the first 3 months as they relaxed accommodation more appropriately for distant targets. More females showed flat accommodation responses (p = 0.029). More males behaved hypermetropically in the first two months of life, but when these hypermetropic infants were excluded from the analysis, the gender difference remained. Gender differences disappeared after three months. Data showed variable responses and infants could behave appropriately and simultaneously on both, neither or only one measure at all ages. If accommodation was appropriate (gain between 0.7 and 1.3; r(2) > 0.7) but vergence was not, males over- and under-converged equally, while the females who accommodated appropriately were more likely to overconverge (p = 0.008). The apparent earlier maturity of the male accommodative responses may be due to refractive error differences but could also reflect gender-specific male preference for blur cues while females show earlier preference for disparity, which may underpin the earlier emerging, disparity dependent, stereopsis and full vergence found in females in other studies.


Fasting glucose GWAS candidate region analysis across ethnic groups in the Multiethnic Study of Atherosclerosis (MESA).
Genetic variants associated with fasting glucose in European ancestry populations are increasingly well understood. However, the nature of the associations between these single nucleotide polymorphisms (SNPs) and fasting glucose in other racial and ethnic groups is unclear. We sought to examine regions previously identified to be associated with fasting glucose in Caucasian genome-wide association studies (GWAS) across multiple ethnicities in the Multiethnic Study of Atherosclerosis (MESA). Nondiabetic MESA participants with fasting glucose measured at the baseline exam and with GWAS genotyping were included; 2,349 Caucasians, 664 individuals of Chinese descent, 1,366 African Americans, and 1,171 Hispanics. Genotype data were generated from the Affymetrix 6.0 array and imputation in IMPUTE. Fasting glucose was regressed on SNP dosage data in each ethnic group adjusting for age, gender, MESA study center, and ethnic-specific principal components. SNPs from the three gene regions with the strongest associations to fasting glucose in previous Caucasian GWAS (MTNR1B / GCK / G6PC2) were examined in depth. There was limited power to replicate associations in other ethnic groups due to smaller allele frequencies and limited sample size; SNP associations may also have differed across ethnic groups due to differing linkage disequilibrium patterns with causal variants. rs10830963 in MTNR1B and rs4607517 in GCK demonstrated consistent magnitude and direction of association with fasting glucose across ethnic groups, although the associations were often not nominally significant. In conclusion, certain SNPs in MTNR1B and GCK demonstrate consistent effects across four racial and ethnic groups, narrowing the putative region for these causal variants.


Mitochondrial Function, Metabolic Regulation, and Human Disease Viewed through the Prism of Sirtuin 4 (SIRT4) Functions.
As cellular metabolic hubs, mitochondria are the main energy producers for the cell. These organelles host essential energy producing biochemical processes, including the TCA cycle, fatty acid oxidation, and oxidative phosphorylation. An accumulating body of literature has demonstrated that a majority of mitochondrial proteins are decorated with diverse posttranslational modifications (PTMs). Given the critical roles of these proteins in cellular metabolic pathways and response to environmental stress or pathogens, understanding the role of PTMs in regulating their functions has become an area of intense investigation. A major family of enzymes that regulate PTMs within the mitochondria are sirtuins (SIRTs). Albeit until recently the least understood sirtuin, SIRT4 has emerged as an enzyme capable of removing diverse PTMs from its substrates, thereby modulating their functions. SIRT4 was shown to have ADP-ribosyltransferase, deacetylase, lipoamidase, and deacylase enzymatic activities. As metabolic dysfunction is linked to human disease, SIRT4 levels and activities have been implicated in modulating susceptibility to hyperinsulinemia and diabetes, liver disease, cancer, neurodegeneration, heart disease, aging, and pathogenic infections. Therefore, SIRT4 has emerged as a possible candidate for targeted therapeutics. Here, we discuss the diverse enzymatic activities and substrates of SIRT4 and its roles in human health and disease.


Effects of resistance training on the rate of muscle protein synthesis in frail elderly people.
Advancing age is associated with a reduction in skeletal muscle protein, muscle strength, muscle quality, and chemical modifications that may impair protein function. Sarcopenia has been coupled with physical disability, frailty, and a loss of independent function. Using stable isotope tracer methodologies and mass spectrometric detection, we observed: (a) 76-92-year-old physically frail and 62-74-year-old middle-age adults have lower mixed muscle protein synthetic rates than 20-32-year-old men and women; (b) 2 weeks and 3 months of weightlifting exercise increased the synthetic rate of myosin heavy chain (MHC) and mixed muscle proteins to a similar magnitude in frail, middle-age, and young women and men; (c) Serum myostatin-immunoreactive protein levels were elevated in physically frail women and were inversely correlated with lean mass. This suggests that the protein synthetic machinery adapts rapidly to increased contractile activity and that the adaptive response(s) are maintained even in frail elders.


Texture analysis of cartilage T2 maps: individuals with risk factors for OA have higher and more heterogeneous knee cartilage MR T2 compared to normal controls--data from the osteoarthritis initiative.
The goals of this study were (i) to compare the prevalence of focal knee abnormalities, the mean cartilage T2 relaxation time, and the spatial distribution of cartilage magnetic resonance (MR) T2 relaxation times between subjects with and without risk factors for Osteoarthritis (OA), (ii) to determine the relationship between MR cartilage T2 parameters, age and cartilage morphology as determined with whole-organ magnetic resonance imaging scores (WORMS) and (iii) to assess the reproducibility of WORMS scoring and T2 relaxation time measurements including the mean and grey level co-occurrence matrix (GLCM) texture parameters. Subjects with risk factors for OA (n = 92) and healthy controls (n = 53) were randomly selected from the Osteoarthritis Initiative (OAI) incidence and control cohorts, respectively. The specific inclusion criteria for this study were (1) age range 45-55 years, (2) body mass index (BMI) of 19-27 kg/m2, (3) Western Ontario and McMaster University (WOMAC) pain score of zero and (4) Kellgren Lawrence (KL) score of zero at baseline. 3.0 Tesla MR images of the right knee were analyzed using morphological gradings of cartilage, bone marrow and menisci (WORMS) as well as compartment specific cartilage T2 mean and heterogeneity. Regression models adjusted for age, gender, and BMI were used to determine the difference in cartilage parameters between groups. While there was no significant difference in the prevalence of knee abnormalities (cartilage lesions, bone marrow lesions, meniscus lesions) between controls and subjects at risk for OA, T2 parameters (mean T2, GLCM contrast, and GLCM variance) were significantly elevated in those at risk for OA. Additionally, a positive significant association between cartilage WORMS score and cartilage T2 parameters was evident. Overall, this study demonstrated that subjects at risk for OA have both higher and more heterogeneous cartilage T2 values than controls, and that T2 parameters are associated with morphologic degeneration.


[A randomized controlled study of rG.CSF in patients with neutropenia after induction therapy for acute myelogenous leukemia. (rG.CSF Clinical Study Group)].
A randomized treated/non-treated study of rG.CSF (5 micrograms/kg/d, d.i.v.) in patients with acute myelogenous leukemia was conducted to assess its efficacy on fever (> or = 38 degrees C) or documented infection after induction therapy. Of 95 patients enrolled, 46 patients were evaluable for safety and 43 for efficacy in the treated group of 47 patients while 37 of 48 patients were eligible for data analysis in the untreated group. Mare patients showed a recovery in the blood neutrophil count (to > 1,000/microliters) during rG.CSF treatment (14 days) than in the non-treated group (p = 0.039) while the number of febrile patients and duration of fever did not significantly differ between the two groups. The treatment with rG.CSF enabled an early recovery in neutrophil count in the patients with neutropenia and overt signs of infection after induction therapy, but there was no hastened allevistion of symptoms of infection in these patients.


Clinical prediction of laboratory-confirmed influenza in adults with influenza-like illness in primary care. A randomized controlled trial secondary analysis in 15 European countries.
Clinical findings do not accurately predict laboratory diagnosis of influenza. Early identification of influenza is considered useful for proper management decisions in primary care. We evaluated the diagnostic value of the presence and the severity of symptoms for the diagnosis of laboratory-confirmed influenza infection among adults presenting with influenza-like illness (ILI) in primary care. Secondary analysis of patients with ILI who participated in a clinical trial from 2015 to 2018 in 15 European countries. Patients rated signs and symptoms as absent, minor, moderate, or major problem. A nasopharyngeal swab was taken for microbiological identification of influenza and other microorganisms. Models were generated considering (i) the presence of individual symptoms and (ii) the severity rating of symptoms. A total of 2,639 patients aged 18 or older were included in the analysis. The mean age was 41.8 ± 14.7 years, and 1,099 were men (42.1%). Influenza was microbiologically confirmed in 1,337 patients (51.1%). The area under the curve (AUC) of the model for the presence of any of seven symptoms for detecting influenza was 0.66 (95% confidence interval [CI]: 0.65-0.68), whereas the AUC of the symptom severity model, which included eight variables-cough, fever, muscle aches, sweating and/or chills, moderate to severe overall disease, age, abdominal pain, and sore throat-was 0.70 (95% CI: 0.69-0.72). Clinical prediction of microbiologically confirmed influenza in adults with ILI is slightly more accurate when based on patient reported symptom severity than when based on the presence or absence of symptoms.


Long-term patterns in interpersonal behaviour amongst psychopathic patients in secure inpatient treatment: A follow-up study.
Psychopathy is a disorder that is partly defined by with maladaptive interpersonal behaviour and has significant effects on treatment outcomes. A previous study (Draycott et al., ) found that higher levels of psychopathy led to a specific interpersonal 'trajectory' amongst patients in a secure psychiatric treatment programme during the first 9 months of their admission. In that programme, more psychopathic patients became increasingly dominant over time, and less psychopathic patients became increasingly hostile. This study is a longer-term follow-up and extension of that study, extending the window of observation to 33 months of treatment. It was found that the more psychopathic patients' increased dominance returned to baseline levels by 33 months, as did the less psychopathic patients' increased hostility. This suggests that treatment for this group is not idiopathic but leaves unanswered the question as to what these divergent trajectories represent.


