Nanoelectrodes, nanoelectrode arrays and their applications.
This review deals with the topic of ultrasmall electrodes, namely nanoelectrodes, arrays of these and discusses possible applications, including to analytical science. It deals exclusively with the use of nanoelectrodes in an electrochemical context. Benefits that accrue from use of very small working electrodes within electrochemical cells are discussed, followed by a review of methods for the preparation of such electrodes. Individual nanoelectrodes and arrays or ensembles of these are addressed, as are nanopore systems which seek to emulate biological transmembrane ion transport processes. Applications within physical electrochemistry, imaging science and analytical science are summarised.


Haplotype structure and phenotypic associations in the chromosomal regions surrounding two Arabidopsis thaliana flowering time loci.
The feasibility of using linkage disequilbrium (LD) to fine-map loci underlying natural variation in Arabidopsis thaliana was investigated by looking for associations between flowering time and marker polymorphism in the genomic regions containing two candidate genes, FRI and FLC, both of which are known to contribute to natural variation in flowering. A sample of 196 accessions was used, and polymorphism was assessed by sequencing a total of 17 roughly 500-bp fragments. Using a novel Bayesian algorithm based on haplotype similarity, we demonstrate that LD could have been used to fine-map the FRI gene to a roughly 30-kb region and to identify two common loss-of-function alleles. Interestingly, because of genetic heterogeneity, simple single-marker associations would not have been able to map FRI with nearly the same precision. No clear evidence for previously unknown alleles at either locus was found, but the effect of population structure in causing false positives was evident.


The relative contribution of provider and ED-level factors to variation among the top 15 reasons for ED admission.
We examine adult emergency department (ED) admission rates for the top 15 most frequently admitted conditions, and assess the relative contribution in admission rate variation attributable to the provider and hospital. This was a retrospective, cross-sectional study of ED encounters (≥18years) from 19 EDs and 603 providers (January 2012-December 2013), linked to the Area Health Resources File for county-level information on healthcare resources. "Hospital admission" was the outcome, a composite of inpatient, observation, or intra-hospital transfer. We studied the 15 most commonly admitted conditions, and calculated condition-specific risk-standardized hospital admission rates (RSARs) using multi-level hierarchical generalized linear models. We then decomposed the relative contribution of provider-level and hospital-level variation for each condition. The top 15 conditions made up 34% of encounters and 49% of admissions. After adjustment, the eight conditions with the highest hospital-level variation were: 1) injuries, 2) extremity fracture (except hip fracture), 3) skin infection, 4) lower respiratory disease, 5) asthma/chronic obstructive pulmonary disease (A&C), 6) abdominal pain, 7) fluid/electrolyte disorders, and 8) chest pain. Hospital-level intra-class correlation coefficients (ICC) ranged from 0.042 for A&C to 0.167 for extremity fractures. Provider-level ICCs ranged from 0.026 for abdominal pain to 0.104 for chest pain. Several patient, hospital, and community factors were associated with admission rates, but these varied across conditions. For different conditions, there were different contributions to variation at the hospital- and provider-level. These findings deserve consideration when designing interventions to optimize admission decisions and in value-based payment programs.


Highly aminated mesoporous silica nanoparticles with cubic pore structure.
Mesoporous silica with cubic symmetry has attracted interest from researchers for some time. Here, we present the room temperature synthesis of mesoporous silica nanoparticles possessing cubic Pm3n symmetry with very high molar ratios (>50%) of 3-aminopropyl triethoxysilane. The synthesis is robust allowing, for example, co-condensation of organic dyes without loss of structure. By means of pore expander molecules, the pore size can be enlarged from 2.7 to 5 nm, while particle size decreases. Adding pore expander and co-condensing fluorescent dyes in the same synthesis reduces average particle size further down to 100 nm. After PEGylation, such fluorescent aminated mesoporous silica nanoparticles are spontaneously taken up by cells as demonstrated by fluorescence microscopy.


