Heterogeneity of Kv2.1 mRNA expression and delayed rectifier current in single isolated myocytes from rat left ventricle.
Expression of the voltage-gated K(+) channel Kv2.1, a possible molecular correlate for the cardiac delayed rectifier current (I(K)), has recently been shown to vary between individual ventricular myocytes. The functional consequences of this cell-to-cell heterogeneity in Kv2.1 expression are not known. Using multiplex single-cell reverse transcriptase-polymerase chain reaction (RT-PCR), we detected Kv2.1 mRNA in 47% of isolated midmyocardial myocytes from the rat left ventricular free wall that were positive for alpha-myosin heavy chain mRNA (n=74). Whole-cell patch-clamp recordings demonstrated marked differences in the magnitude of I(K) (200 to 1450 pA at V(Pip)=40 mV) between individual myocytes of the same origin. Furthermore, the tetraethylammonium (TEA)-sensitive outward current (I(TEA)), known to be partly encoded by Kv2.1 in mice, revealed a wide range of current magnitudes between single cells (150 to 1130 pA at V(Pip)=40 mV). Combined patch-clamp recordings and multiplex single-cell RT-PCR analysis of the same myocytes, however, showed no differences in I(K) or I(TEA) magnitude or inactivation kinetics between myocytes expressing Kv2.1 mRNA and those that did not express Kv2.1 mRNA. In contrast, in all midmyocardial myocytes expressing the transient outward potassium current (I(to1)), Kv4 mRNA, which has been shown to underlie I(to1), was detected (n=10). These results indicate that I(K) heterogeneity among individual left ventricular myocytes cannot be explained by the distribution pattern of Kv2.1 mRNA. Other mechanisms besides Kv2.1 mRNA expression appear to determine magnitude and kinetics of I(K) in rat ventricular myocytes.


The generalized energy-based fragmentation approach with an improved fragmentation scheme: benchmark results and illustrative applications.
We propose an improved fragmentation scheme for the generalized energy-based fragmentation (GEBF) approach, which improves the accuracy of the GEBF approach in total energy calculations and intermolecular interactions. The main modification is to introduce some two-fragment-centered primitive subsystems, which are neglected in the previous GEBF implementation. Numerical calculations demonstrate that the present GEBF approach can provide more accurate ground-state energies and intermolecular interactions. The present GEBF approach with the M06-2X functional and the cc-pVTZ basis set are employed to investigate the structures and binding energies in two dimeric species, which are related to pseudopolymorphism of a phenyleneethynylene-based π-conjugated molecule. A comparison of the binding free energies in a dimeric species and its corresponding model without C-H···F contacts reveal that the substitution of fluorine atoms weakens the binding of monomers in the dimeric species formed by intermolecular O-H···O hydrogen bonds, but strengthens the binding in the dimer formed by the π-π stacking interaction. Therefore, the C-H···F contacts in these two dimeric species are demonstrated to play a less significant role.


Stability of omeprazole in an extemporaneously prepared oral liquid.
The stability of omeprazole 2 mg/mL. in an extemporaneously prepared oral liquid was studied. The contents of five 20-mg omeprazole capsules were mixed with 50 mL of 8.4% sodium bicarbonate solution in a Luer-Lok syringe. Three vials of this liquid were prepared for storage at 24, 5, and -20 degrees C. A 3-mL. sample of each was taken initially and on days 1, 2, 3, 4, 6, 8, 10, 12, 14, 18, 22, 26, and 30 and assayed by high-performance liquid chromatography. The liquids stored at 5 degrees C and at -20 degrees C did not change color during the study period, but the color of the liquid stored at 24 degrees C changed from white to brown. There were no significant changes in the omeprazole concentrations of the liquids stored at 5 and -20 degrees C during the study period, but the omeprazole concentration of the liquid stored at 24 degrees C was < 90% of the initial concentration on day 18. Omeprazole 2 mg/mL in an oral liquid compounded extemporaneously from capsules and sodium bicarbonate injection was stable for up to 14 days at 24 degrees C and for up to 30 days at 5 and -20 degrees C.


Duration of antidepressant drug treatment. What is an adequate trial?
Data from three six-week placebo-controlled randomized antidepressant trials were pooled to test the hypothesis that a four-week trial is insufficient to reach a determination of drug failure in depressed patients. We compared global clinical ratings at weekly intervals for patients receiving drug and patients receiving placebo and calculated the proportion of patients whose clinical status changed over time. We predicted, and found, that a significant proportion of patients who showed no clear-cut response at four weeks would show much improvement at six weeks in drug but not placebo conditions. Baseline Research Diagnostic Criteria diagnosis, baseline illness severity, and drug dose adjustments after four weeks did not predict either late clinical improvement or relapse between four and six weeks. Additional placebo-controlled studies are needed to replicate our findings concerning the advantage of extending trials to five or six weeks in samples of patients of various depressive subtypes.


The Burden of Candidate Pathogenic Variants for Kidney and Genitourinary Disorders Emerging From Exome Sequencing.
Exome sequencing is increasingly being used for clinical diagnostics, with an impetus to expand reporting of incidental findings across a wide range of disorders. Analysis of population cohorts can help reduce risk for genetic variant misclassification and resultant unnecessary referrals to subspecialists. To examine the burden of candidate pathogenic variants for kidney and genitourinary disorders emerging from exome sequencing. Secondary analysis of genetic data. A tertiary care academic medical center. A convenience sample of exome sequence data from 7974 self-declared healthy adults. Assessment of the prevalence of candidate pathogenic variants in 625 genes associated with Mendelian kidney and genitourinary disorders. Of all participants, 23.3% carried a candidate pathogenic variant, most of which were attributable to previously reported variants that had implausibly high allele frequencies. In particular, 25 genes (discovered before the creation of the Exome Aggregation Consortium, a genetic database comprising data from a large control population) accounted for 67.7% of persons with candidate pathogenic variants. After stringent filtering based on allele frequency, 1.4% of persons still had a candidate pathogenic variant, an excessive rate given the prevalence of monogenic kidney and genitourinary disorders. Manual annotation of a subset of variants showed that the majority would be classified as nonbenign under current guidelines for clinical sequence interpretation and could prompt subspecialty referrals if returned. Limited access to health record data prevented comprehensive assessment of the phenotypic concordance with genetic diagnoses. Widespread reporting of incidental genetic findings related to kidney and genitourinary disorders will require stringent curation of clinical variant databases and detailed case-level review to avoid genetic misdiagnosis and unnecessary referrals. These findings motivate similar analyses for genes relevant to other medical subspecialties. National Institute of Diabetes and Digestive and Kidney Diseases and National Human Genome Research Institute.


[Medicine from the computer].
Small molecules can have a significant effect on human metabolic processes. Computational drug design aims at constructing specialized small molecules that selectively and efficiently address specific proteins. The basic ideas of computational molecular design are presented and it will be shown how a virtual protein can be computer designed. This virtual protein can be used to predict the binding affinity of given small molecules without having to synthesize them in a laboratory. Modern computational drug design goes far beyond the lock and key principle. Possible future developments are discussed and a current successful example of computational drug design in the field of painkiller medication is demonstrated.


Variation in the choice of elective surgical procedure for abdominal aortic aneurysm in Spain.
The two main surgical treatments for abdominal aortic aneurysm (AAA) are open surgical repair (OSR) and endovascular aneurysm repair (EVAR). The aim of this study was to analyze variation among Spanish hospitals in the use of OSR or EVAR for AAA. A secondary aim was to assess changes in preferences for these two procedures over time. This was a retrospective longitudinal study based on discharge data from public hospitals in Spain during 2002-2012. Patient inclusion criteria were: age >18 years, elective admission, primary diagnosis of unruptured AAA, and surgical treatment with OSR or EVAR. The characteristics of the treating center, patients, and in-hospital mortality were recorded. We included 16,737 patients from 114 hospitals; 6,809 (40.7%) underwent EVAR and 9,928 (59.3%) underwent OSR. The total volume of surgeries increased throughout the period, and the probability that any given procedure was EVAR increased by 20% per year (OR 1.20, P<0.001). The volume and distribution of the two procedures varied highly across the participating hospitals. Overall, in-hospital mortality rate was 3.6% and it decreased during the study period (5.3% in 2002 and 3.2% in 2012), mainly due to a decrease in OSR-related mortality, despite a slight increase in EVAR-related mortality. Hospitals with higher surgical volumes were more likely to use EVAR and have lower in-hospital mortality rates. This study reveals high variability in the surgical treatment of unruptured AAA across Spanish hospitals. The number of interventions has increased in recent years, with EVAR accounting for a growing percentage of these surgical procedures. Overall in-hospital mortality rates decreased significantly during this period, mainly due to lower mortality among patients undergoing OSR. In-hospital mortality rates were lower in higher-volume centers, regardless of the surgical approach used. Further research on variability and appropriateness of surgical management of AAA is required to assess the suitability of concentrating elective AAA repair in more experienced centers to potentially achieve better outcomes.


Water supply facility damage and water resource operation at disaster base hospitals in miyagi prefecture in the wake of the Great East Japan Earthquake.
The aim of this study was to shed light on damage to water supply facilities and the state of water resource operation at disaster base hospitals in Miyagi Prefecture (Japan) in the wake of the Great East Japan Earthquake (2011), in order to identify issues concerning the operational continuity of hospitals in the event of a disaster. In addition to interview and written questionnaire surveys to 14 disaster base hospitals in Miyagi Prefecture, a number of key elements relating to the damage done to water supply facilities and the operation of water resources were identified from the chronological record of events following the Great East Japan Earthquake. Nine of the 14 hospitals experienced cuts to their water supplies, with a median value of three days (range=one to 20 days) for service recovery time. The hospitals that could utilize well water during the time that water supply was interrupted were able to obtain water in quantities similar to their normal volumes. Hospitals that could not use well water during the period of interruption, and hospitals whose water supply facilities were damaged, experienced significant disruption to dialysis, sterilization equipment, meal services, sanitation, and outpatient care services, though the extent of disruption varied considerably among hospitals. None of the hospitals had determined the amount of water used for different purposes during normal service or formulated a plan for allocation of limited water in the event of a disaster. The present survey showed that it is possible to minimize the disruption and reduction of hospital functions in the event of a disaster by proper maintenance of water supply facilities and by ensuring alternative water resources, such as well water. It is also clear that it is desirable to conclude water supply agreements and formulate strategic water allocation plans in preparation for the eventuality of a long-term interruption to water services.