A Role for Science in Responding to Health Crises.
The Department of Homeland Security's (DHS) Science and Technology (S&T) Directorate plays a role in public health that extends beyond biodefense. These responsibilities were exercised as part of the 2014-16 Ebola outbreak, leading to productive and beneficial contributions to the international public health response and improved operations in the United States. However, we and others have identified numerous areas for improvement. Based on our successes and lessons learned, we propose a number of ways that DHS, the interagency, and academia can act now to ensure improved responses to future public health crises. These include pre-developing scientific capabilities to respond agnostically to threats, and disease-specific master question lists to organize and inform initial efforts. We are generating DHS-specific playbooks and tools for anticipating future needs and capturing requests from DHS components and our national and international partners, where efforts will also be used to refine and exercise communication and information-sharing practices. These experiences and improvement efforts have encouraged discussions on the role of science in developing government policy, specifically responding to public health crises. We propose specific considerations for both scientists and government decision makers to ensure that the best available science is incorporated into policy and operational decisions to facilitate highly effective responses to future health crises.


[Upper arm vein versus subclavian vein for totally implantable venous access ports for patients with gastrointestinal malignancy: a retrospective comparison of complications].
To compare two different routes of totally implantable venous access ports (TIVPs) from the upper arm vein and the subclavian vein in terms of complications for patients with gastrointestinal malignancy. Patients who underwent implantations of TIVPs from September 2013 to January 2015 were retrospectively evaluated. The outcome measurements were rates and types of postprocedural early-stage and long-term complications. A total of 208 patients(upper arm vein group, 86; subclavian vein group, 122) were included in this study. All TIVPs were implanted successfully. The rate of catheter displacement was higher in upper arm vein group(14.0% vs 5.7%, P=0.04), while other postprocedural early-stage complications had no significant difference between the two groups. The occurrence of transfusion obstacle and rates of overall postprocedural long-term complications were significantly lower in upper arm vein group than that in subclavian vein group(1.2% vs. 9.8%, P=0.02; 7.0% vs. 27.0%, P=0.01, respectively). Compared with subclavian vein group, upper arm vein group has lower postprocedural long-term complication rates and is recommended as a safe and comfortable choice for port implantation.


Determination of blood flow in the finger using near-infrared spectroscopy.
Wavelengths in the near-infrared range have much better penetrance in organic substances than visible light. We used near-infrared spectroscopy to determine non-invasively blood flow in the fingertip. We used laser Doppler technology to measure skin blood flow as a comparison procedure. We performed several manoeuvres to change blood flow. These included restriction of flow, thermal stimulation and post-occlusion hyperaemia. Near-infrared measurements had coefficients of variation of 10-15% at the various wavelengths, contrasting with variability of 30-40% with laser Doppler measurement. With restriction of blood flow, there was a downward shift in the absorbance curve. With thermal stimulation and with post-occlusion hyperaemia, there was a rise in the curve. The flow-induced shifts in the absorbance curve were particularly pronounced in the range of 850-970 nm. The correlation between absorbance values and laser Doppler-determined blood flow was also highest in this range, averaging about 0.69 (n = 625). Near-infrared spectroscopy can therefore be used to scan the fingertip. The absorbances obtained do reflect changes in blood flow. There is a correlation with skin blood flow, although near-infrared measurements are affected by blood flow in the full breadth of the finger, not just the skin. We can measure this blood flow with significant reproducibility. It may be possible to use near-infrared spectroscopy to measure the concentration of individual blood components.


Analysis of auditory evoked potential parameters in the presence of radiofrequency fields using a support vector machines method.
The paper presents a study of global system for mobile (GSM) phone radiofrequency effects on human cerebral activity. The work was based on the study of auditory evoked potentials (AEPs) recorded from healthy humans and epileptic patients. The protocol allowed the comparison of AEPs recorded with or without exposure to electrical fields. Ten variables measured from AEPs were employed in the design of a supervised support vector machines classifier. The classification performance measured the classifier's ability to discriminate features performed with or without radiofrequency exposure. Most significant features were chosen by a backward sequential selection that ranked the variables according to their pertinence for the discrimination. Finally, the most discriminating features were analysed statistically by a Wilcoxon signed rank test. For both populations, the N100 amplitudes were reduced under the influence of GSM radiofrequency (mean attenuation of -0.36 microV for healthy subjects and -0.60 microV for epileptic patients). Healthy subjects showed a N100 latency decrease (-5.23 ms in mean), which could be consistent with mild, localised heating. The auditory cortical activity in humans was modified by GSM phone radiofrequencies, but an effect on brain functionality has not been proven.


The StrokeCog study: development and description of a cognition-focused psychological intervention to address cognitive impairment following stroke.
To describe the process of developing a cognitive rehabilitation intervention for patients with post-stroke cognitive impairment (PSCI) and to describe the intervention prior to evaluation in a pilot randomised controlled trial (RCT). Method: The Medical Research Council framework, 'Developing and evaluating complex interventions', was used to develop the cognitive rehabilitation intervention. We conducted a combined analysis of the existing evidence base for PSCI rehabilitation alongside qualitative exploration of the perspectives of stroke survivors, their families, and healthcare professionals providing stroke care, on the necessary components for a cognitive rehabilitation intervention for PSCI. The Template for Intervention Description and Replication checklist was used as a structural framework for the description of the intervention. Results: The intervention comprises a five-week intervention integrating group-based activities, supported by a clinical neuropsychologist, with home-based activities to encourage self-efficacy through the practice of adjustment and compensatory strategies learned in the group format to achieve the patients' identified goals in managing their PSCI. Conclusion: A cognitive rehabilitation intervention for patients with PSCI has been developed and described. We are in the process of developing a structured intervention manual to standardise the content and delivery of the intervention for further testing in a pilot RCT.


Quality of neonatal care and outcome.
High quality of care in neonatology implies providing an appropriate level of care to well newborn babies as well as more specialised care for the few babies who need it. Audit, surveillance and outcome studies may not always capture the complexity of quality of care and its contribution to outcome, and a more focused approach to standards of care evaluation may be required. Future progress in this field in the UK would benefit from a more coordinated approach from different organisations to bring together expertise in large database, management and analysis, audit and a national profile for feedback, evidence-based guidelines and guidelines development skills, expertise in the practice of changes together with the promotion by credible perinatal authorities of clinical practice.


Adjuvant ovarian suppression versus chemotherapy for premenopausal, hormone-responsive breast cancer: quality of life and efficacy tradeoffs.
Recent clinical trials suggest that adjuvant ovarian suppression may be an equally effective and less toxic alternative to systemic chemotherapy in premenopausal women with hormone-responsive breast cancer. We used a decision-analytic framework to evaluate tradeoffs between efficacy and quality of life in the choice between these treatments. We used a Markov state-transition model to simulate clinical practice in a cohort of 40-year-old premenopausal women with newly diagnosed, hormone-responsive early breast cancer. We assessed three adjuvant treatments: chemotherapy, surgical ovarian suppression, and medical ovarian suppression. Outcomes were recurrence-free, overall, and quality-adjusted survival. Quality-adjusted survival reflected effects of cancer, treatment-related side effects, and menopausal symptoms. Assuming equal efficacy, ovarian suppression was superior to chemotherapy when the relative utility of chemotherapy side effects compared with ovarian suppression side effects was less than 0.95. Results were sensitive to assumptions about the likelihood, duration and consequences of treatment-induced menopause. Treatment choice was affected by a 7% proportional increase in the efficacy of one therapy relative to the others, independent of other factors. If adjuvant chemotherapy and ovarian suppression have similar efficacy, then there may be a subgroup of women for whom quality-of-life considerations dominate the choice of treatment. However, small differences in the relative efficacy of these therapies have a substantial impact on treatment choice, regardless of side effects and menopausal transitions.


How fast are hospital prices really rising?
The hospital services component of the Consumer Price Index (CPI) measures the cost of hospital services to private patients paying list prices. It is, however, widely used as an estimate of the overall rate of inflation in hospital prices in spite of the fact that there are strong reasons to believe that it is inappropriate to use the CPI for this purpose. This is because: 1) A growing number of patients are enrolled in health maintenance organizations (HMOs) and preferred provider organizations (PPOs), which negotiate discounts from list prices; and 2) the size of the discounts may have been increasing. The potential result is a gap between the rate of inflation of list prices and the rate of inflation of actual prices paid in transactions. This study explores whether such a gap exists and determines its possible magnitude. In addition, parallel indices for list and actual prices are computed on the basis of data from California hospitals for fiscal years 1983-1988. The analysis suggests that list price inflation has greatly exceeded actual inflation--by a factor of two for recent years. These findings have broad implications for evaluating not only inflation but also the impact of cost containment strategies.


Space charge effects in photoemission electron microscopy using amplified femtosecond laser pulses.
Linear and nonlinear photoemission microscopy is used to study the origin of space charge effects that are frequently observed if amplified femtosecond lasers are used for generation of photoelectrons. Space charge effects are apparent in the width of the photoemission spectra, but also create image blur. The onset threshold for space charge effects is determined by recording the width of photoemission spectra and by finding the conditions under which spectral broadening is just less than the energy resolution of the microscope. The principal findings are independent if harmonics of the fundamental of the fs laser pulses are used, but the space charge effects are found to be more dominant at lower repetition rates. By inserting apertures into the electron path, the place at which space charge effects occur can be localized.