The relationship between psychosocial correlates and physical activity in underserved adolescent boys and girls in the ACT trial.
Previous research suggests motivation, enjoyment, and self-efficacy may be important psychosocial factors for understanding physical activity (PA) in youth. While previous studies have shown mixed results, emerging evidence indicates relationships between psychosocial factors and PA may be stronger in boys than girls. This study expands on previous research by examining the effects of motivation, enjoyment and self-efficacy on PA in underserved adolescent (low income, ethnic minorities) boys and girls. Based on previous literature, it was hypothesized the effects of motivation, enjoyment and self-efficacy on moderate-to-vigorous PA (MVPA) would be stronger in boys than in girls. Baseline cross-sectional data were obtained from a randomized, school-based trial (Active by Choice Today; ACT) in underserved 6th graders (N=771 girls, 651 boys). Intrapersonal variables for PA were assessed via self-report and confirmatory factor analyses were conducted for each predictor. MVPA was assessed with 7-day accelerometry estimates. Multivariate regression analyses stratified by sex demonstrated a significant positive main effect of self-efficacy and motivation on MVPA for girls. Boys also showed a positive trend for the effect of motivation on MVPA. The results from this study suggest motivation and self-efficacy should be better integrated to facilitate the development of more effective interventions for increasing PA in underserved adolescents.


Antioxidant activity and inhibitory effects of 2-hydroxy-3-methylcyclopent-2-enone isolated from ribose-histidine Maillard reaction products on aldose reductase and tyrosinase.
This study aimed to better understand the functional properties of ribose and 20 amino acid Maillard reaction products (MRPs). The ABTS+ radical scavenging ability of the ribose-20 amino acid MRPs was evaluated. Among the MRPs, ribose-histidine MRPs (RH-MRPs) showed the highest inhibitory activities on the ABTS+ radical scavenging ability, aldose reductase (AR), and tyrosinase compared to other MRPs. Functional compounds with antioxidant and AR inhibitory activities have been recognized as an important strategy in the prevention and treatment of diabetic complications, and the search for tyrosinase inhibitors is important for the treatment of hyperpigmentation, development of skin-whitening agents, and use as preservatives in the food industry. On this basis, we sought to isolate and identify compounds with inhibitory activities against AR and tyrosinase. RH-MRPs were heated at 120 °C for 2 h and fractionated using four solvents: methylene chloride (MC), ethyl acetate, n-butanol, and water. The highest inhibitions were found in the MC fraction. The two compounds from this fraction were purified by silica gel column and preparative thin layer chromatography, and identified as 2-hydroxy-3-methylcyclopent-2-enone and furan-3-carboxylic acid. AR inhibition, tyrosinase inhibition, and ABTS+ scavenging (IC50) of 2-hydroxy-3-methylcyclopent-2-enone were 4.47, 721.91 and 9.81 μg mL-1, respectively. In this study, inhibitory effects of 2-hydroxy-3-methylcyclopent-2-enone isolated from RH-MRP were demonstrated on AR, tyrosinase, and its antioxidant activity for the first time. RH-MRP and its constituents can be developed as beneficial functional food sources and cosmetic materials and should be investigated further as potential functional food sources.


Evaluation of the traveling vision examiner program in the submacular surgery trials pilot study.
To describe methods and results and to assess the value of a Traveling Vision Examiner (TVE) Program designed to provide masked vision measurements by expert vision examiners who were independent of, and traveled to, local clinical centers. The Submacular Surgery Trials (SST) Pilot Study was conducted to refine the design and methods for a set of multicenter, randomized clinical trials to evaluate submacular surgery in patients with subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) or ocular histoplasmosis (OHS), or idiopathic CNV in which the primary study outcome would be change in 2-year best-corrected vision from baseline. As part of the SST Pilot Study, the feasibility and value of a TVE Program was assessed. The goal of the program was to obtain unbiased vision measurements, according to a standard protocol, of best-corrected visual acuity, reading speed, and contrast threshold, of each patient at 2 and 4 years after enrollment. Eighty-three visits by TVEs were made to 16 centers participating in the SST Pilot Study; 239 patients had at least one masked vision examination. Comparison of pairs of vision measurements of the traveling vision examiners and local vision examiners for 71 patients made on the same day showed good agreement overall (intraclass correlation coefficient > or = 0.81). The proposed TVE Program was judged to be a feasible and useful method of providing standardized, unbiased, masked vision measurements. This approach was incorporated into the larger clinical trials conducted by the SST Research Group.