An innovative optics lab design for residency training in ophthalmology.
Proper understanding of the optical function of the eye is the foundation of clinical understanding of ophthalmologists. Although teaching principals of optics has always been a part of ophthalmology residency curriculum, it seems that successful strategies other than lecture-based methods are needed to engage students and facilitate the understanding of optical principals. A collaborative team of physicists (optics Ph.D.), ophthalmologists and medical education experts designed an optics lab for ophthalmology residents to help them practically simulate different optical phenomena. The educational course consisted of 4 sessions of 90 min to practice the optical tests using the lab instruments. Each class consisted of 6-9 residents, divided into 3 groups with a fully equipped unit, and two mentors (an optics Ph.D. professor and an ophthalmology professor). A quasi-experimental design with pre-post test was used to evaluate the effectiveness of the training workshop in changing the ophthalmology residents' optical knowledge and attitude. Thirty-five residents participated in the study. The average score of residents' performance before the workshop was 5.21 (out of 100), which increased significantly to 66.1 after the workshop. Also, the average knowledge of residents, which was measured as self-reported, increased significantly from 28.85 to 71.09. The average score of students' attitudes and interest was increased from 40.49 to 74.81. It seems that training workshops and labs are effective to bring about change in knowledge and attitude of ophthalmology residents toward optics as a new teaching strategy that would be implemented in their curriculum.


Non-invasive mapping of deep-tissue lymph nodes in live animals using a multimodal PET/MRI nanoparticle.
The invasion status of tumour-draining lymph nodes (LNs) is a critical indicator of cancer stage and is important for treatment planning. Clinicians currently use planar scintigraphy and single-photon emission computed tomography (SPECT) with (99m)Tc-radiocolloid to guide biopsy and resection of LNs. However, emerging multimodality approaches such as positron emission tomography combined with magnetic resonance imaging (PET/MRI) detect sites of disease with higher sensitivity and accuracy. Here we present a multimodal nanoparticle, (89)Zr-ferumoxytol, for the enhanced detection of LNs with PET/MRI. For genuine translational potential, we leverage a clinical iron oxide formulation, altered with minimal modification for radiolabelling. Axillary drainage in naive mice and from healthy and tumour-bearing prostates was investigated. We demonstrate that (89)Zr-ferumoxytol can be used for high-resolution tomographic studies of lymphatic drainage in preclinical disease models. This nanoparticle platform has significant translational potential to improve preoperative planning for nodal resection and tumour staging.


Radiotherapy, Especially at Young Age, Increases the Risk for De Novo Brain Tumors in Patients Treated for Pituitary/Sellar Lesions.
De novo brain tumors developing after treatment of pituitary/sellar lesions have been reported, but it is unknown whether this is linked to any of the treatment modalities. To study the occurrence of malignant brain tumors and meningiomas in a large cohort of patients treated for pituitary/sellar lesions, with special emphasis on the role of radiotherapy (RT). Patients (n = 8917) who were hypopituitary due to pituitary adenomas, craniopharyngiomas, and other sellar tumors followed in KIMS (Pfizer International Metabolic Database) from 1994 to 2012 were included. Treatment consisted of surgery and/or medical therapy in 4927 patients, RT alone, or with surgery in 3236 patients; data were missing in 754. Incidence rate ratios (RRs) were analyzed through Poisson regression methods with internal comparisons. During 53,786 patient-years, 17 cases of malignant brain tumors (13 exposed to RT) and 27 meningiomas (22 exposed to RT) were reported. RR for RT vs no RT was 3.34 [95% confidence interval (CI), 1.06 to 10.6] for malignant brain tumors, and 4.06 (95% CI, 1.51 to 10.9) for meningiomas. The risk of developing a malignant brain tumor increased by 2.4-fold (P = 0.005) and meningioma by 1.6-fold with every 10 years of younger age at RT (P = 0.05). Incidence rates were similar in patients treated with conventional RT compared with stereotactic RT. RT of pituitary tumors is associated with increased risk of developing malignant brain tumors and meningiomas, especially when given at younger ages. In balancing risks and benefits of RT, our findings emphasize that special consideration should be given to the age of the patient.


The impacts of climate change and disturbance on spatio-temporal trajectories of biodiversity in a temperate forest landscape.
1. The ongoing changes to climate challenge the conservation of forest biodiversity. Yet, in thermally limited systems, such as temperate forests, not all species groups might be affected negatively. Furthermore, simultaneous changes in the disturbance regime have the potential to mitigate climate-related impacts on forest species. Here, we (i) investigated the potential long-term effect of climate change on biodiversity in a mountain forest landscape, (ii) assessed the effects of different disturbance frequencies, severities and sizes and (iii) identified biodiversity hotspots at the landscape scale to facilitate conservation management. 2. We employed the model iLand to dynamically simulate the tree vegetation on 13 865 ha of the Kalkalpen National Park in Austria over 1000 years, and investigated 36 unique combinations of different disturbance and climate scenarios. We used simulated changes in tree cover and composition as well as projected temperature and precipitation to predict changes in the diversity of Araneae, Carabidae, ground vegetation, Hemiptera, Hymenoptera, Mollusca, saproxylic beetles, Symphyta and Syrphidae, using empirical response functions. 3. Our findings revealed widely varying responses of biodiversity indicators to climate change. Five indicators showed overall negative effects, with Carabidae, saproxylic beetles and tree species diversity projected to decrease by more than 33%. Six indicators responded positively to climate change, with Hymenoptera, Mollusca and Syrphidae diversity projected to increase more than twofold. 4. Disturbances were generally beneficial for the studied indicators of biodiversity. Our results indicated that increasing disturbance frequency and severity have a positive effect on biodiversity, while increasing disturbance size has a moderately negative effect. Spatial hotspots of biodiversity were currently found in low- to mid-elevation areas of the mountainous study landscape, but shifted to higher-elevation zones under changing climate conditions. 5.Synthesis and applications. Our results highlight that intensifying disturbance regimes may alleviate some of the impacts of climate change on forest biodiversity. However, the projected shift in biodiversity hotspots is a challenge for static conservation areas. In this regard, overlapping hotspots under current and expected future conditions highlight priority areas for robust conservation management.


Prescriptions for saying good-bye: teaching termination to family practice residents.
Physicians terminate doctor-patient relationships at various times during their careers. Preparing physicians for this process should be part of residency training in family practice. This report describes the structured role-playing exercises and physician scripts used to teach termination skills. Evaluation of these teaching methods suggests that residents value termination instruction, prefer participative approaches, and report greater sensitivity to the feelings and issues evoked by termination.


[Age and management decisions in patients with primary lung cancer].
Therapeutic decisions are difficult in elderly patients because of the heterogeneity of this population. Our objective was to evaluate the role of age in the management of patients suffering from primary lung cancer seen in the department of respiratory diseases of the Limoges regional teaching hospital between 2002 and 2004. A cross sectional study analysed the management of 363 patients suffering from primary lung cancer. The patients were divided into two groups according to their age (less than seventy or seventy and over). A comparison was made between the management of the two groups. The comparisons according to age produced evidence of reduced activity, greater dependence, an increased Charlson score, less frequently administered radiotherapy and chemotherapy, and more frequent symptomatic treatment in the elderly group (p<0.001). The geriatric assessment of patients suffering from primary lung cancer should make allowance for the physiological age of the patient and adapt the management to ensure the best quality of life.


Six features of Medicare coordinated care demonstration programs that cut hospital admissions of high-risk patients.
As policy makers seek to slow the growth in Medicare spending, they have appropriately focused attention on beneficiaries with multiple chronic conditions. Many care coordination and disease management programs designed to improve beneficiaries' care and reduce their need for hospitalizations have been tested, but few have been successful. This study, however, found that four of eleven programs that were part of the Medicare Coordinated Care Demonstration reduced hospitalizations by 8-33 percent among enrollees who had a high risk of near-term hospitalization. The six approaches practiced by care coordinators in at least three of the four programs were as follows: supplementing telephone calls to patients with frequent in-person meetings; occasionally meeting in person with providers; acting as a communications hub for providers; delivering evidence-based education to patients; providing strong medication management; and providing timely and comprehensive transitional care after hospitalizations. When care management fees were included, the programs were essentially cost-neutral, but none of these programs generated net savings to Medicare. Our results suggest that incorporating these approaches into medical homes, accountable care organizations, and other policy initiatives could reduce hospitalizations and improve patients' lives. However, the approaches would save money only if care coordination fees were modest and organizations found cost-effective ways to deliver the interventions.


ADCY9 Genetic Variants and Cardiovascular Outcomes With Evacetrapib in Patients With High-Risk Vascular Disease: A Nested Case-Control Study.
A pharmacogenetic analysis of dalcetrapib, a cholesteryl ester transfer protein inhibitor, reported an association between a single-nucleotide polymorphism (SNP) in the ADCY9 gene (rs1967309) and reduction in major adverse cardiovascular events despite a neutral result for the overall trial. To determine whether the association between the SNP in the ADCY9 gene and a reduction in major adverse cardiovascular events could be replicated for another cholesteryl ester transfer protein inhibitor, evacetrapib, in patients with high-risk vascular disease. A nested case-control study examining the rs1967309 SNP in 1427 cases and 1532 matched controls selected from the 12 092-patient Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial, a randomized, double-blind, placebo-controlled phase 3 trial conducted in patients with high-risk vascular disease randomized from October 2012 through December 2013. The genotyping was conducted from January 2017 to March 2017, and the data analyses were conducted from July 2017 to November 2017. Evacetrapib, 130 mg, or matching placebo. The primary analyses used a conditional logistic regression model to assess the odds ratio (OR) for major adverse cardiovascular events for evacetrapib compared with placebo for each genotype. The basic model included adjustment for age, sex, and the top 5 principal components. An additional model included cardiovascular risk factors to adjust for potential bias in selecting control patients. The primary major adverse cardiovascular event end point was the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. For patients with the AA genotype reported to demonstrate a beneficial effect from dalcetrapib, the OR for evacetrapib compared with placebo was 0.88 (95% CI, 0.69-1.12). For patients with the AG genotype, the OR was 1.04 (95% CI, 0.90-1.21). For patients with the GG genotype reported to show evidence for a harmful effect from dalcetrapib, the OR for evacetrapib was 1.18 (95% CI, 0.98-1.41). The interaction P value among the 3 genotypes was P = .17 and the trend P value was P = .06. When adjusted for cardiovascular risk factors, the OR for evacetrapib was 0.93 (95% CI, 0.73-1.19) for the AA genotype, 1.05 (95% CI, 0.91-1.22) for the AG genotype, and 1.02 (95% CI 0.85-1.24) for the GG genotype; interaction P = .71 and trend P = .59. Pharmacogenetic analysis did not show a significant association between the ADCY9 SNP (rs1967309) and cardiovascular benefit or harm for the cholesteryl ester transfer protein inhibitor evacetrapib.