Laminar differences in plasticity in area 17 following retinal lesions in kittens or adult cats.
Circumscribed retinal lesions in adult cats result in a reorganization of circuitry in area 17 such that neurons in the lesion projection zone (LPZ) can now be activated, not from their original receptive fields (RFs) but from regions of normal retina adjacent to the lesion ('ectopic' RFs). We have studied this phenomenon further by making circumscribed monocular retinal lesions in 8-week-old kittens and recording responses to visual stimuli of neurons in the LPZ of area 17 when these cats reached adulthood. These responses have been compared with those in adult-lesioned cats either of relatively short postlesion survival (2-24 weeks) or long postlesion survival (3.5-4.5 years). In both kitten-lesioned and adult-lesioned animals most LPZ neurons recorded from the supragranular layers (II and III) not only exhibited new ectopic RFs when stimuli were presented via the lesioned eye but the RF properties (e.g. the sizes of excitatory RFs, orientation and direction selectivities, velocity preferences and upper cut-off velocities) were often indistinguishable from those seen when stimuli were presented via the nonlesioned eye. Similarly, in both kitten-lesioned and adult-lesioned animals, most LPZ neurons recorded from the granular and infragranular layers (IV, V, VI), like those recorded from the supragranular layers, were binocular. However, in adult-lesioned but not in kitten-lesioned animals, the responses and the upper cut-off velocities of LPZ cells recorded from the granular and infragranular layers to stimuli presented via ectopic RFs tended to be, respectively, substantially weaker and lower than those for stimuli presented via the nonlesioned eye. The age-related laminar differences in reorganizational plasticity of cat striate cortex correlate with the lamino-temporal pattern of distribution of N-methyl-d-aspartate glutamate receptors in striate cortex.


Zigzag turning preference of freely crawling cells.
The coordinated motion of a cell is fundamental to many important biological processes such as development, wound healing, and phagocytosis. For eukaryotic cells, such as amoebae or animal cells, the cell motility is based on crawling and involves a complex set of internal biochemical events. A recent study reported very interesting crawling behavior of single cell amoeba: in the absence of an external cue, free amoebae move randomly with a noisy, yet, discernible sequence of 'run-and-turns' analogous to the 'run-and-tumbles' of swimming bacteria. Interestingly, amoeboid trajectories favor zigzag turns. In other words, the cells bias their crawling by making a turn in the opposite direction to a previous turn. This property enhances the long range directional persistence of the moving trajectories. This study proposes that such a zigzag crawling behavior can be a general property of any crawling cells by demonstrating that 1) microglia, which are the immune cells of the brain, and 2) a simple rule-based model cell, which incorporates the actual biochemistry and mechanics behind cell crawling, both exhibit similar type of crawling behavior. Almost all legged animals walk by alternating their feet. Similarly, all crawling cells appear to move forward by alternating the direction of their movement, even though the regularity and degree of zigzag preference vary from one type to the other.


Intraoperative adjusted-dose heparin thromboembolic prophylaxis in primary total hip arthroplasty.
Intraoperative, fixed, intermittent, low-dose intravenous heparin prophylaxis has been reported to significantly reduce the incidence of thromboembolic disease from 24.3% to 8.3% after primary total hip arthroplasty (THA). This study examined the potential efficacy of adjusted-dose intraoperative heparin administration, keeping the activated clotting time at 30%-50% greater than normal. It was hypothesized that prolongation of clotting parameters in a uniform manner would further decrease the incidence of thromboembolic disease postoperatively. Sixty-one patients completed the protocol. The overall incidence of thromboembolic disease was 9.8%. Five patients had a positive postoperative venogram: four in the calf and one in the proximal deep thigh vein. One patient had a symptomatic nonfatal pulmonary embolus diagnosed by ventilation-perfusion scan. There were no complications related to heparin administration. This approach was therefore equally as effective as the fixed-dose regimen, and it further confirmed the efficacy and safety of an intraoperative heparin prophylaxis regimen. The extra efforts required to maintain a constant intraoperative level of anticoagulation did not prove advantageous over the simpler, fixed-dose regimen in reducing the incidence of thromboembolic disease after primary THA.


The promotion of hair regrowth by topical application of a Perilla frutescens extract through increased cell viability and antagonism of testosterone and dihydrotestosterone.
This study investigated the potential hair regrowth effects associated with a plant extract of Perilla frutescens, which was selected due to its putative hair regrowth activity. Extracts were prepared from dried P. frutescens suspended in distilled water, where the resultant aqueous suspension was fractionated sequentially using hexane, ethyl acetate, n-butanol, and distilled water. We observed that the n-butanol fraction resulted in the highest hair regrowth activity. The n-butanol soluble fraction of P. frutescens extract (BFPE) was further separated using AB-8 macroporous resin and silica gel chromatography to obtain rosmarinic acid (RA), which demonstrated effective hair growth regeneration potential. BFPE also showed in vivo anti-androgenic activity following the use of a hair growth assay in testosterone-sensitive male C57Bl/6NCrSlc mice. Furthermore, the effects of cell viability promotion were investigated following an in vitro analysis in primary hair follicle fibroblast cells (PHFCs) treated with RA. The results suggested that RA was the active compound in P. frutescens that triggers hair growth, and RA could be a potential therapeutic agent for the promotion of hair growth and prevention of androgenetic alopecia (AGA).


Molecular biology of renal Na(+)-H+ exchangers.
Na(+)-H+ exchangers are plasma membrane proteins that are responsible for Cl- and HCO3- reabsorption and regulation of intracellular pH in several nephron segments. Recently, a cDNA encoding a human Na(+)-H+ exchanger of unknown tissue origin was cloned, and Northern blot analysis revealed that structurally similar transcripts were expressed in rabbit kidney and porcine renal epithelial cells (LLC-PK1). To clone these renal transcripts we employed cDNA library screening and the polymerase chain reaction (PCR). We obtained 2.5 kb and 1.4 kb cDNAs corresponding to the 5' untranslated region and the membrane-associated domain of a rabbit renal Na(+)-H+ exchanger. From LLC-PK1 cells we obtained 1.5 kb and 1.3 kb cDNAs encoding the membrane-associated and cytoplasmic domains. The sequences of cDNAs from these three species were very similar and suggested a high degree of evolutionary conservation. Immunolocalization of synthetic oligopeptides derived from the deduced amino acid sequences indicated that the cloned cDNAs encoded the amiloride-sensitive form of the Na(+)-H+ exchanger present in basolateral membranes of epithelia. cDNAs were also used to study regulation of Na(+)-H+ exchanger gene expression in the kidney, and we found that metabolic acidosis stimulated both the transport rate and steady-state transcript levels of the basolateral Na(+)-H+ exchanger in LLC-PK1 cells.


microRNA-141 is involved in a nasopharyngeal carcinoma-related genes network.
microRNAs (miRNAs) are small non-coding RNAs and have been implicated in the pathology of various diseases, including cancer. Here we report that the miRNA profiles have been changed after knockdown of one of the most important oncogene c-MYC or re-expression of a candidate tumor suppressor gene SPLUNC1 in nasopharyngeal carcinoma (NPC) cells. Both c-MYC knockdown and SPLUNC1 re-expression can down-regulate microRNA-141 (miR-141). miR-141 is up-regulated in NPC specimens in comparison with normal nasopharyngeal epithelium. Inhibition of miR-141 could affect cell cycle, apoptosis, cell growth, migration and invasion in NPC cells. We found that BRD3, UBAP1 and PTEN are potential targets of miR-141, which had been confirmed following luciferase reporter assays and western blotting. BRD3 and UBAP1 are both involved in NPC carcinogenesis as confirmed through our previous studies and PTEN is a crucial tumor suppressor in many tumor types. BRD3 is involved in the regulation of the Rb/E2F pathway. Inhibition of miR-141 could affect some important molecules in the Rb/E2F, JNK2 and AKT pathways. It is well known that carcinogenesis of NPC is involved in the networks of genetic and epigenetic alteration events. We propose that miR-141- and tumor-related genes c-MYC, SPLUNC1, BRD3, UBAP1 and PTEN may constitute a gene-miRNA network to contribute to NPC development.


Measurement of BTEX (benzene, toluene, ethybenzene, and xylene) levels at urban and semirural areas of Algiers City using passive air samplers.
The study presents the levels of air pollution by aromatic organic compounds BTEX (benzene, toluene, ethylbenzene, o-, m-, and p-xylenes) in the city of Algiers. The sampling was carried out using Radiello passive sampler. Three sampling campaigns were carried out in roadside, tunnel, urban background, and semirural sites in Algiers. In order to determine the diurnal mean levels of air pollution by BTEX to which people are exposed, a modified passive sampler was used for the first time. In addition, monitoring of pollution inside vehicles was also made. In the spring of 2009, more than 27 samplings were carried out. In the background and road traffic sites the Radiello sampler was exposed for 7 days, whereas the time exposure was reduced to 1 day in the case of the vehicle as well as the tunnel. The results indicate that average benzene concentrations in the roadside and inside vehicle exceed largely the limit value of 5 microg m(-3) established by the European Community (EC). On the other hand, it has been noticed that the concentration levels of other BTEX are relatively high. Also, in order to identify the origin of emission sources, ratios and correlations between the BTEX species have been highlighted. This study shows that road traffic remains the main source of many local emission in Algiers. The vehicle fleet in Algeria is growing rapidly since the 1990s following economic growth and is responsible for the increasing air pollution in large cities. Because there are no data collection of BTEX carried out by national air quality network, all environmental and transportation policies are based on European emissions standards, but national emission standards are currently not in place. This work will contribute to the analysis of real emissions of BTEX in Algiers, for the development of management and for assessment of population exposure variation depending on the location in the city of Algiers.