Ideal cardiovascular health duration and risk of chronic kidney disease and cardiovascular disease.
Increasing number of clinical guidelines are adopting comprehensive cardiovascular risk assessment tools for treatment decision and disease management. Yet, little is known regarding cardiovascular risks associated with the length of favourable cardiometabolic profile. In this context, we examined whether the duration of strictly ideal cardiovascular health (CVH), based on body mass index, blood pressure, fasting glucose, total cholesterol, cigarette smoking, alcohol drinking and physical activity, in middle age is associated with risk of developing chronic kidney disease (CKD) and cardiovascular disease (CVD) in mid-to-late life. From the Korean Genome and Epidemiology Study Ansung-Ansan cohort, we included 8020 participants (median age 50.0 years, 47.9% male), of whom, 7854 without CKD and 7796 without CVD at baseline. Cox proportional hazards models were employed to assess CKD and CVD risks, adjusting for age, sex, education level, examination sites and renal markers. Over a median follow-up of 15.0 years, 1401 cases of CKD and 493 cases of CVD were newly developed. Compared with participants with <5 years of ideal CVH duration, HR (95% CI) of those who maintained for 5-<10 years or ≥10 years had negatively graded risks for CKD (5-<10 years, 0.63 (0.39 to 0.93); ≥10 years, 0.33 (0.15 to 0.74)) and CVD (5-<10 years, 0.83 (0.54 to 1.27); ≥10 years, 0.22 (0.08 to 0.60)). In parallel, participants with delayed decline to suboptimal level had lower disease risks compared with counterparts with consistently suboptimal CVH. Our findings confer that maintaining favourable health behaviours and clinical risk factor levels in midlife will improve later-life cardiovascular outcomes.


When to intervene in chronic aortic regurgitation.
Symptomatic patients with chronic aortic regurgitation should undergo aortic valve replacement. Asymptomatic patients with normal left ventricular function are not surgical candidates, but aortic valve replacement should be performed in most patients with left ventricular dysfunction, even if symptoms are not yet present. The short-term administration of vasodilators is generally beneficial, but there is only meager evidence that the hemodynamic benefits are maintained; for this reason, the wide application of these agents should be postponed until well-designed clinical trials document a long-term benefit.


R3-Noria-methanesulfonate: A Molecular Cage with Superior Hyperpolarized Xenon-129 MRI Contrast.
Hyperpolarized (HP) xenon-129 (129Xe) magnetic resonance imaging (MRI) has the potential to be used as a molecular imaging modality. For this purpose, numerous supramolecular cages have been developed and evaluated in the past. Herein, we report a novel and unique macrocycle that can be successfully utilized for xenon MRI, the resorcinarene trimer methanesulfonate (R3-Noria-MeSO3H). This molecule is capable of two different contrast mechanisms for xenon-MRI, resulting from an increase in the effective spin-spin relaxation and hyperpolarized chemical exchange saturation transfer (HyperCEST). We have demonstrated a superior negative contrast caused by R3-Noria-MeSO3H on HP 129Xe MRI at 3.0 T as well as HyperCEST imaging of the studied macrocycle. Additionally, we have found that the complex aggregation behaviors of R3-Noria-methanesulfonate and its impact on xenon-129 relaxivity are an area for future study.


Mapping of the antigenic determinants of the Leishmania infantum gp63 protein recognized by antibodies elicited during canine visceral leishmaniasis.
The gp63 gene encoding the major surface antigen of Leishmania infantum has been cloned and sequenced. In spite of the overall sequence homology with the gp63 genes from other Leishmania species, particularly with the constitutively expressed Leishmania chagasi Gp63 gene, the carboxy-terminal ends of these genes are clearly divergent (62% homology). To study the prevalence of anti-gp63 antibodies in the sera from dogs with visceral leishmaniasis, a recombinant L. infantum gp63 protein was expressed in Escherichia coli. It was found that 100% of the sera from these dogs recognized the recombinant gp63 protein, suggesting that it must function as a potent B cell immunogen during natural canine visceral leishmaniasis. However, heterogeneity in the level of response was observed. Fine mapping of the antigenic determinants was performed by means of 6 overlapping subfragments of the gp63 protein and by the use of a library of synthetic peptides. The data showed that there is some degree of immunological restriction in the recognition of the protein since reactivity was observed preferentially against the most divergent region. The epitope mapping of this region showed 2 immunodominant peptides the response to which seems to be preferentially of the IgG2 type.