Recent advances in features generation for membrane protein sequences: From multiple sequence alignment to pre-trained language models.
Membrane proteins play a crucial role in various cellular processes and are essential components of cell membranes. Computational methods have emerged as a powerful tool for studying membrane proteins due to their complex structures and properties that make them difficult to analyze experimentally. Traditional features for protein sequence analysis based on amino acid types, composition, and pair composition have limitations in capturing higher-order sequence patterns. Recently, multiple sequence alignment (MSA) and pre-trained language models (PLMs) have been used to generate features from protein sequences. However, the significant computational resources required for MSA-based features generation can be a major bottleneck for many applications. Several methods and tools have been developed to accelerate the generation of MSAs and reduce their computational cost, including heuristics and approximate algorithms. Additionally, the use of PLMs such as BERT has shown great potential in generating informative embeddings for protein sequence analysis. In this review, we provide an overview of traditional and more recent methods for generating features from protein sequences, with a particular focus on MSAs and PLMs. We highlight the advantages and limitations of these approaches and discuss the methods and tools developed to address the computational challenges associated with features generation. Overall, the advancements in computational methods and tools provide a promising avenue for gaining deeper insights into the function and properties of membrane proteins, which can have significant implications in drug discovery and personalized medicine.


Molecular markers predicting radiotherapy response: report and recommendations from an International Atomic Energy Agency technical meeting.
There is increasing interest in radiogenomics and the characterization of molecular profiles that predict normal tissue and tumor radioresponse. A meeting in Amsterdam was organized by the International Atomic Energy Agency to discuss this topic on an international basis. This report is not completely exhaustive, but highlights some of the ongoing studies and new initiatives being carried out worldwide in the banking of tumor and normal tissue samples underpinning the development of molecular marker profiles for predicting patient response to radiotherapy. It is generally considered that these profiles will more accurately define individual or group radiosensitivities compared with the nondefinitive findings from the previous era of cellular-based techniques. However, so far there are only a few robust reports of molecular markers predicting normal tissue or tumor response. Many centers in different countries have initiated tissue and tumor banks to store samples from clinical trials for future molecular profiling analysis, to identify profiles that predict for radiotherapy response. The European Society for Therapeutic Radiology and Oncology GENEtic pathways for the Prediction of the effects of Irradiation (GENEPI) project, to store, document, and analyze sample characteristics vs. response, is the most comprehensive in this regard. The next 5-10 years are likely to see the results of these and other correlative studies, and promising associations of profiles with response should be validated in larger definitive trials.


Face and Voice Perception: Understanding Commonalities and Differences.
Faces and voices are of high importance in interpersonal communication, and there are notable parallels between face and voice perception. However, these parallels do not sit entirely comfortably with the full range of available evidence. In this review, we evaluate parallels between the functional and neural organisation of face and voice perception, while locating these in the context of ways in which faces and voices also differ. We take the discussion to the next level by asking why these commonalities and differences exist. A novel synthesis is offered, grounded in the interaction between intrinsic characteristics of faces and voices and the demands of everyday life, showing how the pattern of findings reflects a system that can respond optimally to different everyday demands.


Sliding Water Droplet on Oil Impregnated Surface and Dust Particle Mitigation.
Self-cleaning of surfaces becomes challenging for energy harvesting devices because of the requirements of high optical transmittance of device surfaces. Surface texturing towards hydrophobizing can improve the self-cleaning ability of surfaces, yet lowers the optical transmittance. Introducing optical matching fluid, such as silicon oil, over the hydrophobized surface improves the optical transmittance. However, self-cleaning ability, such as dust mitigation, of the oil-impregnated hydrophobic surfaces needs to be investigated. Hence, solution crystallization of the polycarbonate surface towards creating hydrophobic texture is considered and silicon oil impregnation of the crystallized surface is explored for improved optical transmittance and self-cleaning ability. The condition for silicon oil spreading over the solution treated surface is assessed and silicon oil and water infusions on the dust particles are evaluated. The movement of the water droplet over the silicon oil-impregnated sample is examined utilizing the high-speed facility and the tracker program. The effect of oil film thickness and the tilting angle of the surface on the sliding droplet velocity is estimated for two droplet volumes. The mechanism for the dust particle mitigation from the oil film surface by the sliding water droplet is analyzed. The findings reveal that silicon oil impregnation of the crystallized sample surface improves the optical transmittance significantly. The sliding velocity of the water droplet over the thick film (~700 µm) remains higher than that of the small thickness oil film (~50 µm), which is attributed to the large interfacial resistance created between the moving droplet and the oil on the crystallized surface. The environmental dust particles can be mitigated from the oil film surface by the sliding water droplet. The droplet fluid infusion over the dust particle enables to reorient the particle inside the droplet fluid. As the dust particle settles at the trailing edge of the droplet, the sliding velocity decays on the oil-impregnated sample.


MDM2 promotes ubiquitination and degradation of MDMX.
The p53 tumor suppressor is regulated by MDM2-mediated ubiquitination and degradation. Mitogenic signals activate p53 by induction of ARF expression, which inhibits p53 ubiquitination by MDM2. Recent studies showed that the MDM2 homolog MDMX is also an important regulator of p53. We present evidence that MDM2 promotes MDMX ubiquitination and degradation by the proteasomes. This effect is stimulated by ARF and correlates with the ability of ARF to bind MDM2. Promotion of MDM2-mediated MDMX ubiquitination requires the N-terminal domain of ARF, which normally inhibits MDM2 ubiquitination of p53. An intact RING domain of MDM2 is also required, both to interact with MDMX and to provide E3 ligase function. Increase of MDM2 and ARF levels by DNA damage, recombinant ARF adenovirus infection, or inducible MDM2 expression leads to proteasome-mediated down-regulation of MDMX levels. Therefore, MDMX and MDM2 are coordinately regulated by stress signals. The ARF tumor suppressor differentially regulates the ability of MDM2 to promote p53 and MDMX ubiquitination and activates p53 by targeting both members of the MDM2 family.


Radio Frequency Induction Welding of Silver Nanowire Networks for Transparent Heat Films.
Transparent heat films (THFs) are attracting increasing attention for their usefulness in various applications, such as vehicle windows, outdoor displays, and biosensors. In this study, the effects of induction power and radio frequency on the welding characteristics of silver nanowires (Ag NWs) and Ag NW-based THFs were investigated. The results showed that higher induction frequency and higher power increased the welding of the Ag NWs through the nano-welding at the junctions of the Ag NWs, which produced lower sheet resistance, and improved the adhesion of the Ag NWs. Using the inductive welding condition of 800 kHz and 6 kW for 60 s, 100 ohm/sq of Ag NW thin film with 95% transmittance at 550 nm after induction heating could be decreased to 56.13 ohm/sq, without decreasing the optical transmittance. In addition, induction welding of the Ag NW-based THFs improved haziness, increased bending resistance, enabled higher operating temperature at a given voltage, and improved stability.


Directional Defect Management in Perovskites by In Situ Decomposition of Organic Metal Chalcogenides for Efficient Solar Cells.
Directional defects management in polycrystalline perovskite film with inorganic passivator is highly demanded while yet realized for fabricating efficient and stable perovskite solar cells (PSCs). Here, we develop a directional passivation strategy employing a two-dimensional (2D) material, Cu-(4-mercaptophenol) (Cu-HBT), as a passivator precursor. Cu-HBT combines the merits of the targeted modification from organic passivator and excellent stability offered by inorganic passivator. Featuring with dense organic functional motifs on its surfaces, Cu-HBT has the capability to "find" and fasten to the Pb defect sites in perovskites through coordination interactions during a spin-coating process. During subsequent annealing treatment, the organic functional motifs cleave from Cu-HBT and convert in situ into p-type semiconductors, Cu2 S and PbS. The resultant Cu2 S and PbS not only serve as stable inorganic passivators on the perovskite surface, significantly enhancing cell stability, but also facilitate efficient charge extraction and transport, resulting in an impressive efficiency of up to 23.5 %. This work contributes a new defect management strategy by directionally yielding the stable inorganic passivators for highly efficient and stable PSCs.


Molecular analyses of HLA-DRB1, -DPB1, and -DQB1 in Jing ethnic minority of Southwest China.
In the present study, DNA typing for HLA-DRB1, DQB1 and DPB1 was performed using polymerase chain reaction-sequencing based typing (PCR-SBT) method in 144 random selected Jing ethnic individuals inhabiting in South China. Allele frequencies and two-locus haplotypes (DRB1-DQB1) were statistically analyzed and 20 DPB1 alleles, 27 DRB1 and 20 DQB1 were detected. The most frequent DPB1 allele was DPB1*0501 with the percentage of 36.9% followed by DPB1*1301 (15.7%), DPB1*0401 (11.0%) and DPB1*020102 (9.8%). Among the 27 detected DRB1 alleles, DRB1*120201 (13.8%) was most commonly observed followed by DRB1*150201, *030101 and *090102 alleles with the frequencies of 9.4%, 9.1% and 8.3%, respectively. Among the 20 detected DQB1 alleles the most predominant one was DQB1*030101/0309 (19.9%). DQB1*050201 (19.1%), DQB1*0201/0202 (16.1%) and DQB1*050101 (12.3%) were also frequently observed in Jing population. Statistical analysis of two-locus haplotypes showed that DRB1*120201-DQB1*030101/DRB1*120201-DQB1*0309 (HF = 9.4%, D = 6.65x10(-2)) was most predominant followed by DRB1*030101-DQB1*0201/DRB1*030101-DQB1*0202 (HF = 8.1%, D = 6.66 x 10(-2)). The comparison of HLA class II allele and haplotype frequencies in Jing with those in other populations all over the world and a dendrogram based on the DRB1, DQB1 and DPB1 genes suggested that Jing ethnic population has an origin of Southeast Asia and is belonged to the southern group of Chinese populations.