Benefits and Harms of Intensive Blood Pressure Treatment in Adults Aged 60 Years or Older: A Systematic Review and Meta-analysis.
Recent guidelines recommend a systolic blood pressure (SBP) goal of less than 150 mm Hg for adults aged 60 years or older, but the balance of benefits and harms is unclear in light of newer evidence. To systematically review the effects of more versus less intensive BP control in older adults. Multiple databases through January 2015 and MEDLINE to September 2016. 21 randomized, controlled trials comparing BP targets or treatment intensity, and 3 observational studies that assessed harms. Two investigators extracted data, assessed study quality, and graded the evidence using published criteria. Nine trials provided high-strength evidence that BP control to less than 150/90 mm Hg reduces mortality (relative risk [RR], 0.90 [95% CI, 0.83 to 0.98]), cardiac events (RR, 0.77 [CI, 0.68 to 0.89]), and stroke (RR, 0.74 [CI, 0.65 to 0.84]). Six trials yielded low- to moderate-strength evidence that lower targets (≤140/85 mm Hg) are associated with marginally significant decreases in cardiac events (RR, 0.82 [CI, 0.64 to 1.00]) and stroke (RR, 0.79 [CI, 0.59 to 0.99]) and nonsignificantly fewer deaths (RR, 0.86 [CI, 0.69 to 1.06]). Low- to moderate-strength evidence showed that lower BP targets do not increase falls or cognitive impairment. Data relevant to frail elderly adults and the effect of multimorbidity are limited. Treatment to at least current guideline standards for BP (<150/90 mm Hg) substantially improves health outcomes in older adults. There is less consistent evidence, largely from 1 trial targeting SBP less than 120 mm Hg, that lower BP targets are beneficial for high-risk patients. Lower BP targets did not increase falls or cognitive decline but are associated with hypotension, syncope, and greater medication burden. U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. (PROSPERO 2015: CRD42015017677).


Angiostrongylus vasorum and Eucoleus aerophilus in foxes (Vulpes vulpes) in Great Britain.
The nematode parasite Angiostrongylus vasorum is a source of increasing concern in several parts of the world, where it causes significant disease in dogs. Wild canids, especially foxes, are likely to have a role in the epidemiology of canine infection, and the parasite could also affect fox health and population dynamics. The heart and pulmonary vasculature of 546 foxes culled mostly by gamekeepers in Great Britain in 2005-2006 were examined by dissection and a modified flushing technique. Forty foxes were found to be infected, giving an overall prevalence in the UK fox population of 7.3% (5.3-9.9). Prevalence varied widely between regions, from 0% (0-3) in Scotland and northern England to 23% (16-32) in south-east England. This closely matches the perceived incidence of disease in dogs, which is commonly diagnosed in the south-east but rarely in the north. In the Midlands, where disease has recently appeared in dogs, prevalence in foxes was 4.8% (2-11). Close geographical overlap of parasite distribution in foxes and dogs does not necessarily indicate an important wildlife reservoir of infection, but does suggest that A. vasorum might be spreading northwards. The hearts of infected foxes had thicker right ventricles than those of uninfected foxes, suggesting that the parasite could affect fox health and fitness. Burdens ranged from 1 to 59 adult nematodes. Sex, age and body condition were not significantly associated with infection. Eucoleus aerophilus and Crenosoma vulpis, nematode parasites of the respiratory system, were found in 213 and 11 foxes respectively, with slightly higher prevalence of E. aerophilus in the south and east. No specimens of the heartworm Dirofilaria immitis were found, giving an upper 95% confidence interval for prevalence of 0.84%.


Treatment of chloroquine-resistant Plasmodium vivax with chloroquine and primaquine or halofantrine.
Optimal therapy for infection by chloroquine-resistant Plasmodium vivax has not been established. From 1992 to 1994 during three separate studies, 147 Javanese residents of Irian Jaya infected by P. vivax were treated with either chloroquine (25 mg of base/kg during 3 days or 10 mg of base/kg in one dose) plus primaquine (10 mg/kg during 28 days or 2.5 mg/kg during 3 days) (n = 78), chloroquine plus placebo (n = 50), or halofantrine (24 mg base/kg in 12 h; n = 19). There was no difference in tolerance to or side effects of any of the regimens. Within 14 days of starting therapy, therapeutic failure among these patients was 44% for chloroquine, 5% for chloroquine plus primaquine (P < .001), and 0 for halofantrine (P < .001). After 28 days, therapeutic failure was 78%, 15%, and 6%, respectively. Thus, chloroquine plus primaquine in combination and halofantrine alone are effective therapies for chloroquine-resistant P. vivax.


Proteomic profiling of Cronobacter turicensis 3032, a food-borne opportunistic pathogen.
Members of the genus Cronobacter are opportunistic pathogens for neonates and are often associated with contaminated milk powder formulas. At present little is known about the virulence mechanisms or the natural reservoir of these organisms. The proteome of Cronobacter turicensis 3032, which has recently caused two deaths, was mapped aiming at a better understanding of physiology and putative pathogenic traits of this clinical isolate. Our analyses of extracellular, surface-associated and whole-cell proteins by two complementary proteomics approaches, 1D-SDS-PAGE combined with LC-ESI-MS/MS and 2D-LC-MALDI-TOF/TOF MS, lead to the identification of 832 proteins corresponding to a remarkable 19% of the theoretically expressed protein complement of C. turicensis. The majority of the identified proteins are involved in central metabolic pathways, translation, protein folding and stability. Several putative virulence factors, whose expressions were confirmed by phenotypic assays, could be identified: a macrophage infectivity potentiator involved in C. turicensis persistence in host cells, a superoxide dismutase protecting the pathogen against reactive oxygen species and an enterobactin-receptor protein for the uptake of siderophore-bound iron. Most interestingly, a chitinase and a metalloprotease that might act against insects and fungi but no casein hydrolysing enzymes were found, suggesting that there is an environmental natural habitat of C. turicensis 3032.


Denervation does not alter the number of neuronal bungarotoxin binding sites on autonomic neurons in the frog cardiac ganglion.
The binding of neuronal bungarotoxin (n-BuTX; also known as bungarotoxin 3.1, kappa-bungarotoxin, and toxin F) was analyzed in normal and denervated parasympathetic cardiac ganglia of the frog Rana pipiens, n-BuTX blocks both EPSPs and ACh potentials at 5-20 nM, as determined by intracellular recording techniques. Scatchard analysis on homogenates indicates that cardiac ganglia have two classes of binding sites for 125I-n-BuTX: a high-affinity site with an apparent dissociation constant (Kd,app) of 1.7 nM and a Bmax (number of binding sites) of 3.8 fmol/ganglion and a low-affinity site with a Kd,app of 12 microM and a Bmax of 14 pmol/ganglion. alpha-Bungarotoxin does not appear to interfere with the binding of 125I-n-BuTX to either site. The high-affinity binding site is likely to be the functional nicotinic ACh receptor (AChR), given the similarity between its affinity for 125I-n-BuTX and the concentration of n-BuTX required to block AChR function. Light microscopic autoradiographic analysis of 125I-n-BuTX binding to the ganglion cell surface reveals that toxin binding is concentrated at synaptic sites, which were identified using a synaptic vesicle-specific antibody. Scatchard analysis of autoradiographic data reveals that 125I-n-BuTX binding to the neuronal surface is saturable and has a Kd,app similar to that of the high-affinity binding site characterized in homogenates. Surface binding of 125I-n-BuTX is blocked by nicotine, carbachol, and d-tubocurarine (IC50 less than 20 microM), but not by atropine (IC50 greater than 10 mM). Denervation of the heart increases the ACh sensitivity of cardiac ganglion cells but has no effect upon the number of high-affinity binding sites for 125I-n-BuTX in tissue homogenates. Moreover, autoradiographic analysis indicates that denervation does not alter the number of 125I-n-BuTX binding sites on the ganglion cell surface. n-BuTX is as effective in reducing ganglion cell responses to ACh in denervated ganglia as it is in normally innervated ganglia. These results suggest that denervation alters neither the total number of nicotinic AChRs in the cardiac ganglion nor the number found on the surface of ganglion cells. These autonomic neurons thus respond differently to denervation than do skeletal myofibers. The increase in ACh sensitivity displayed by cardiac ganglion cells upon denervation cannot be explained by changes in AChR number.


The ultrasound characteristics of regions identified as suspicious by magnetic resonance imaging (MRI) predict the likelihood of clinically significant cancer on MRI-ultrasound fusion-targeted biopsy.
To determine whether the presence of an ultrasound hypoechoic region at the site of a region of interest (ROI) on magnetic resonance imaging (MRI) results in improved prostate cancer (PCa) detection and predicts clinically significant PCa on MRI-ultrasonography fusion-targeted prostate biopsy (MRF-TB). Between July 2011 and June 2017, 1058 men who underwent MRF-TB, with or without systematic biopsy, by a single surgeon were prospectively entered into an institutional review board-approved database. Each MRI ROI was identified and scored for suspicion by a single radiologist, and was prospectively evaluated for presence of a hypoechoic region at the site by the surgeon and graded as 0, 1 or 2, representing none, a poorly demarcated ROI-HyR, or a well demarcated ROI-HyR, respectively. The interaction of MRI suspicion score (mSS) and ultrasonography grade (USG), and the prediction of cancer detection rate by USG, were evaluated through univariate and multivariate analysis. For 672 men, the overall and Gleason score (GS) ≥7 cancer detection rates were 61.2% and 39.6%, respectively. The cancer detection rates for USGs 0, 1 and 2 were 46.2%, 58.6% and 76.0% (P < 0.001) for any cancer, and 18.7%, 35.2% and 61.1% (P < 0.001) for GS ≥7 cancer, respectively. For MRF-TB only, the GS ≥7 cancer detection rates for USG 0, 1 and 2 were 12.8%, 25.7% and 52.0%, respectively (P < 0.001). On univariate analysis, in men with mSS 2-4, USG was predictive of GS ≥7 cancer detection rate. Multivariable regression analysis showed that USG, prostate-specific antigen density and mSS were predictive of GS ≥7 PCa on MRF-TB. Ultrasonography findings at the site of an MRI ROI independently predict the likelihood of GS ≥7 PCa, as men with a well-demarcated ROI-HyR at the time of MRF-TB have a higher risk than men without.