[Economic impact of nosocomial infections].
A retrospective, analytic and descriptive study of cases of nosocomial infection at Hospital General de Zona 1, IMSS at Aguascalientes, Ags, during the last five years, was carried out. The objectives were incidence; most frequent cases; treatment, and care costs, for both the Hospital General, and Gynecology and Obstetrics Service. A calculation of costs for 1995, according to the obtained results, was done, as well; this showed the great economical, social and laboral impact produced by these complications.


Membrane recognition and dynamics of the RNA degradosome.
RNase E, which is the central component of the multienzyme RNA degradosome, serves as a scaffold for interaction with other enzymes involved in mRNA degradation including the DEAD-box RNA helicase RhlB. Epifluorescence microscopy under live cell conditions shows that RNase E and RhlB are membrane associated, but neither protein forms cytoskeletal-like structures as reported earlier by Taghbalout and Rothfield. We show that association of RhlB with the membrane depends on a direct protein interaction with RNase E, which is anchored to the inner cytoplasmic membrane through an MTS (Membrane Targeting Sequence). Molecular dynamics simulations show that the MTS interacts with the phospholipid bilayer by forming a stabilized amphipathic α-helix with the helical axis oriented parallel to the plane of the bilayer and hydrophobic side chains buried deep in the acyl core of the membrane. Based on the molecular dynamics simulations, we propose that the MTS freely diffuses in the membrane by a novel mechanism in which a large number of weak contacts are rapidly broken and reformed. TIRFm (Total Internal Reflection microscopy) shows that RNase E in live cells rapidly diffuses over the entire inner membrane forming short-lived foci. Diffusion could be part of a scanning mechanism facilitating substrate recognition and cooperativity. Remarkably, RNase E foci disappear and the rate of RNase E diffusion increases with rifampicin treatment. Control experiments show that the effect of rifampicin is specific to RNase E and that the effect is not a secondary consequence of the shut off of E. coli transcription. We therefore interpret the effect of rifampicin as being due to the depletion of RNA substrates for degradation. We propose a model in which formation of foci and constraints on diffusion arise from the transient clustering of RNase E into cooperative degradation bodies.


[Surgical tactics in complicated pulmonary echinococcosis].
The authors analyse treatment of 326 patients with hydatid disease of the lungs. Complications were found in 112 (34.3%) of them. Broncho-fibroscopy was included in the complex of therapeutic measures in rupture of the cyst into the bronchus, and pleural puncture, therapeutico-diagnostic thoracoscopy and drainage of the pleural cavity in rupture into the pleural cavity. Temporary occlusion of the draining bronchus with Fogarty's catheter was conducted to prevent intraoperative aspiration complications. If organ-preserving operations are indicated, preference is given to A. A. Vishnevsky's echinococcectomy with a laser scalpel since the Delbet's method is fraught with the danger of cutting of the sutures due to acute inflammatory changes of the wall with the formation of a residual cavity or an abscess of the lung. A differentiated approach to preoperative management and the choice of the operative techniques reduced the incidence of postoperative complications and reduced mortality in complicated hydatid disease of the lungs to 0.9%.