Does Regular Exercise Counter T Cell Immunosenescence Reducing the Risk of Developing Cancer and Promoting Successful Treatment of Malignancies?
Moderate intensity aerobic exercise training or regular physical activity is beneficial for immune function. For example, some evidence shows that individuals with an active lifestyle exhibit stronger immune responses to vaccination compared to those who are inactive. Encouragingly, poor vaccine responses, which are characteristic of an ageing immune system, can be improved by single or repeated bouts of exercise. In addition, exercise-induced lymphocytosis, and the subsequent lymphocytopenia, is thought to facilitate immune surveillance, whereby lymphocytes search tissues for antigens derived from viruses, bacteria, or malignant transformation. Aerobic exercise training is anti-inflammatory and is linked to lower morbidity and mortality from diseases with infectious, immunological, and inflammatory aetiologies, including cancer. These observations have led to the view that aerobic exercise training might counter the age-associated decline in immune function, referred to as immunosenescence. This article summarises the aspects of immune function that are sensitive to exercise-induced change, highlighting the observations which have stimulated the idea that aerobic exercise training could prevent, limit, or delay immunosenescence, perhaps even restoring aged immune profiles. These potential exercise-induced anti-immunosenescence effects might contribute to the mechanisms by which active lifestyles reduce the risk of developing cancer and perhaps benefit patients undergoing cancer therapy.


Myelination of cultured dorsal root ganglion neurons by oligodendrocytes obtained from adult rats.
Enzymatically dissociated cell suspensions from adult rat spinal cord were added at low densities (5 X 10(3) cells/culture) to cultures of pure dorsal root ganglion neurons. Oligodendrocytes, identified by immunostaining with a monoclonal antibody to galactocerebroside, began to proliferate by 4 days after their addition, forming large colonies of cells by the 14th day. Myelin formation by oligodendrocytes began 4 weeks after addition and myelin was abundant by 6 weeks. Oligodendrocyte proliferation and myelination did not require the immediate presence of astrocytes; the number of astrocytes overall remained low throughout the culture period. Preliminary studies indicated that the specific removal of galactocerebroside-positive cells from the cultures with anti-galactocerebroside antibody and complement 3 days after their addition prevented the subsequent generation of new oligodendrocytes and myelination. These preliminary results suggest that a major source of new myelinating cells in the adult central nervous system (CNS) might be already committed, galactocerebroside-positive, oligodendrocytes rather than uncommitted stem cells. The absence of cellular barriers between the myelinating cells and the medium make these cultures well suited for studies probing cellular and molecular mechanisms of myelination in the CNS.


Effects of human exposure to atmospheric epsilon-caprolactam.
There is little published information on the human toxicology of epsilon-caprolactam, the monomer precursor of nylon 6. This paper reports an investigation of a group of eight workers who had been chronically exposed to atmospheric caprolactam levels of around 70 times the current ACGIH threshold limit value (TLV). No evidence of systemic toxicity was found, although all workers showed a greater or lesser degree of skin change in the form of peeling and/or fissuring.


SPIN1, a K homology domain protein negatively regulated and ubiquitinated by the E3 ubiquitin ligase SPL11, is involved in flowering time control in rice.
The rice (Oryza sativa) E3 ligase SPOTTED LEAF11 (SPL11) negatively regulates programmed cell death and disease resistance. We demonstrate here that SPL11 also regulates flowering via interaction with SPIN1 (for SPL11-interacting protein1), a Signal Transduction and Activation of RNA family member. SPIN1 binds RNA and DNA in vitro and interacts with SPL11 in the nucleus. Spl11 mutants have delayed flowering under long-day conditions. Spin1 overexpression causes late flowering independently of daylength; expression analyses of flowering marker genes in these lines suggested that SPIN1 represses flowering by downregulating the flowering promoter gene Heading date3a (Hd3a) via Hd1-dependent mechanisms in short days and by targeting Hd1-independent factors in long days. Both Spin1 and Spl11 are regulated diurnally in opposing phases. SPL11 negatively regulates Spin1 transcript levels, while SPIN1 also affects Spl11 expression. Moreover, we show that coincidence of high accumulation of Spin1 mRNA with the light in the morning and early evening is needed to repress flowering. SPIN1 is monoubiquitinated by SPL11, suggesting that it is not targeted for degradation. Our data are consistent with a model in which SPIN1 acts as a negative regulator of flowering that itself is negatively regulated by SPL11, possibly via ubiquitination.


Evaluation of Bystander Cell Killing Effects in Suicide Gene Therapy of Cancer: Engineered Thymidylate Kinase (TMPK)/AZT Enzyme-Prodrug Axis.
Suicide gene therapy of cancer (SGTC) entails the introduction of a cDNA sequence into tumor cells whose polypeptide product is capable of either directly activating apoptotic pathways itself or facilitating the activation of pharmacologic agents that do so. The latter class of SGTC approaches is of the greater utility in cancer therapy owing to the ability of some small, activated cytotoxic compounds to diffuse from their site of activation into neighboring malignant cells, where they can also mediate destruction. This phenomenon, termed "bystander killing", can be highly advantageous in driving significant tumor regression in vivo without the requirement of transduction of each and every tumor cell with the suicide gene. We have developed a robust suicide gene therapy enzyme/prodrug system based on an engineered variant of the human thymidylate kinase (TMPK), which has been endowed with the ability to drive azidothymidine (AZT) activation. Delivery of this suicide gene sequence into tumors by means of recombinant lentivirus-mediated transduction embodies an SGTC strategy that successfully employs bystander cell killing as a mechanism to achieve significant ablation of solid tumors in vivo. Thus, this engineered TMPK/AZT suicide gene therapy axis holds great promise for clinical application in the treatment of inoperable solid tumors in the neoadjuvant setting. Here we present detailed procedures for the preparation of recombinant TMPK-based lentivirus, transduction of target cells, and various approaches for the evaluation of bystander cell killing effects in SGCT in both in vitro and in vivo models.


The management of infertility.
Infertility remains a difficult clinical problem but with only a small amount of effort most clinics can improve facilities and streamline investigations. Lack of continuity remains one of the most trying problems for both patient and clinician. Reasonable time limits limits must be placed on investigations and the idea of adoption should be introduced at the appropriate time. Future developments may gradually help to eradicate the problem.


A point mutation in ribosomal protein L7/L12 reduces its ability to form a compact dimer structure and to assemble into the GTPase center.
An Escherichia coli mutant, LL103, harboring a mutation (Ser15 to Phe) in ribosomal protein L7/L12 was isolated among revertants of a streptomycin-dependent strain. In the crystal structure of the L7/L12 dimer, residue 15 within the N-terminal domain contacts the C-terminal domain of the partner monomer. We tested effects of the mutation on molecular assembly by biochemical approaches. Gel electrophoretic analysis showed that the Phe15-L7/L12 variant had reduced ability in binding to L10, an effect enhanced in the presence of 0.05% of nonionic detergent. Mobility of Phe15-L7/L12 on gel containing the detergent was very low compared to the wild-type proteins, presumably because of an extended structural state of the mutant L7/L12. Ribosomes isolated from LL103 cells contained a reduced amount of L7/L12 and showed low levels (15-30% of wild-type ribosomes) of activities dependent on elongation factors and in translation of natural mRNA. The ribosomal activity was completely recovered by addition of an excess amount of Phe15-L7/L12 to the ribosomes, suggesting that the mutant L7/L12 exerts normal functions when bound on the ribosome. The interaction of Ser15 with the C-terminal domain of the partner molecule seems to contribute to formation of the compact dimer structure and its efficient assembly into the ribosomal GTPase center. We propose a model relating compact and elongated forms of L7/L12 dimers. Phe15-L7/L12 provides a new tool for studying the functional structure of the homodimer.


Anticancer Activity of Kefir on Glioblastoma Cancer Cell as a New Treatment.
Kefir drink is one of the most important probiotic products, which is made using kefir microorganisms in fermenting the milk. Numerous investigation have been accomplished in the field of the therapeutic property of probiotic products. In the present study, we assessed the cytotoxic effect of kefir on the rate of growth and increase of glioblastoma cancer cell as the most severe form of brain tumors. In this experimental study, we used a U87 cancer cell line (glioblastoma). The interaction between cancer cells and different concentrations of kefir drink and supernatants at 24 and 48 hours was considered. The cell cytotoxicity of kefir and sedimentation of cell lysate and extract of kefir was assessed using the MTT test after 24 and 48 hours. The result of the MTT test, treatment of the cells with the 48-hour fermented drink, demonstrated the most cell cytotoxicity in comparison with the control group. Results showed that the toxicity effect in all groups was dose-dependent, and by increasing the concentration, cell survival decreased noticeably. The results indicated that the supernatant of fermented kefir drink as a probiotic product has more toxicity and lethality effect on the glioblastoma cancer cell. This product can be utilized as a replacement or a complementary therapy of cancer.


Dynamic integration of reward and stimulus information in perceptual decision-making.
In perceptual decision-making, ideal decision-makers should bias their choices toward alternatives associated with larger rewards, and the extent of the bias should decrease as stimulus sensitivity increases. When responses must be made at different times after stimulus onset, stimulus sensitivity grows with time from zero to a final asymptotic level. Are decision makers able to produce responses that are more biased if they are made soon after stimulus onset, but less biased if they are made after more evidence has been accumulated? If so, how close to optimal can they come in doing this, and how might their performance be achieved mechanistically? We report an experiment in which the payoff for each alternative is indicated before stimulus onset. Processing time is controlled by a "go" cue occurring at different times post stimulus onset, requiring a response within msec. Reward bias does start high when processing time is short and decreases as sensitivity increases, leveling off at a non-zero value. However, the degree of bias is sub-optimal for shorter processing times. We present a mechanistic account of participants' performance within the framework of the leaky competing accumulator model [1], in which accumulators for each alternative accumulate noisy information subject to leakage and mutual inhibition. The leveling off of accuracy is attributed to mutual inhibition between the accumulators, allowing the accumulator that gathers the most evidence early in a trial to suppress the alternative. Three ways reward might affect decision making in this framework are considered. One of the three, in which reward affects the starting point of the evidence accumulation process, is consistent with the qualitative pattern of the observed reward bias effect, while the other two are not. Incorporating this assumption into the leaky competing accumulator model, we are able to provide close quantitative fits to individual participant data.