A filter paper-based microdevice for low-cost, rapid, and automated DNA extraction and amplification from diverse sample types.
A plastic microfluidic device that integrates a filter disc as a DNA capture phase was successfully developed for low-cost, rapid and automated DNA extraction and PCR amplification from various raw samples. The microdevice was constructed by sandwiching a piece of Fusion 5 filter, as well as a PDMS (polydimethylsiloxane) membrane, between two PMMA (poly(methyl methacrylate)) layers. An automated DNA extraction from 1 μL of human whole blood can be finished on the chip in 7 minutes by sequentially aspirating NaOH, HCl, and water through the filter. The filter disc containing extracted DNA was then taken out directly for PCR. On-chip DNA purification from 0.25-1 μL of human whole blood yielded 8.1-21.8 ng of DNA, higher than those obtained using QIAamp® DNA Micro kits. To realize DNA extraction from raw samples, an additional sample loading chamber containing a filter net with an 80 μm mesh size was designed in front of the extraction chamber to accommodate sample materials. Real-world samples, including whole blood, dried blood stains on Whatman® 903 paper, dried blood stains on FTA™ cards, buccal swabs, saliva, and cigarette butts, can all be processed in the system in 8 minutes. In addition, multiplex amplification of 15 STR (short tandem repeat) loci and Sanger-based DNA sequencing of the 520 bp GJB2 gene were accomplished from the filters that contained extracted DNA from blood. To further prove the feasibility of integrating this extraction method with downstream analyses, "in situ" PCR amplifications were successfully performed in the DNA extraction chamber following DNA purification from blood and blood stains without DNA elution. Using a modified protocol to bond the PDMS and PMMA, our plastic PDMS devices withstood the PCR process without any leakage. This study represents a significant step towards the practical application of on-chip DNA extraction methods, as well as the development of fully integrated genetic analytical systems.


The parallel programming of landing position in saccadic eye movement sequences.
Saccadic eye movements occur in sequences, gathering new information about the visual environment to support successful task completion. Here, we examine the control of these saccadic sequences and specifically the extent to which the spatial aspects of the saccadic responses are programmed in parallel. We asked participants to saccade to a series of visual targets and, while they shifted their gaze around the display, we displaced select targets. We found that saccade landing position was deviated toward the previous location of the target suggesting that partial parallel programming of target location information was occurring. The saccade landing position was also affected by the new target location, which demonstrates that the saccade landing position was also partially updated following the shift. This pattern was present even for targets that were the subject of the next fixation. Having a greater preview about the sequence path influenced saccade accuracy with saccades being less affected by relocations when there is less preview information. The results demonstrate that landing positions from a saccade sequence are programmed in parallel and combined with more immediate visual signals.


Environmental Perceptions and Health before and after Relocation to a Green Building.
Green buildings are designed to have low environmental impacts and improved occupant health and well-being. Improvements to the built environment including ventilation, lighting, and materials have resulted in improved indoor environmental quality (IEQ) in green buildings, but the evidence around occupant health is currently centered around environmental perceptions and self-reported health. To investigate the objective impact of green buildings on health, we tracked IEQ, self-reported health, and heart rate in 30 participants from green and conventional buildings for two weeks. 24 participants were then selected to be relocated to the Syracuse Center of Excellence, a LEED platinum building, for six workdays. While they were there, ventilation, CO2, and volatile organic compound (VOC) levels were changed on different days to match the IEQ of conventional, green, and green+ (green with increased ventilation) buildings. Participants reported improved air quality, odors, thermal comfort, ergonomics, noise and lighting and fewer health symptoms in green buildings prior to relocation. After relocation, participants consistently reported fewer symptoms during the green building conditions compared to the conventional one, yet symptom counts were more closely associated with environmental perceptions than with measured IEQ. On average, participants had 4.7 times the odds of reporting a lack of air movement, 1.4 more symptoms (p-value = 0.019) and a 2 bpm higher heart rate (p-value < 0.001) for a 1000 ppm increase in indoor CO2 concentration. These findings suggest that occupant health in green and conventional buildings is driven by both environmental perceptions and physiological pathways.


Non-Hodgkin's lymphoma among asthmatics exposed to pesticides.
We conducted a pooled analysis of population-based case-control studies in Iowa, Minnesota and Nebraska to investigate whether asthma modifies risk of non-Hodgkin's lymphoma (NHL) associated with pesticide exposures. Cases (n = 872) diagnosed with NHL from 1980 to 1986 and frequency-matched controls (n = 2,381) randomly selected from the same geographic areas as the cases were included. Information on use of pesticides and history of asthma was based on interviews. Unconditional logistic regression was used to calculate ORs, adjusted for age, state and vital status. Of all subjects, 177 (45 cases, 132 controls) reported having been told by their doctor that they had asthma. Subjects with an asthma history had a nonsignificantly lower risk of NHL than nonasthmatics (OR = 0.6, 95% CI 0.3-1.4), and there was no main effect of pesticide exposure (OR = 1.0, 95% CI 0.8-1.2). However, asthmatics tended to have larger ORs associated with exposure to pesticides than nonasthmatics. The OR among asthmatics was 1.8 (95% CI 1.1-3.2) for ever-use of crop insecticides, 2.7 (95% CI 1.0-7.2) for chlordane, 2.4 (95% CI 1.0-5.7) for lindane and 3.7 (95% CI 1.3-10.9) for fonofos. Among nonasthmatics, ORs were 1.1 (0.9-1.3), 1.5 (1.1-2.2), 1.3 (0.97-1.8) and 1.6 (1.0-2.4), respectively. Although there is limited power for assessing interaction, our results suggest that the risk of NHL among asthmatics with pesticide exposure may be higher than among nonasthmatics with pesticide exposure.


Crystallographic analysis reveals octamerization of viroplasm matrix protein P9-1 of Rice black streaked dwarf virus.
The P9-1 protein of Rice black streaked dwarf virus accumulates in viroplasm inclusions, which are structures that appear to play an important role in viral morphogenesis and are commonly found in viruses in the family Reoviridae. Crystallographic analysis of P9-1 revealed structural features that allow the protein to form dimers via hydrophobic interactions. Each dimer has carboxy-terminal regions, resembling arms, that extend to neighboring dimers, thereby uniting sets of four dimers via lateral hydrophobic interactions, to yield cylindrical octamers. The importance of these regions for the formation of viroplasm-like inclusions was confirmed by the absence of such inclusions when P9-1 was expressed without its carboxy-terminal arm. The octamers are vertically elongated cylinders resembling the structures formed by NSP2 of rotavirus, even though there are no significant similarities between the respective primary and secondary structures of the two proteins. Our results suggest that an octameric structure with an internal pore might be important for the functioning of the respective proteins in the events that occur in the viroplasm, which might include viral morphogenesis.


A new acoustic portal into the odontocete ear and vibrational analysis of the tympanoperiotic complex.
Global concern over the possible deleterious effects of noise on marine organisms was catalyzed when toothed whales stranded and died in the presence of high intensity sound. The lack of knowledge about mechanisms of hearing in toothed whales prompted our group to study the anatomy and build a finite element model to simulate sound reception in odontocetes. The primary auditory pathway in toothed whales is an evolutionary novelty, compensating for the impedance mismatch experienced by whale ancestors as they moved from hearing in air to hearing in water. The mechanism by which high-frequency vibrations pass from the low density fats of the lower jaw into the dense bones of the auditory apparatus is a key to understanding odontocete hearing. Here we identify a new acoustic portal into the ear complex, the tympanoperiotic complex (TPC) and a plausible mechanism by which sound is transduced into the bony components. We reveal the intact anatomic geometry using CT scanning, and test functional preconceptions using finite element modeling and vibrational analysis. We show that the mandibular fat bodies bifurcate posteriorly, attaching to the TPC in two distinct locations. The smaller branch is an inconspicuous, previously undescribed channel, a cone-shaped fat body that fits into a thin-walled bony funnel just anterior to the sigmoid process of the TPC. The TPC also contains regions of thin translucent bone that define zones of differential flexibility, enabling the TPC to bend in response to sound pressure, thus providing a mechanism for vibrations to pass through the ossicular chain. The techniques used to discover the new acoustic portal in toothed whales, provide a means to decipher auditory filtering, beam formation, impedance matching, and transduction. These tools can also be used to address concerns about the potential deleterious effects of high-intensity sound in a broad spectrum of marine organisms, from whales to fish.


SFDR enhancement in analog photonic links by simultaneous compensation for dispersion and nonlinearity.
A method to improve the spurious-free dynamic range (SFDR) of analog photonic links has been proposed and experimentally demonstrated, which only consists of a phase modulator (PM), a polarizer and an optical filter. Such structure could compensate for the chromatic dispersion and the nonlinearity of the modulator simultaneously. In addition, by adjusting the states of polarization (SOPs) launching into the PM and the polarizer, the proposed scheme could also be reconfigured to mitigate the second harmonic nonlinearity induced by the photodetector. Experimental results show that the suppressions of the second-order and third-order intermodulation distortions (IMD2 & IMD3) are larger than 14-dB and 25.4-dB, respectively. Furthermore, the SFDR can achieve ~110-dB · Hz(4/5) for 40-km fiber transmission, which is 26-dB higher than that of the link without compensation.


Randomized controlled trial of levamisole hydrochloride as adjunctive therapy in severe falciparum malaria with high parasitemia.
Cytoadherence and sequestration of erythrocytes containing mature stages of Plasmodium falciparum are central to the pathogenesis of severe malaria. The oral anthelminthic drug levamisole inhibits cytoadherence in vitro and reduces sequestration of late-stage parasites in uncomplicated falciparum malaria treated with quinine. Fifty-six adult patients with severe malaria and high parasitemia admitted to a referral hospital in Bangladesh were randomized to receive a single dose of levamisole hydrochloride (150 mg) or no adjuvant to antimalarial treatment with intravenous artesunate. Circulating late-stage parasites measured as the median area under the parasite clearance curves were 2150 (interquartile range [IQR], 0-28 025) parasites/µL × hour in patients treated with levamisole and 5489 (IQR, 192-25 848) parasites/µL × hour in controls (P = .25). The "sequestration ratios" at 6 and 12 hours for all parasite stages and changes in microvascular blood flow did not differ between treatment groups (all P > .40). The median time to normalization of plasma lactate (<2 mmol/L) was 24 (IQR, 12-30) hours with levamisole vs 28 (IQR, 12-36) hours without levamisole (P = .15). There was no benefit of a single-dose of levamisole hydrochloride as adjuvant to intravenous artesunate in the treatment of adults with severe falciparum malaria. Rapid parasite killing by intravenous artesunate might obscure the effects of levamisole.


Association of HLA-DRB1 alleles with giant cell tumour of bone.
To examine the possible influence of the MHC class II antigens alleles in the formation of the multinucleate aggressive giant cell tumour of bone. HLA class II antigen alleles were investigated in eight white patients from north east England with confirmed diagnosis of giant cell tumour of bone. All had locally aggressive, immunophenotypically HLA-DR negative giant cell tumours. Five of the eight patients were found to be positive for HLA-DRB1*0801/3, the distribution of this allele in healthy white controls being quite low (2%). All but one of the patients possessing DRB1*080 also expressed DRB1*070. HLA-DRB1*080 is pre-dominant in patients with immunophenotypic HLA-DR negative giant cell tumour of bone; individuals with the genotype 070/080 are at particularly high risk of developing giant cell tumour of bone.


Current advances in T-cell-based cancer immunotherapy.
Cancer is a leading cause of death worldwide; due to the lack of ideal cancer biomarkers for early detection or diagnosis, most patients present with late-stage disease at the time of diagnosis, thus limiting the potential for successful treatment. Traditional cancer treatments, including surgery, chemotherapy and radiation therapy, have demonstrated very limited efficacy for patients with late-stage disease. Therefore, innovative and effective cancer treatments are urgently needed for cancer patients with late-stage and refractory disease. Cancer immunotherapy, particularly adoptive cell transfer, has shown great promise in the treatment of patients with late-stage disease, including those who are refractory to standard therapies. In this review, we will highlight recent advances and discuss future directions in adoptive cell transfer based cancer immunotherapy.


Key determinants of target DNA recognition by retroviral intasomes.
Retroviral integration favors weakly conserved palindrome sequences at the sites of viral DNA joining and generates a short (4-6 bp) duplication of host DNA flanking the provirus. We previously determined two key parameters that underlie the target DNA preference for prototype foamy virus (PFV) and human immunodeficiency virus type 1 (HIV-1) integration: flexible pyrimidine (Y)/purine (R) dinucleotide steps at the centers of the integration sites, and base contacts with specific integrase residues, such as Ala188 in PFV integrase and Ser119 in HIV-1 integrase. Here we examined the dinucleotide preference profiles of a range of retroviruses and correlated these findings with respect to length of target site duplication (TSD). Integration datasets covering six viral genera and the three lengths of TSD were accessed from the literature or generated in this work. All viruses exhibited significant enrichments of flexible YR and/or selection against rigid RY dinucleotide steps at the centers of integration sites, and the magnitude of this enrichment inversely correlated with TSD length. The DNA sequence environments of in vivo-generated HIV-1 and PFV sites were consistent with integration into nucleosomes, however, the local sequence preferences were largely independent of target DNA chromatinization. Integration sites derived from cells infected with the gammaretrovirus reticuloendotheliosis virus strain A (Rev-A), which yields a 5 bp TSD, revealed the targeting of global chromatin features most similar to those of Moloney murine leukemia virus, which yields a 4 bp duplication. In vitro assays revealed that Rev-A integrase interacts with and is catalytically stimulated by cellular bromodomain containing 4 protein. Retroviral integrases have likely evolved to bend target DNA to fit scissile phosphodiester bonds into two active sites for integration, and viruses that cut target DNA with a 6 bp stagger may not need to bend DNA as sharply as viruses that cleave with 4 bp or 5 bp staggers. For PFV and HIV-1, the selection of signature bases and central flexibility at sites of integration is largely independent of chromatin structure. Furthermore, global Rev-A integration is likely directed to chromatin features by bromodomain and extraterminal domain proteins.


How Does Circadian Rhythm Impact Salt Sensitivity of Blood Pressure in Mice? A Study in Two Close C57Bl/6 Substrains.
Mouse transgenesis has provided the unique opportunity to investigate mechanisms underlying sodium kidney reabsorption as well as end organ damage. However, understanding mouse background and the experimental conditions effects on phenotypic readouts of engineered mouse lines such as blood pressure presents a challenge. Despite the ability to generate high sodium and chloride plasma levels during high-salt diet, observed changes in blood pressure are not consistent between wild-type background strains and studies. The present work was designed in an attempt to determine guidelines in the field of salt-induced hypertension by recording continuously blood pressure by telemetry in mice submitted to different sodium and potassium loaded diets and changing experimental conditions in both C57BL/6N and C57BL/6J mice strain (Normal salt vs. Low salt vs. High-salt/normal potassium vs. High salt/low potassium, standard vs. modified light cycle, Non-invasive tail cuff blood pressure vs. telemetry). In this study, we have shown that, despite a strong blood pressure (BP) basal difference between C57BL/6N and C57BL/6J mice, High salt/normal potassium diet increases BP and heart rate during the active phase only (dark period) in the same extent in both strains. On the other hand, while potassium level has no effect on salt-induced hypertension in C57BL/6N mice, high-salt/low potassium diet amplifies the effect of the high-salt challenge only in C57BL/6J mice. Indeed, in this condition, salt-induced hypertension can also be detected during light period even though this BP increase is lower compared to the one occurring during the dark period. Finally, from a methodological perspective, light cycle inversion has no effect on this circadian BP phenotype and tail-cuff method is less sensitive than telemetry to detect BP phenotypes due to salt challenges. Therefore, to carry investigations on salt-induced hypertension in mice, chronic telemetry and studies in the active phase are essential prerequisites.


Cadherin 5 is regulated by corticosteroids and associated with central serous chorioretinopathy.
Central serous chorioretinopathy (CSC) is characterized by leakage of fluid from the choroid into the subretinal space and, consequently, loss of central vision. The disease is triggered by endogenous and exogenous corticosteroid imbalance and psychosocial stress and is much more prevalent in men. We studied the association of genetic variation in 44 genes from stress response and corticosteroid metabolism pathways with the CSC phenotype in two independent cohorts of 400 CSC cases and 1,400 matched controls. The expression of cadherin 5 (CDH5), the major cell-cell adhesion molecule in vascular endothelium, was downregulated by corticosteroids which may increase permeability of choroidal vasculature, leading to fluid leakage under the retina. We found a significant association of four common CDH5 SNPs with CSC in male patients in both cohorts. Two common intronic variants, rs7499886:A>G and rs1073584:C>T, exhibit strongly significant associations with CSC; P = 0.00012; odds ratio (OR) = 1.5; 95%CI [1.2;1.8], and P = 0.0014; OR = 0.70; 95%CI [0.57;0.87], respectively. A common haplotype was present in 25.4% male CSC cases and in 35.8% controls (P = 0.0002; OR = 0.61, 95% CI [0.47-0.79]). We propose that genetically predetermined variation in CDH5, when combined with triggering events such as corticosteroid treatment or severe hormonal imbalance, underlie a substantial proportion of CSC in the male population.


Molecular characterization of antimicrobial peptide genes of the carpenter ant Camponotus floridanus.
The production of antimicrobial peptides (AMPs) is a major defense mechanism against pathogen infestation and of particular importance for insects relying exclusively on an innate immune system. Here, we report on the characterization of three AMPs from the carpenter ant Camponotus floridanus. Due to sequence similarities and amino acid composition these peptides can be classified into the cysteine-rich (e.g. defensin) and glycine-rich (e.g. hymenoptaecin) AMP groups, respectively. The gene and cDNA sequences of these AMPs were established and their expression was shown to be induced by microbial challenge. We characterized two different defensin genes. The defensin-2 gene has a single intron, whereas the defensin-1 gene has two introns. The deduced amino acid sequence of the C. floridanus defensins is very similar to other known ant defensins with the exception of a short C-terminal extension of defensin-1. The hymenoptaecin gene has a single intron and a very peculiar domain structure. The corresponding precursor protein consists of a signal- and a pro-sequence followed by a hymenoptaecin-like domain and six directly repeated hymenoptaecin domains. Each of the hymenoptaecin domains is flanked by an EAEP-spacer sequence and a RR-site known to be a proteolytic processing site. Thus, proteolytic processing of the multipeptide precursor may generate several mature AMPs leading to an amplification of the immune response. Bioinformatical analyses revealed the presence of hymenoptaecin genes with similar multipeptide precursor structure in genomes of other ant species suggesting an evolutionary conserved important role of this gene in ant immunity.