An Investigation of the Risk Factors of Osteoporosis and the Correlation between Opium Consumption and Osteoporosis in Adults.
Osteoporosis and osteopenia are the most common metabolic bone diseases making the patients vulnerable to bone fragility and fracture. In this study, the association of opium consumption and osteoporosis adjusted for other risk factors was studied. In this cross-sectional study, 619 cases including 73 men and 546 women referred to densitometry center in Kerman, Iran, were studied. Demographic information, history of opium consumption, medications, and other risk factors were collected using a structured questionnaire. In a univariate analysis, opium consumption, aging, and having a body mass index (BMI) lower than 24 accompanied an increased chance of osteoporosis, while taking physical exercises on a daily basis reduces the chance of osteoporosis. Through multivariable analysis, the two variables of age group and BMI group turned out to be of significance; that is, the chance of osteoporosis or osteopenia in the age group of higher than 60 years and 45-60 years being placed in one of the levels of osteoporosis or osteopenia was 4.9 and 3.1 times higher than the age groups lower than 45 years, respectively, after being adjusted to the other variables. Considering the results of this study, though the risk of bone density reduction in the individuals consuming opium was higher, due to the disparity between opium consumption in the two sexes, the difference was not significant between the two groups, and it is proposed that studies on larger samples and in the both sexes be conducted to determine the impacts of opium on the bone density.


Medical schools' attitudes and perceptions regarding the use of central institutional review boards.
To investigate the current practices, attitudes, perceptions, and future plans of U.S. medical schools regarding the use of central institutional review boards (IRBs) to review research involving human participants. In 2003, a survey instrument was distributed via fax and e-mail to the deans of research at the 125 accredited U.S. medical schools. Each dean was asked to have the instrument completed by the official at that school who decided on the use of a central versus local IRB. The survey instrument consisted primarily of a variety of closed-ended questions. Eighty-eight medical schools (69.8%) completed the instrument; 76% of these indicated that they had never used a central IRB and 24% had used a central IRB. Most of the respondents expressed no interest in using a central IRB in the future because they believed that their local IRB was working efficiently, and they were concerned about issues of institutional liability and the loss of local representation in the review process. Of the medical schools that had used a central IRB, most were pleased with the performance of the central IRB and would continue to use a central IRB in the future. Of interest, most of these respondents did not agree that a central IRB had helped them to attract industry-sponsored research. In spite of much discussion about the advantages of central IRBs in expediting overview of human subjects research, especially in multicenter trials, the majority of medical schools surveyed had never used a central IRB and expressed no interest in doing so.


Genetic implications of double primary cancers of the colorectum and endometrium.
Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant condition predisposing to cancers of the colorectum and endometrium. Endometrial cancer is the most commonly occurring extracolonic cancer in HNPCC. Estimates of the cumulative incidence of endometrial cancer in women with mutations in the HNPCC genes range from 22-43%. In order to determine how frequently double primary cancers of the colorectum and endometrium are the result of a hereditary factor, we conducted a registry based study in Ontario and Quebec, Canada. We obtained pedigrees on 80 women diagnosed with double primary cancers of the colorectum and endometrium at less than 70 years of age. Family histories of cancer were obtained for all first degree relatives of these women and cancer rates were compared with age standardised provincial incidence rates in order to estimate the relative risks. There was a total of 82 cancers observed in relatives below the age of 55, compared with 31.2 expected, giving a relative risk of 2.6 (95% confidence interval (CI) 2.1-3.3). The relative risk for colorectal cancer below 55 was 16.1 (95% CI 11.6-21.8). This risk decreased with increasing age of onset of cancers in probands. For probands with both colorectal and endometrial cancer diagnosed under the age of 55, the relative risk of colorectal cancer in relatives below the age of 55 was 30.5 (95% CI 18.8-46.6). Similar patterns were observed for endometrial and pancreatic cancer. There were non-significant increases in rates of cancer of the oesophagus, stomach, small intestine, and bladder. There was no increased risk of breast cancer. The risk of lung cancer was decreased, especially in older relatives. Our findings indicate the presence of a significant genetic component of cancer in women with double primary cancers of the colorectum and endometrium.


Modeling the emergence of whisker direction maps in rat barrel cortex.
Based on measuring responses to rat whiskers as they are mechanically stimulated, one recent study suggests that barrel-related areas in layer 2/3 rat primary somatosensory cortex (S1) contain a pinwheel map of whisker motion directions. Because this map is reminiscent of topographic organization for visual direction in primary visual cortex (V1) of higher mammals, we asked whether the S1 pinwheels could be explained by an input-driven developmental process as is often suggested for V1. We developed a computational model to capture how whisker stimuli are conveyed to supragranular S1, and simulate lateral cortical interactions using an established self-organizing algorithm. Inputs to the model each represent the deflection of a subset of 25 whiskers as they are contacted by a moving stimulus object. The subset of deflected whiskers corresponds with the shape of the stimulus, and the deflection direction corresponds with the movement direction of the stimulus. If these two features of the inputs are correlated during the training of the model, a somatotopically aligned map of direction emerges for each whisker in S1. Predictions of the model that are immediately testable include (1) that somatotopic pinwheel maps of whisker direction exist in adult layer 2/3 barrel cortex for every large whisker on the rat's face, even peripheral whiskers; and (2) in the adult, neurons with similar directional tuning are interconnected by a network of horizontal connections, spanning distances of many whisker representations. We also propose specific experiments for testing the predictions of the model by manipulating patterns of whisker inputs experienced during early development. The results suggest that similar intracortical mechanisms guide the development of primate V1 and rat S1.


Femtosecond X-ray diffraction from two-dimensional protein crystals.
X-ray diffraction patterns from two-dimensional (2-D) protein crystals obtained using femtosecond X-ray pulses from an X-ray free-electron laser (XFEL) are presented. To date, it has not been possible to acquire transmission X-ray diffraction patterns from individual 2-D protein crystals due to radiation damage. However, the intense and ultrafast pulses generated by an XFEL permit a new method of collecting diffraction data before the sample is destroyed. Utilizing a diffract-before-destroy approach at the Linac Coherent Light Source, Bragg diffraction was acquired to better than 8.5 Å resolution for two different 2-D protein crystal samples each less than 10 nm thick and maintained at room temperature. These proof-of-principle results show promise for structural analysis of both soluble and membrane proteins arranged as 2-D crystals without requiring cryogenic conditions or the formation of three-dimensional crystals.


B3GNT3, a Direct Target of miR-149-5p, Promotes Lung Cancer Development and Indicates Poor Prognosis of Lung Cancer.
B3GNT3 (β1, 3-N-acetylglucosaminyltransferase-3) belongs to the β3GlcNAcT family and is essential to form extended core 1 oligosaccharides. Previous studies revealed that B3GNT3 expression was dysregulated in multiple cancers. Here, we aimed to understand the expression profile and function of B3GNT3 in lung cancer. The expression of B3GNT3 was measured by immunohistochemistry and public database analysis. B3GNT3 was knocked down to evaluate the lung cancer cell proliferation, migration and invasion in in vitro and in vivo tumor formation experiments. miR-149-5p targeting B3GNT3 was identified with TargetScan analysis and confirmed with reporter assay. Overexpression of miR-149-5p was achieved using microRNA mimics and function of microRNA-149-5p/B3GNT3 axis was tested in vitro. B3GNT3 was upregulated in lung cancer, and B3GNT3 overexpression was associated with poor prognosis of lung cancer patients. High expression of B3GNT3 was associated with advanced TNM stages, larger tumor size, tumor metastasis and recurrence. Functionally, we demonstrated that knockdown of B3GNT3 suppressed lung cancer cell growth and invasion in vitro. Knockdown of B3GNT3 suppressed lung cancer development in a xenograft tumor model. Moreover, miR-149-5p was validated to negatively regulate B3GNT3 expression through directly targeting B3GNT3 3'-UTR. Overexpression of miR-149-5p could antagonize the tumorigenesis effect of B3GNT3 in vitro. In summary, our study demonstrated that B3GNT3 overexpression was correlated with poor prognosis of lung cancer patient, indicating that B3GNT3 could be a promising prognostic biomarker for lung cancer. miR-149-5p negatively regulated B3GNT3 expression, which might be utilized for therapeutic target in lung cancer.


MicroRNA in the adaptive immune system, in sickness and in health.
MicroRNA are emerging as key regulators of the development and function of adaptive immunity. These 19-24 nucleotide regulatory RNA molecules have essential roles in multiple faucets of adaptive immunity, from regulating the development of the key cellular players to the activation and function in immune responses. MicroRNA are involved in T cell and B cell differentiation in the thymus and bone marrow, and subsequent peripheral homeostasis. The contribution of specific microRNA to the adaptive immune response becomes even more apparent during the effector phases: class switching and germinal centre formation in B cells, differentiation into functional lineages in T cells, and activation of antigen-presentation cells through pattern-recognition pathways. With the capacity of microRNA to alter the survival and death of T and B cells, control over microRNA expression is essential to prevent adaptive immune cells from unregulated proliferation. MicroRNA can act both as 'oncomirs' and tumour suppressors, and thus dysregulation of microRNA in lymphocytes can cause malignancies. In this review, we will describe the role of microRNA in generating a productive adaptive response, and the consequences if microRNA-mediated repression of lymphocytes is perturbed.


Left inferior-parietal lobe activity in perspective tasks: identity statements.
We investigate the theory that the left inferior parietal lobe (IPL) is closely associated with tracking potential differences of perspective. Developmental studies find that perspective tasks are mastered at around 4 years of age. Our first study, meta-analyses of brain imaging studies shows that perspective tasks specifically activate a region in the left IPL and precuneus. These tasks include processing of false belief, visual perspective, and episodic memory. We test the location specificity theory in our second study with an unusual and novel kind of perspective task: identity statements. According to Frege's classical logical analysis, identity statements require appreciation of modes of presentation (perspectives). We show that identity statements, e.g., "the tour guide is also the driver" activate the left IPL in contrast to a control statements, "the tour guide has an apprentice." This activation overlaps with the activations found in the meta-analysis. This finding is confirmed in a third study with different types of statements and different comparisons. All studies support the theory that the left IPL has as one of its overarching functions the tracking of perspective differences. We discuss how this function relates to the bottom-up attention function proposed for the bilateral IPL.


Occupational inequalities in mortality in Korea: an analysis using nationally representative mortality follow-up data from the late 2000s and after.
Many Korean and international studies have found higher mortality rates and poorer health conditions among manual workers than among non-manual workers. However, a recent study using unlinked data argued that since the economic crisis in Korea in the late 2000s, the mortality estimates of male Korean non-manual workers have been higher than those of manual workers. Our work using individually linked data from the late 2000s and after aimed to examine mortality inequality by occupational class. We analyzed Korea National Health and Nutrition Examination Survey data that were individually linked to cause-of-death data. Cox regression analysis was used to identify the hazard ratios for mortality by occupational class. Of 11,766 males aged between 35 and 64, 397 died between 2007 and 2018: 142 died from cancer, 68 from cardiovascular disease, 88 from external causes, and 99 from other causes. After controlling for age, the mortality estimates for manual workers were 1.85 times higher than those for upper non-manual workers (p<0.05). We observed no evidence of reversed mortality inequality among occupational classes in Korea since the 2000s; this previously reported finding might have been due to numerator-denominator bias arising from the use of unlinked data.


Automatic Respiratory Gating Hepatic DCEUS-based Dual-phase Multi-parametric Functional Perfusion Imaging using a Derivative Principal Component Analysis.
Purpose: Angiogenesis in liver cancers can be characterized by hepatic functional perfusion imaging (FPI) on the basis of dynamic contrast-enhanced ultrasound (DCEUS). However, accuracy is limited by breathing motion which results in out-of-plane image artifacts. Current hepatic FPI studies do not correct for these artifacts and lack the evaluation of correction accuracy. Thus, a hepatic DCEUS-based dual-phase multi-parametric FPI (DM-FPI) scheme using a derivative principal component analysis (PCA) respiratory gating is proposed to overcome these limitations. Materials and Methods: By considering severe 3D out-of-plane respiratory motions, the proposed scheme's accuracy was verified with in vitro DCEUS experiments in a flow model mimicking a hepatic vein. The feasibility was further demonstrated by considering in vivo DCEUS measurements in normal rabbit livers, and hepatic cavernous hemangioma and hepatocellular carcinoma in patients. After respiratory kinetics was extracted through PCA of DCEUS sequences under free-breathing condition, dual-phase respiratory gating microbubble kinetics was identified by using a derivative PCA zero-crossing dual-phase detection, respectively. Six dual-phase hemodynamic parameters were estimated from the dual-phase microbubble kinetics and DM-FPI was then reconstructed via color-coding to quantify 2.5D angiogenic hemodynamic distribution for live tumors. Results: Compared with no respiratory gating, the mean square error of respiratory gating DM-FPI decreased by 1893.9 ± 965.4 (p < 0.05), and mean noise coefficients decreased by 17.5 ± 7.1 (p < 0.05), whereas correlation coefficients improved by 0.4 ± 0.2 (p < 0.01). DM-FPI observably removed severe respiratory motion artifacts on PFI and markedly enhanced the accuracy and robustness both in vitro and in vivo. Conclusions: DM-FPI precisely characterized and distinguished the heterogeneous angiogenic hemodynamics about perfusion volume, blood flow and flow rate within two anatomical sections in the normal liver, and in benign and malignant hepatic tumors. DCEUS-based DM-FPI scheme might be a useful tool to help clinicians diagnose and provide suitable therapies for liver tumors.


Opening wedge high tibial osteotomy: a novel technique for harvesting autograft bone.
High tibial osteotomy can provide 10 to 15 years of consistent pain relief and improved function for most patients with unicompartmental knee arthritis. However, some studies have reported less predictable results, with deteriorating survivorship after 10 years of follow-up. Therefore, it is paramount to carefully select patients and to understand that technical errors during surgery often lead to poor outcomes. It is well established that obese patients, as well as undercorrected osteotomies, often lead to early failure, with rapid degeneration of the arthritic compartment. Although many surgical techniques describing high tibial osteotomies have been previously published, most techniques share similar surgical principles. What differentiates our technique from others is the mode of harvesting local autograft bone to fill our osteotomy site. For several years, a specialized harvester has been used to obtain distal femoral cancellous bone. This technique is simple, efficient, reproducible, and safe. This article reviews the novel technique for opening wedge high tibial osteotomies.


Detection of new methicillin-resistant Staphylococcus aureus strains that carry a novel genetic homologue and important virulence determinants.
In this study, 18 methicillin-resistant Staphylococcus aureus (MRSA) isolates harboring staphylococcal cassette chromosome mec (SCCmec) type XI, recovered in the Dutch-German Euregio, were characterized by DNA microarrays. In contrast to previous data, we found two MRSA strains of different clonal lineages possessing SCCmec XI that carried important virulence determinants. The worrisome emergence of such toxigenic MRSA strains raises concerns that MRSA strains with enhanced virulence potential and impaired detectability by standard molecular assays may spread in Europe.


Effects of proprioception and core stability training on gait parameters of deaf adolescents: a randomized controlled trial.
The current study aimed to explore the effects of proprioception versus core stability training over 8 weeks on the gait parameters of deaf adolescents. A total of 20 deaf adolescents were randomized into two groups: one group receiving proprioception training (PT, n = 10), another group receiving core stability training (CST, n = 10), and eleven typically developing adolescents assigned into the control group (CON; n = 11). Gait was recorded by two digital cameras; then, using the Kinovea software, the parameters of gait included: gait velocity, cadence, stride length, stride time, stance time, and swing time were calculated in terms of percentages of the walking cycle. After 8 weeks of PT, no significant differences were observed for all gait parameters between PT and control groups (p > 0.05). Also, after 8 weeks of CST, no significant differences were observed in gait velocity and cadence between the CST and control groups (p > 0.05). However, after 8 weeks of CST, stride length (p = 0.02) was higher in the control group; Stride time (p = 0.03), stance time (p = 0.04) and swing time (p = 0.04) were higher in the CST group. Moreover, after 8 weeks of PT, values showed significant improvements in all gait parameters (p = 0.001). Also, after 8 weeks of CST, values showed significant improvements in gait velocity and cadence (p = 0.001), but no significant differences were observed in other gait parameters (p > 0.05). The findings of this study indicated that PT improved all gait parameters, whereas CST improved gait velocity and cadence. The results of the present study also demonstrated that PT had a greater effect on gait parameters of deaf adolescents compared with CST. It seems that PT induces more training effects than CTS for enhancing gait parameters of deaf adolescents.Trial registration: Clinical trial registry number: IRCT20170312033029N2. URL: https://en.irct.ir/trial/25584 .


[Dynamic monitoring of minimal residual disease in acute lymphoid leukemia].
The aim of this study was to establish a method for quantitative detection of immunoglobulin heavy chain (IgH) gene rearrangements and to explore its clinical application in monitoring minimal residual disease (MRD) of acute lymphoid leukemia (ALL). Clonal IgH gene rearrangements in 51 patients with ALL at diagnosis were identified by multiplex PCR assay. PCR products were sequenced and pairwise in IMGT data base. Allele-specific oligonucleotides primers were designed complementary to the junctional region. The conservative JH primers combined with TaqMan probes were used to monitor the level of MRD in ALL patients. The sensitivity and specificity were assessed as well. The results indicated that out of all the 51 ALL patients, IgH rearrangements were identified in 21 cases, and 15 patients out of them were quantified. The slope of the standard curves was -3.1 to -3.9 and the correlation coefficients of all standard curves were > 0.98. The sensitivity was between 10(-4) and 10(-5), only one patient's sensitivity was 10(-3). Most of the quantitative range was less than 10(-4). The background's nonspecific amplification was detectable at a low level and had a little influence on results. 7 patients whose MRD level below 10(-3) kept complete remission and another 8 patients whose MRD level above 10(-3) had a higher relapse rate. It is concluded that the analysis of IgH gene rearrangements with RQ-PCR is a highly sensitive, specific and reliable method for accurate evaluation of MRD in ALL. The data indicates a high correlation between the level of IgH rearrangements and the prognosis in ALL patients.


Sex differences in carotid endarterectomy outcomes: results from the Ontario Carotid Endarterectomy Registry.
The existing literature provides conflicting evidence on surgical risks of carotid endarterectomy in women compared with men. We used data from a large population-based carotid surgery registry to determine whether sex differences exist in the risk of perioperative complications from carotid endarterectomy. We analyzed data from the Ontario Carotid Endarterectomy Registry, which contains data on all patients who underwent carotid endarterectomy in the province of Ontario between 1994 and 1997. We compared the risk of death or stroke at 30 days in women and men and used multivariate analyses to adjust for age, comorbid conditions, and surgical factors. Secondary analyses compared the risks of death and/or stroke in women and men at 2 years after surgery. The study sample consisted of 6038 patients (35% women). The risks of perioperative stroke or death were not significantly different in women compared with men (adjusted hazard ratio, 1.10; 95% CI, 0.90 to 1.35). The combined risk of stroke or death at 2 years after surgery was also similar in women and men (adjusted hazard ratio, 1.05; 95% CI, 0.92 to 1.21). However, women were more likely to have a stroke (adjusted hazard ratio, 1.26; 95% CI, 1.05 to 1.51) and less likely to die (adjusted hazard ratio, 0.82; 95% CI, 0.68 to 0.99) within 2 years after surgery. Perioperative complication rates from carotid endarterectomy are similar in women and men. Women should not be discouraged from carotid endarterectomy solely on the basis of surgical risks.


Ultra-thin electrospun nanocomposite scaffold of poly (3-hydroxybutyrate)-chitosan/magnetic mesoporous bioactive glasses for bone tissue engineering applications.
Bioglass is widely used in skeletal tissue engineering due to its outstanding bioactive properties. In the present study, magnetic mesoporous bioglass (MMBG) synthesized through the sol-gel method was incorporated into poly(3-hydroxybutyrate)-chitosan (PHB-Cs) solution and the resulting electrospun nanocomposite scaffolds were investigated and compared with MMBG free scaffold. The addition of 10 wt% MMBG has an outstanding effect on producing ultra-thin electrospun nanocomposite fibers due to its magnetic content (diameter of ≃128 nm). This improvement led to better mechanical properties, including an increase in both tensile modulus (up to ≃229 MPa) and tensile strength (to ≃4.95 MPa). Although the inclusion of MMBG slightly decreased the surface roughness of the nanofibrous scaffold (RMS from ≃197 to 154 nm), it could improve the wettability (WCA from ≃54 to 44°). This achievement has the potential to bring an enhancement in biomineralization and biological response. These outputs, combined with the observed increase in human osteoblast MG-63 cell viability (≃53 % improvement) as measured by MTT assay, DAPI, and SEM indicate prefer cell behavior of this nanocomposite structure. Additionally, the qualitative improvement in Alizarin Red staining and the quantitative enhancement of ALP secretion, serve as further evidence of the PHB-Cs/MMBG ultrathin nanofibers potential in bone tissue engineering.