Polypharmacy and specific comorbidities in university primary care settings.
Polypharmacy is associated with adverse events and multimorbidity, but data are limited on its association with specific comorbidities in primary care settings. We measured the prevalence of polypharmacy and inappropriate prescribing, and assessed the association of polypharmacy with specific comorbidities. We did a cross-sectional analysis of 1002 patients aged 50-80years followed in Swiss university primary care settings. We defined polypharmacy as ≥5 long-term prescribed drugs and multimorbidity as ≥2 comorbidities. We used logistic mixed-effects regression to assess the association of polypharmacy with the number of comorbidities, multimorbidity, specific sets of comorbidities, potentially inappropriate prescribing (PIP) and potential prescribing omission (PPO). We used multilevel mixed-effects Poisson regression to assess the association of the number of drugs with the same parameters. Patients (mean age 63.5years, 67.5% ≥2 comorbidities, 37.0% ≥5 drugs) had a mean of 3.9 (range 0-17) drugs. Age, BMI, multimorbidity, hypertension, diabetes mellitus, chronic kidney disease, and cardiovascular diseases were independently associated with polypharmacy. The association was particularly strong for hypertension (OR 8.49, 95%CI 5.25-13.73), multimorbidity (OR 6.14, 95%CI 4.16-9.08), and oldest age (75-80years: OR 4.73, 95%CI 2.46-9.10 vs.50-54years). The prevalence of PPO was 32.2% and PIP was more frequent among participants with polypharmacy (9.3% vs. 3.2%, p<0.006). Polypharmacy is common in university primary care settings, is strongly associated with hypertension, diabetes mellitus, chronic kidney disease and cardiovascular diseases, and increases potentially inappropriate prescribing. Multimorbid patients should be included in further trials for developing adapted guidelines and avoiding inappropriate prescribing.


Tackling soil diversity with the assembly of large, complex metagenomes.
The large volumes of sequencing data required to sample deeply the microbial communities of complex environments pose new challenges to sequence analysis. De novo metagenomic assembly effectively reduces the total amount of data to be analyzed but requires substantial computational resources. We combine two preassembly filtering approaches--digital normalization and partitioning--to generate previously intractable large metagenome assemblies. Using a human-gut mock community dataset, we demonstrate that these methods result in assemblies nearly identical to assemblies from unprocessed data. We then assemble two large soil metagenomes totaling 398 billion bp (equivalent to 88,000 Escherichia coli genomes) from matched Iowa corn and native prairie soils. The resulting assembled contigs could be used to identify molecular interactions and reaction networks of known metabolic pathways using the Kyoto Encyclopedia of Genes and Genomes Orthology database. Nonetheless, more than 60% of predicted proteins in assemblies could not be annotated against known databases. Many of these unknown proteins were abundant in both corn and prairie soils, highlighting the benefits of assembly for the discovery and characterization of novelty in soil biodiversity. Moreover, 80% of the sequencing data could not be assembled because of low coverage, suggesting that considerably more sequencing data are needed to characterize the functional content of soil.


Written pain neuroscience education in fibromyalgia: a multicenter randomized controlled trial.
Mounting evidence supports the use of face-to-face pain neuroscience education for the treatment of chronic pain patients. This study aimed at examining whether written education about pain neuroscience improves illness perceptions, catastrophizing, and health status in patients with fibromyalgia. A double-blind, multicenter randomized controlled clinical trial with 6-month follow-up was conducted. Patients with FM (n = 114) that consented to participate were randomly allocated to receive either written pain neuroscience education or written relaxation training. Written pain neuroscience education comprised of a booklet with pain neuroscience education plus a telephone call to clarify any difficulties; the relaxation group received a booklet with relaxation education and a telephone call. The revised illness perception questionnaire, Pain Catastrophizing Scale, and fibromyalgia impact questionnaire were used as outcome measures. Both patients and assessors were blinded. Repeated-measures analyses with last observation carried forward principle were performed. Cohen's d effect sizes (ES) were calculated for all within-group changes and between-group differences. The results reveal that written pain neuroscience education does not change the impact of FM on daily life, catastrophizing, or perceived symptoms of patients with FM. Compared with written relaxation training, written pain neuroscience education improved beliefs in a chronic timeline of FM (P = 0.03; ES = 0.50), but it does not impact upon other domains of illness perceptions. Compared with written relaxation training, written pain neuroscience education slightly improved illness perceptions of patients with FM, but it did not impart clinically meaningful effects on pain, catastrophizing, or the impact of FM on daily life. Face-to-face sessions of pain neuroscience education are required to change inappropriate cognitions and perceived health in patients with FM.


Increased production of retinoic acid by intestinal macrophages contributes to their inflammatory phenotype in patients with Crohn's disease.
Reduced generation of all-trans retinoic acid (RA) by CD103(+) intestinal dendritic cells (DCs) is linked to intestinal inflammation in mice. However, the role of RA in intestinal inflammation in humans is unclear. We investigated which antigen-presenting cells (APCs) produce RA in the human intestine and whether generation of RA is reduced in patients with Crohn's disease (CD). Ileal and colonic tissues were collected from patients with CD during endoscopy or surgery, and healthy tissues were collected from subjects who were undergoing follow-up because of rectal bleeding, altered bowel habits, or cancer (controls). Cells were isolated from the tissue samples, and APCs were isolated by flow cytometry. Retinaldehyde dehydrogenase (RALDH) activity was assessed by Aldefluor assay, and ALDH1A expression was measured by quantitative real-time polymerase chain reaction. Macrophages were derived by incubation of human blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF). CD103(+) and CD103(-) DCs and CD14(+) macrophages from healthy human intestine had RALDH activity. Although ALDH1A1 was not expressed by DCs, it was the predominant RALDH enzyme isoform expressed by intestinal CD14(+) macrophages and their putative precursors, CD14(+) monocytes. RALDH activity was up-regulated in all 3 populations of APCs from patients with CD; in CD14(+) macrophages, it was associated with local induction of ALDH1A1 expression. Blocking of RA receptor signaling during GM-CSF-mediated differentiation of monocytes into macrophages down-regulated CD14 and HLA-DR expression and reduced the development of tumor necrosis factor α-producing inflammatory macrophages. RA receptor signaling promotes differentiation of human tumor necrosis factor α-producing inflammatory macrophages in vitro. In vivo, more CD14(+) macrophages from the intestinal mucosa of patients with CD than from controls are capable of generating RA, which might increase the inflammatory phenotype of these cells. Strategies to reduce the generation of RA by CD14(+) macrophages could provide new therapeutic options for patients with CD.


Asking about the last four drinking occasions on a tablet computer as a way to record alcohol consumption in Aboriginal and Torres Strait Islander Australians: a validation.
Alcohol consumption among Indigenous Australians can be irregular, depending on social and geographic context. The Finnish method uses the last four drinking occasions to estimate drinking quantity and pattern. The Grog Survey App is an interactive and visual tablet computer application which uses touch-screen technology to deliver questions on drinking. Alcohol consumption recorded on the Grog Survey App using the last four occasions (Finnish) method was compared with a clinical interview conducted by an Indigenous Australian health professional. To assess convergent validity, Spearman's ranked correlations between consumption estimates from the App and from interview were calculated. Sensitivity and specificity analyses were used to compare how well the App and clinical interview agreed when classifying drinkers' risk. To assess criterion validity, average grams alcohol per day as estimated by the App (and by interview) were compared against presence of self-reported withdrawal tremors (from App or interview). Test-retest reliability was assessed by correlations between measures of alcohol consumption recorded on two occasions. The App recorded higher numbers of standard drinks consumed per drinking occasion than the interview. There was reasonable agreement between the App and interview across common reference periods (sensitivity 92.7%, specificity 69.8%, short-term risk; sensitivity 70.7%, specificity 68.8%, long-term risk). Average consumption recorded by the App was as good or better predictor of withdrawal tremors than consumption as estimated by interview. The Finnish method, as delivered by the App, offers an innovative way to collect survey data on alcohol in a population with an intermittent drinking pattern.


Histological, histomorphometric and microtomographic analyses of retrieval hip resurfacing arthroplasty failed at different times.
Metal-on-metal hip resurfacing arthroplasty (HR) has been gaining popularity especially for young and active patients. Although different series report good mid-term results, the long-term outcome and failure mechanisms are still concerning. In this consecutive revision case series, 9 retrieved specimens of a failed Birmingham Hip Resurfacing (BHR) were divided according to the time to fracture: 3 specimens failed at less than 6 months (Group 1), 3 failed between 6 months and 3 years (Group 2) and 3 failed later than 3 years (Group 3). The objective of the study was to examine by a specific quantitative histomorphometry and microtomography (micro-CT) method the characteristics of bone quality and its microarchitecture in retrieved metal-on-metal HR. A series of 948 BHR were performed between 2001 and 2009. Among these implants 10 failures occurred and nine of these underwent revision surgery and were examined by histomorphometry and micro-CT. Histomorphometry showed a significant increase in trabecular separation (Tb.Sp) in Group 3 in comparison with Group 1 (113%, p < 0.05). In the top region, micro-CT showed that Groups 2 and 3 presented significant lower bone volume (Group 2: 61%, p < 0.005; Group 3: 1%, p < 0.05), trabecular number (Group 2: 53%, p < 0.005; Group 3: 40%, p < 0.05), and higher Tb.Sp (Group: 71%,p < 0.05) when compared to Group 1. Additionally, histomorphometry showed that the top regions in Group 1 had a significantly lower mean percentage of empty osteocyte lacunae than the top regions in both Group 2 and 3 (p < 0.05). This study showed that the morphometric parameters considered are crucial for a good understanding of mechanical properties of HR and may be of significant importance in the pathogenesis of HR failure particularly in the development of late fractures.