Prevalence of mitral valvar prolapse in young athletes.
The prevalence of mitral valvar prolapse has been reported to be between 0.6 and 21%. The goal of our study was to evaluate its prevalence in young athletes who underwent hand-held echocardiography as a screening mostly in southern California. We retrospectively analyzed 1742 echocardiograms that were performed as a part of a cardiac screening of teenage athletes. The total prevalence of mitral valvar prolapse was calculated and stratified based on gender. We screened a total of 1172 male and 570 female high school athletes. The echocardiographic prevalence of mitral valvar prolapse was 0.9%. The prevalence was similar in both genders, at 1.2% in male and 0.7% in female athletes. The prevalence of mitral valvar prolapse in young athletes mostly in southern California was found to be less than 1%, and was similar in both genders.


Effect of chronic administration of cisapride on gastric emptying of a solid meal and on dyspeptic symptoms in patients with idiopathic gastroparesis.
In a double blind crossover comparison with placebo, the effects of cisapride (10 mg tid for two weeks), a non-antidopaminergic gastrointestinal prokinetic drug, on gastric emptying times and on symptoms were evaluated in 12 patients with chronic idiopathic dyspepsia and gastroparesis. Gastric emptying was studied by a radioisotopic gamma camera technique. The test meal was labelled in the solid component (99mTc-sulphur colloid infiltrated chicken liver). Nine symptoms (nausea, belching, regurgitations, vomiting, postprandial drowsiness, early satiety, epigastric pain or burning, heartburn) were graded weekly on a questionnaire. Cisapride was significantly more effective than placebo in shortening the t1/2 of gastric emptying (p2 = 0.04), but no significant difference was observed between the two treatments with regard to the improvement of total symptom score (p2 = 0.09). No side effects were reported during the study.


Serum carboxymethyl-lysine, an advanced glycation end product, is associated with arterial stiffness in older adults.
The objective of this study is to examine the relationship of serum carboxymethyl-lysine (CML), an advanced glycation end product (AGE), with pulse pressure (PP), aortic pulse wave velocity (aPWV) and hypertension in older adults. AGEs are bioactive molecules that accumulate in tissues with ageing and can both cross-link collagen and induce inflammation in model systems. The relationship of AGEs with arterial stiffness and hypertension has not been well characterized in community-dwelling older adults. We measured serum CML and blood pressure in 3044 adults, aged 70-79 years, who participated in the Health, Aging and Body Composition Study, a population-based study of ageing in Pittsburgh, Pennsylvania and Memphis, Tennessee. aPWV was measured in 2468 participants. Participants in the highest tertile of serum CML had higher PP (highest tertile: beta = 2.85, SE = 0.82, P = 0.0005; middle tertile: beta = 0.60, SE = 0.80, P = 0.45), and higher aPWV (highest tertile: beta = 51.4, SE = 20.1, P = 0.01; middle tertile: beta = 3.2, SE = 19.8, P = 0.87) than those in the lowest tertile in multivariable linear regression models adjusting for age, sex, race, education, BMI, smoking, alcohol use, total cholesterol, high-density lipoprotein (HDL) cholesterol, diabetes, cardiovascular disease and chronic kidney disease. Participants in the highest and middle tertiles of serum CML had higher odds of hypertension [odds ratio (OR) 1.32, 95% confidence interval (95% CI) 1.06-1.60, P = 0.005; OR 1.27, 95% CI 1.05-1.53, P = 0.01, respectively] than those in the lowest tertile in a multivariable logistic regression model adjusting for the same covariates. Elevated serum CML was associated with arterial stiffness, as reflected by higher PP and aPWV, in older, community-dwelling adults.


Non-invasive monitoring of adrenocortical function in female domestic pigs using saliva and faeces as sample matrices.
Intensive pig management involves in a commercial setting the housing and implementation of certain procedures, such as castration and tail docking, which may be stressful for the animal. Good farming practices include the reduction of stress due to management processes, but assessing the level of stress perceived entirely through behavioural observations can be challenging. The monitoring stress-related physiological markers, like glucocorticoids (GC), can be an accurate alternative that would presumably be more objective. In order to avoid an additional stressor by taking blood, a non-invasive approach is advisable. We used an adrenocorticotropic hormone (ACTH) stimulation test and the effect of transport to examine the suitability of different enzyme immunoassays (EIAs) for monitoring adrenocortical function in domestic pigs using saliva and faeces as sample matrices. An assay measuring faecal glucocorticoid metabolites (fGCMs) with a 3ß,11ß-diol group has proven suited to determine adrenocortical activity, showing an overall increase of 180% in fGCM concentrations related to ACTH administration and of 70% related to transport, respectively. A cortisol EIA was used to detect salivary glucocorticoid (sGC) concentrations, revealing a 1100% increase in sGC concentrations after ACTH administration. The stability of fGCM concentrations post-defecation was determined to assess possible changes in measured fGCM concentrations in unpreserved faecal material over time, with fGCM concentrations being relatively stable (maximal 12% change) under natural conditions for approximately two days after defecation. This implicates that untreated faecal material from pigs can be analysed for up to two days after collection without appreciable level of depreciation in fGCM concentrations. Being able to assess the physiological stress response of domestic pigs non-invasively can help to improve the well-being of commercially reared pigs.


Magnesium intake and risk of type 2 diabetes: a meta-analysis.
To assess the association between magnesium intake and risk of type 2 diabetes. Meta-analysis of prospective cohort studies. We retrieved studies published in any language by systematically searching MEDLINE from 1966 to February 2007 and by manually examining the references of the original articles. We included prospective cohort studies reporting relative risks with 95% confidence intervals for the association between magnesium intake and incidence of type 2 diabetes. The seven identified cohort studies of magnesium intake [from foods only (n = 4) or from foods and supplements combined (n = 3)] and incidence of type 2 diabetes included 286,668 participants and 10,912 cases. All but one study found an inverse relation between magnesium intake and risk of type 2 diabetes, and in four studies the association was statistically significant. The overall relative risk for a 100 mg day(-1) increase in magnesium intake was 0.85 (95% CI, 0.79-0.92). Results were similar for intake of dietary magnesium (RR, 0.86; 95% CI, 0.77-0.95) and total magnesium (RR, 0.83; 95% CI, 0.77-0.89). There was no evidence of publication bias (P = 0.99). Magnesium intake was inversely associated with incidence of type 2 diabetes. This finding suggests that increased consumption of magnesium-rich foods such as whole grains, beans, nuts, and green leafy vegetables may reduce the risk of type 2 diabetes.


Percutaneous transluminal coronary angioplasty in patients with spasm superimposed on atherosclerotic narrowing.
Of 552 patients undergoing percutaneous transluminal coronary angioplasty 102 had coronary artery spasm superimposed on atherosclerotic narrowing. Coronary angioplasty was successful in 97 (95%). The patients were discharged on a regimen of nifedipine (40-60 mg/day). Seventy six patients were symptom free 6-8 months after the procedure. Restenosis was detected in 35% of patients. Coronary artery spasm was provoked in 38 (44%) of the 87 patients who underwent an ergometrine maleate test. Twenty seven of the 34 patients with restenosis had a provocation test and coronary artery spasm was superimposed on restenosis in 22 (81.5%). Coronary angioplasty is feasible in patients with coronary artery spasm superimposed on atherosclerotic narrowing but the rate of restenosis is high and coronary artery spasm could have a role in the pathogenesis of restenosis.


A folded, secondary structure in step-growth oligomers from covalently linked, crowded aromatics.
This study delineates general methods to create a new class of folded oligomers by covalently attaching overcrowded aromatics to each other. Crucial to observing the secondary structure in these oligomers was the employment of C-shaped linkers. These linkers preorganize the strands to form intramolecular hydrogen bonds. In solution, one- and two-dimensional (1)H NMR data show well-defined columnar conformations. The side chains in these oligomers are critical for the secondary structure to emerge in solution. Using tris(dodecyloxy)phenethyl side chains in combination with tert-butyl side chains in the terminal subunit provides a soluble trimer and prevents intermolecular association above millimolar concentrations. This new folding motif, formed through a synergy between hydrogen bonds and pi-stacking, is so robust that even dimers have secondary structure in solution.


Pro-adrenocorticotropin/endorphin-derived peptides: coordinate action on adrenal steroidogenesis.
A synthetic peptide, representing a portion of the 16K (16,000 dalton)-fragment sequence within the pro-adrenocorticotropin/endorphin precursor molecule, potentiates the steroidogenic action of the 1 to 24 portion of adrenocorticotropin [ACTH(1-24)] on the rat adrenal cortex. The peptide has 27 amino acid residues and consists of gamma-melanotropin with a carboxyl terminal extension. It affects both the inner and outer adrenocortical zones of hypophysectomized animals, as evidenced by a synergistic augmentation of corticosterone and aldosterone production, respectively. The peptide can be distinguished from adrenocorticotropin by its activation of cholesterol ester hydrolase and its failure to stimulate cholesterol side-chain cleavage.


Association of a body mass index genetic risk score with growth throughout childhood and adolescence.
While the number of established genetic variants associated with adult body mass index (BMI) is growing, the relationships between these variants and growth during childhood are yet to be fully characterised. We examined the association between validated adult BMI associated single nucleotide polymorphisms (SNPs) and growth trajectories across childhood. We investigated the timing of onset of the genetic effect and whether it was sex specific. Children from the ALSPAC and Raine birth cohorts were used for analysis (n = 9,328). Genotype data from 32 adult BMI associated SNPs were investigated individually and as an allelic score. Linear mixed effects models with smoothing splines were used for longitudinal modelling of the growth parameters and measures of adiposity peak and rebound were derived. The allelic score was associated with BMI growth throughout childhood, explaining 0.58% of the total variance in BMI in females and 0.44% in males. The allelic score was associated with higher BMI at the adiposity peak (females = 0.0163 kg/m(2) per allele, males = 0.0123 kg/m(2) per allele) and earlier age (-0.0362 years per allele in males and females) and higher BMI (0.0332 kg/m(2) per allele in females and 0.0364 kg/m(2) per allele in males) at the adiposity rebound. No gene:sex interactions were detected for BMI growth. This study suggests that known adult genetic determinants of BMI have observable effects on growth from early childhood, and is consistent with the hypothesis that genetic determinants of adult susceptibility to obesity act from early childhood and develop over the life course.


Nerve growth factor and corneal wound healing in dogs.
Nerve growth factor in the tear film and corneal epithelium is hypothesized to play an important role in ocular surface maintenance and corneal wound healing. The purpose of this study was to determine the expression of nerve growth factor and its high affinity (trkA) receptor in tears, cornea, and lacrimal glands of normal dogs, the modulation of nerve growth factor and its trkA receptor during corneal wound healing, and the effect of topical nerve growth factor application on canine corneal epithelial wound healing. In the first of three experiments, the nerve growth factor content of tears, corneal epithelium, lacrimal gland, and 3rd eyelid gland was determined in normal dogs by enzyme-linked immunosorbent assay and the expression of nerve growth factor and its trkA receptor were evaluated in the cornea and lacrimal glands by immunohistochemistry. In a second experiment, unilateral corneal epithelial defects were created, and tissues were evaluated for changes in nerve growth factor or trkA expression for 1 week. In a third experiment, bilateral corneal epithelial defects were created and the right eyes in each animal were treated 4 times daily with either recombinant human nerve growth factor, murine nerve growth factor, or nerve growth factor-blocking antibody. The results of this study showed that nerve growth factor levels in normal dog tears, corneal epithelium, third eyelid gland and lacrimal gland were 15.4+/-4.6 ng ml(-1), 33.5+/-12.3, 52.4+/-17.4 and 48.8+/-9.4 ng g(-1), respectively. NGF and trkA receptors were identified by immunohistochemistry in all tissues examined. After unilateral corneal wounding, nerve growth factor concentration increased in the tears bilaterally for 3 days, especially in the wounded eye, and then returned to pre-wounding values. Nerve growth factor content, and immunohistochemical staining for nerve growth factor and trkA, increased significantly in the ipsilateral cornea epithelium following unilateral wounding. Nerve growth factor concentrations in lacrimal and third eyelid glands also increased bilaterally (p<0.01) after unilateral wounding. Time to wound closure and rate of epithelial migration did not differ significantly between nerve growth factor-treated, nerve growth factor antibody-treated, and control eyes. In conclusion, nerve growth factor is present under resting physiologic conditions in normal canine tears, and nerve growth factor and its trkA receptor are present under resting conditions in normal canine corneal epithelium, lacrimal gland and third eyelid gland. Nerve growth factor is elevated in the tears, cornea, and lacrimal glands after corneal epithelial wounding; however, topical application of nerve growth factor, or its blocking antibody does not modulate corneal wound healing in the normal dog eye.


Sphingosine 1-phosphate stimulates proliferation and migration of human endothelial cells possibly through the lipid receptors, Edg-1 and Edg-3.
Sphingosine 1-phosphate (S1P) stimulates thymidine incorporation (DNA synthesis), cell growth and cell migration in human aortic endothelial cells (HAECs). The extent of the S1P-induced responses are comparable to those stimulated by vascular endothelial growth factor, one of the most potent stimulators of angiogenesis. These responses to S1P were mimicked by dihydrosphingosine 1-phosphate, an S1P receptor agonist, and inhibited by pertussis toxin (PTX), an inactivator of G(i)/G(o)-proteins. S1P also induced activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAP kinase). The activation of these enzymes was inhibited again by PTX and also by suramin, a non-selective receptor antagonist. S1P-induced DNA synthesis and ERK activation were inhibited by PD98059, an ERK kinase inhibitor, but not by SB203580, a p38 MAP kinase inhibitor. In contrast, cell migration and p38 MAP kinase activation, in response to S1P, were inhibited by SB203580 but not by PD98059. In HAECs, high-affinity S1P binding activity and expression of Edg-1 and Edg-3 mRNA were detected. These results suggest that S1P might be a novel angiogenesis factor and that the lipid-induced proliferation and migration of endothelial cells are possibly mediated through cell-surface S1P receptors, Edg-1 and Edg-3, which are linked to signalling pathways.


Education and data-intensive science in the beginning of the 21st century.
Data-intensive science will open up new avenues to explore, new questions to ask, and new ways to answer. Yet, this potential cannot be unlocked without new emphasis on education of the researchers gathering data, the analysts analyzing data and the cross-disciplinary participants working together to make it happen. This article is a summary of the education issues and challenges of data-intensive sciences and cloud computing as discussed in the Data-Intensive Science (DIS) workshop in Seattle, September 19-20, 2010.


Epstein-Barr virus-associated B-cell lymphomas: pathogenesis and clinical outcomes.
Epstein-Barr virus (EBV) is a ubiquitous human γ-herpesvirus that establishes a life-long asymptomatic infection in immunocompetent hosts. It is also found to be frequently associated with a broad spectrum of B-cell lymphomas predominantly seen in immunodeficient patients. Despite many resemblances, these EBV-linked lymphoproliferative disorders display heterogeneity at the clinical and the molecular level. Moreover, EBV-associated lymphoproliferative diseases differ in their differential expression patterns of the EBV-encoded latent antigens, which are directly related to their interactions with the host. EBV-driven primary B-cell immortalization is linked to the cooperative functions of these latent proteins, which are critical for perturbing many important cell-signaling pathways maintaining B-cell proliferation. Additionally, it is used as a surrogate model to explore the underlying mechanisms involved in the development of B-cell neoplasms. Recent discoveries have revealed that a number of sophisticated mechanisms are exploited by EBV during cancer progression. This finding will be instrumental in the design of novel approaches for therapeutic interventions against EBV-associated B-cell lymphomas. This review limits the discussion to the biology and pathogenesis of EBV-associated B-cell lymphomas and the related clinical implications.


Capturing Biochemical Diversity in Cassava ( Manihot esculenta Crantz) through the Application of Metabolite Profiling.
Cassava ( Manihot esculenta Crantz) is the predominant staple food in Sub-Saharan Africa (SSA) and an industrial crop in South East Asia. Despite focused breeding efforts for increased yield, resistance, and nutritional value, cassava breeding has not advanced at the same rapidity as other staple crops. In the present study, metabolomic techniques were implemented to characterize the chemotypes of selected cassava accessions and assess potential resources for the breeding program. The metabolite data analyzed was applied to describe the biochemical diversity available in the panel, identifying South American accessions as the most diverse. Genotypes with distinct phenotypic traits showed a representative metabolite profile and could be clearly identified, even if the phenotypic trait was a root characteristic, e.g., high amylose content.


Pertussis models to inform vaccine policy.
Pertussis remains a challenging public health problem with many aspects of infection, disease and immunity poorly understood. Initially controlled by mass vaccination, pertussis resurgence has occurred in some countries with well-established vaccination programs, particularly among adolescents and young adults. Several studies have used mathematical models to investigate drivers of pertussis epidemiology and predict the likely impact of different vaccination strategies. We reviewed a number of these models to evaluate their suitability to answer questions of public health importance regarding optimal vaccine scheduling. We critically discuss the approaches adopted and the impact of chosen model structures and assumptions on study conclusions. Common limitations were a lack of contemporary, population relevant data for parameterization and a limited understanding of the relationship between infection and disease. We make recommendations for future model development and suggest epidemiologic data collections that would facilitate efforts to reduce uncertainty and improve the robustness of model-derived conclusions.


High glucose induces mitochondrial dysfunction independently of protein O-GlcNAcylation.
Diabetes is characterized by hyperglycaemia and perturbations in intermediary metabolism. In particular, diabetes can augment flux through accessory pathways of glucose metabolism, such as the hexosamine biosynthetic pathway (HBP), which produces the sugar donor for the β-O-linked-N-acetylglucosamine (O-GlcNAc) post-translational modification of proteins. Diabetes also promotes mitochondrial dysfunction. Nevertheless, the relationships among diabetes, hyperglycaemia, mitochondrial dysfunction and O-GlcNAc modifications remain unclear. In the present study, we tested whether high-glucose-induced increases in O-GlcNAc modifications directly regulate mitochondrial function in isolated cardiomyocytes. Augmentation of O-GlcNAcylation with high glucose (33 mM) was associated with diminished basal and maximal cardiomyocyte respiration, a decreased mitochondrial reserve capacity and lower Complex II-dependent respiration (P<0.05); however, pharmacological or genetic modulation of O-GlcNAc modifications under normal or high glucose conditions showed few significant effects on mitochondrial respiration, suggesting that O-GlcNAc does not play a major role in regulating cardiomyocyte mitochondrial function. Furthermore, an osmotic control recapitulated high-glucose-induced changes to mitochondrial metabolism (P<0.05) without increasing O-GlcNAcylation. Thus, increased O-GlcNAcylation is neither sufficient nor necessary for high-glucose-induced suppression of mitochondrial metabolism in isolated cardiomyocytes.


[Sensitivity of Gonococcus to different antibiotics].
The sensitivity of gonococcus to penicillin, tetracycline, and streptomycin was determined through the dish-dilution method. 49.3% of 75 strains were less sensitive to penicillin; 28% of 50 strains were less sensitive to tetracycline; 41% of 27 strains were resistant to streptomycin. Correspondence of germ sensitivity to penicillin, tetracycline, and streptomycin was found.


GATA-3 transcriptional imprinting in Th2 lymphocytes: a mathematical model.
Immunological memory involves the fast recall of cytokine expression by T helper (Th) lymphocytes. Two distinct profiles of cytokine expression, Th1 and Th2, can be induced by antigen and polarizing signals during activation of naive Th cells and can subsequently be reexpressed on stimulation by antigen alone. The transcription factor GATA-3 induces Th2 development. GATA-3 is activated by the Th2-polarizing stimulus, IL-4, and has recently been observed to autoactivate its transcription. Based on these experimental data, we developed a mathematical model of GATA-3 expression that assumes independent activation of GATA-3 transcription by IL-4 and by GATA-3. Cooperativity of GATA-3 transcriptional activation is shown to create a threshold for autoactivation, resulting in the coexistence of two distinct GATA-3 expression states: a state of basal expression and a state of high expression sustained by autoactivation. Suprathreshold IL-4 signals induce a transition from basal to high GATA-3 expression. Thus, GATA-3 autoactivation creates a bistable system that can memorize a transient inductive signal. The model further predicts conditions under which the state of high GATA-3 expression can be abolished, which may extinguish the Th2 cytokine memory.