Effects of surface treatments on bond strength of glass-infiltrated ceramic.
The purpose of this study was to evaluate the effects of various surface treatments on the bond strength at the In-Ceram/resin composite interface. Ninety-eight In-Ceram specimens were divided into seven groups and exposed to various surface treatments as follows: (A) control (B) saliva contamination (C) saliva contamination plus aluminum oxide sandblasting (D) glove powder contamination (E) glove powder contamination plus aluminum oxide sandblasting (F) rough aluminum oxide sandblasting and (G) excess glass infiltration. A resin composite cylinder was cemented to each In-Ceram specimen with Panavia 21 resin luting cement. Half of the cemented specimens in each group were stored in water for 24 h, and the other half were stored in water for 2 weeks and then were thermo-cycled for 2000 cycles. Shear bond strengths (SBS) of seven specimens in each subgroup were determined and analysed using analysis of variance (ANOVA) and Tukey HSD test as well as Student's t-test. Scanning electronic microscopy was used to identify the type of bond failure. Shear bond strength was significantly decreased by saliva and glove powder contaminations (P < 0.05). Sandblasting treatment did not improve the saliva-contaminated specimens. However, the glove powder plus sandblasting group showed no significant difference in SBS compared with the control group. There was no significant difference in SBS between the excess glass-infiltrating group and the control group. The SBS was significantly decreased by rough aluminum oxide sandblasting (P < 0.05). The SBS values of groups without thermocycling were significantly greater than those of groups with thermocycling (P < 0.05). There were no significant differences among SBS values of the seven groups with thermocycling. Combined cohesive and adhesive bond failures were seen in every group. Various surface treatments or contaminants may significantly influence the bond strength of In-Ceram restorative in clinical use.


Structural analysis uncovers lipid-binding properties of Notch ligands.
The Notch pathway is a core cell-cell signaling system in metazoan organisms with key roles in cell-fate determination, stem cell maintenance, immune system activation, and angiogenesis. Signals are initiated by extracellular interactions of the Notch receptor with Delta/Serrate/Lag-2 (DSL) ligands, whose structure is highly conserved throughout evolution. To date, no structure or activity has been associated with the extreme N termini of the ligands, even though numerous mutations in this region of Jagged-1 ligand lead to human disease. Here, we demonstrate that the N terminus of human Jagged-1 is a C2 phospholipid recognition domain that binds phospholipid bilayers in a calcium-dependent fashion. Furthermore, we show that this activity is shared by a member of the other class of Notch ligands, human Delta-like-1, and the evolutionary distant Drosophila Serrate. Targeted mutagenesis of Jagged-1 C2 domain residues implicated in calcium-dependent phospholipid binding leaves Notch interactions intact but can reduce Notch activation. These results reveal an important and previously unsuspected role for phospholipid recognition in control of this key signaling system.


An introduction to ALS-inhibiting herbicides.
Herbicides that inhibit acetolactate synthase (ALS), the enzyme common to the biosynthesis of the branch-chain amino acids (valine, leucine, and isoleucine), affect many species of higher plants as well as bacteria, fungi, yeasts, and algae. The novel mechanism of action attributed to ALS inhibitors, their effect on the reproduction of some plant species, their potency at extremely low concentrations, and the rapid evolution of resistance to these herbicides in some plants and microorganisms are characteristics that set ALS inhibitors apart from their predecessors. This class of chemicals affects seedling growth. Older plants exhibit varied signs of malformation, stunting, and reduced seed production. These herbicides are so potent that they can affect plants at levels that are undetectable by any standard chemical protocol. Weeds quickly become resistant to ALS inhibitors, presumably because these herbicides have a single mode of action and because many have long residual activity. Concern now is directed towards developing the technology to detect very low concentrations of ALS inhibitors in the environment and their indirect effects on plant and animal health.


Biotechnological approaches to determine the impact of viruses in the energy crop plant Jatropha curcas.
Geminiviruses infect a wide range of plant species including Jatropha and cassava both belonging to family Euphorbiaceae. Cassava is traditionally an important food crop in Sub - Saharan countries, while Jatropha is considered as valuable biofuel plant with great perspectives in the future. A total of 127 Jatropha samples from Ethiopia and Kenya and 124 cassava samples from Kenya were tested by Enzyme-Linked Immunosorbent Assay (ELISA) for RNA viruses and polymerase chain reaction for geminiviruses. Jatropha samples from 4 different districts in Kenya and Ethiopia (analyzed by ELISA) were negative for all three RNA viruses tested: Cassava brown streak virus (CBSV), Cassava common mosaic virus, Cucumber mosaic virus, Three cassava samples from Busia district (Kenya) contained CBSV. Efforts to develop diagnostic approaches allowing reliable pathogen detection in Jatropha, involved the amplification and sequencing of the entire DNA A molecules of 40 Kenyan isolates belonging to African cassava mosaic virus (ACMV) and East African cassava mosaic virus - Uganda. This information enabled the design of novel primers to address different questions: a) primers amplifying longer sequences led to a phylogenetic tree of isolates, allowing some predictions on the evolutionary aspects of Begomoviruses in Jatrophia; b) primers amplifying shorter sequences represent a reliable diagnostic tool. This is the first report of the two Begomoviruses in J. curcas. Two cassava samples were co - infected with cassava mosaic geminivirus and CBSV. A Defective DNA A of ACMV was found for the first time in Jatropha. Cassava geminiviruses occurring in Jatropha might be spread wider than anticipated. If not taken care of, this virus infection might negatively impact large scale plantations for biofuel production. Being hosts for similar pathogens, the planting vicinity of the two crop plants needs to be handled carefully.


Intraocular gnathostomiasis: report of a case and review of literature.
Intraocular gnathostomiasis is a rare parasitic infection caused by the third-stage larvae of spiruroid nematode Gnanthostoma spp. seen mostly in tropical and subtropical regions. It is a food-borne zoonosis caused by ingestion of raw or undercooked freshwater fish, amphibians, reptiles, birds, and mammals, all of which are known to harbor advanced third-stage larvae of Gnanthostoma spp. To date, 74 cases of intraocular gnathostomiasis have been reported from 12 different countries. Only four countries have reported more than 10 cases each, and India shares the rare distinction of being one of them, with 14 cases. Surprisingly, not a single case of cutaneous gnanthostomiasis has ever been reported from India. We present one such case of intraocular gnathostomiasis in a 41-year-old male who presented with an actively motile worm attached to the iris, and we review the pertinent literature of all such cases reported from India.


The regulation of stearoyl-CoA desaturase gene expression is tissue specific in chickens.
Emerging evidence suggests a potential role of stearoyl-CoA desaturase (SCD)-1 in the control of body weight and energy homeostasis. The present study was conducted to investigate the effects of several energy balance-related factors (leptin, cerulenin, food deprivation, genotype, and gender) on SCD gene expression in chickens. In experiment 1, 6-week-old female and male broiler chickens were used. In experiment 2, two groups of 3-week-old broiler chickens were continuously infused with recombinant chicken leptin (8 micro g/kg/h) or vehicle for 6 h. In experiment 3, two groups of 2-week-old broiler chickens received i.v. injections of cerulenin (15 mg/kg) or vehicle. In experiment 4, two broiler chicken lines (fat and lean) were submitted to two nutritional states (food deprivation for 16 or 24 h and feeding ad libitum). At the end of each experiment, tissues were collected for analyzing SCD gene expression. Data from experiment 1 showed that SCD is ubiquitously expressed in chicken tissues with highest levels in the proventriculus followed by the ovary, hypothalamus, kidney, liver, and adipose tissue in female, and hypothalamus, leg muscle, pancreas, liver, and adipose tissue in male. Female chickens exhibited significantly higher SCD mRNA levels in kidney, breast muscle, proventriculus, and intestine than male chickens. However, hypothalamic SCD gene expression was higher in male than in female (P < 0.05). Leptin increased SCD gene expression in chicken liver (P < 0.05), whereas cerulenin decreased SCD mRNA levels in muscle. Both leptin and cerulenin significantly reduced food intake (P < 0.05). Food deprivation for either 16 or 24 h decreased the hepatic SCD gene expression in fat line and lean line chickens compared with their fed counterparts (P < 0.05). The hypothalamic SCD mRNA levels were decreased in both lines only after 24 h of food deprivation (P < 0.05). In conclusion, SCD is ubiquitously expressed in chickens and it is regulated by leptin, cerulenin, nutritional state, and gender in a tissue-specific manner.


Comparison of Meat Quality and Fatty Acid Composition of Longissimus Muscles from Purebred Pigs and Three-way Crossbred LYD Pigs.
This study was conducted to find pork quality to meet the needs of consumers. Thus, the meat quality and fatty acid composition of longissimus muscles from purebred pigs (Landrace, Yorkshire, and Duroc) and three-way crossbred LYD pigs were compared and evaluated. Chemical compositions of longissimus muscles were significant (p<0.05) different among pigs. Duroc contained significant (p<0.05) higher fat contents than other pigs, whereas significant (p<0.05) higher moisture contents were observed in Landrace, Yorkshire, and LYD pigs compared to those of Duroc pigs. The values of pH24 h and pH14 d were the highest in Landrace pigs. Myoglobin contents of LYD pigs were higher (p<0.05) than those of purebred pigs. Regarding meat color, Duroc and Yorkshire pigs had higher redness values than Landrace and LYD pigs, while Landrace pigs had the lowest (p<0.05) color values among all pigs. There was no significant difference in shear force or water holding capacity (WHC). Duroc pigs maintained the lowest drip loss during 14 d of cold storage. In sensory evaluation, the marbling scores of Duroc pigs were higher (p<0.05) than other pigs. Regarding fatty acid compositions, total USFA, poly-, n-3, and n-6 contents were the highest (p<0.05) in LYD pigs, while total SFA contents were the highest (p<0.05) in Duroc pigs. Based on these results, purebred pigs had superior overall meat quality to crossbred pigs.