[Clinical evaluation of the efficacy of Salsomaggiore (Italy) thermal water in the treatment of rhinosinusal pathologies].
Aim of the research was to demonstrate the efficacy of a treatment with thermal water as nasal spray (Salsomaggiore Italy) vs saline on chronic rhinosinusitis with/out nasal polyps. 55 patients affected by chronic rhinosinusitis with/out I degree nasal polyposis randomised into two groups were enrolled. 30 patients of the study group were treated with thermal water nasal spray 4 times/day for 4 weeks. 25 patients of the control group were treated, with the same protocol, with saline. At the beginning and at the end of the study, in all the subjects the clinical history, objective examination and the instrumental analysis of nasal functions by active anterior rhinomanometry, mucociliary transport (MCT) time determination and nasal cytology were performed. At the end of the treatment patients in the study group showed an improvement statistically significant, with respect to the control group, of headache, rhinorrea and hiposmia. Significant differences were also observed between the study and control group concerning objective examination (nasal mucosa appearance and crusts) and instrumental analysis (rhinomanometric values and mucociliary transport times). Nasal cytology (epithelial and goblet cells, neutrophils, eosinophils, bacteria) improved in both groups without any statistical difference. Thermal water (Salsomaggiore Italy) nasal spray showed a greater efficacy with respect to saline in the treatment of patients affected by chronic rhinosinusitis.


Obesity, metabolic syndrome and other comorbidities in rheumatoid arthritis and psoriatic arthritis: influence on disease activity and quality of life.
In obesity, especially if visceral, and in rheumatic diseases, the production of pro-inflammatory cytokines contributes to an increased cardiovascular risk. Moreover, classic cardiovascular risk factors are more common in these patients. We intended to assess the influence of body mass index (BMI), abdominal circumference (AC) and metabolic syndrome (MS) on disease activity and quality of life in Rheumatoid Arthritis (RA) and Psoriatic Arthritis patients and to compare the results between the RA and PsA patients. We performed a cross-sectional study, including 150 patients with RA and 75 patients with PsA. PsA patients had significantly higher BMI, AC and total of comorbidities than RA patients . Independently the underlying pathology (RA or PsA), the number of comorbidities was correlated positively with DAS28, HAQ , CRP and ESR. In RA group, overweight/obesity (BMI≥25kg/m2) were associated with at least one painful joint and the risk of having at least one swollen joint was 3.4 times higher in patients with increased AC. There was an association between the BMI and AC and the CRP value. Patients with BMI≥25 kg/m2 and increased AC had significantly higher DAS28 scores. MS was associated with significantly higher ESR. There was a positive correlation of both BMI and AC with HAQ and also MS was associated with highest HAQ values. In PsA group, patients with BMI≥25kg/m2 had equally more painful joints and higher CRP values. Patients with MS had higher CRP values, more joint pain and higher disease activity according to DAS28. None of the patients with normal BMI had swollen joints, however 20.4% of overweight patients had at least one swollen joint. The number of comorbidities showed to influence inflammatory parameters, disease activity and quality of life. We found that BMI, AC and MS are associated with disease activity, which may be improved by weight reduction and comorbidities control.


Risk Factors for Emergency Room and Hospital Care Among Patients With Solid Tumors on Immune Checkpoint Inhibitor Therapy.
Immune checkpoint inhibitors (ICIs) are being increasingly used across cancer types. Emergency room (ER) and inpatient (IP) care, common in patients with cancer, remain poorly defined in this specific population, and risk factors for such care are unknown. We retrospectively reviewed charts for patients with solid tumors who received >1 ICI dose at 1 of 2 sites from January 1, 2011 to April 28, 2017. Demographics, medical history, cancer diagnosis/therapy/toxicity details, and outcomes were recorded. Descriptive data detailing ER/IP care at the 2 associated hospitals during ICI therapy (from first dose to 3 mo after last dose) were collected. The Fisher exact test and multivariate regression analysis was used to study differences between patients with versus without ER/IP care during ICI treatment. Among 345 patients studied, 50% had at least 1 ER visit during ICI treatment and 43% had at least 1 IP admission. Six percent of ER/IP visits eventually required intensive care. A total of 12% of ER/IP visits were associated with suspected or confirmed immune-related adverse events. Predictors of ER care were African-American race (odds ratio [OR]: 3.83, P=0.001), Hispanic ethnicity (OR: 3.12, P=0.007), and coronary artery disease (OR: 2.43, P=0.006). Predictors of IP care were African-American race (OR: 2.38, P=0.024), Hispanic ethnicity (OR: 2.29, P=0.045), chronic kidney disease (OR: 3.89, P=0.006), angiotensin converting enzyme inhibitor/angiotensin receptor blocker medication use (OR: 0.44, P=0.009), and liver metastasis (OR: 2.32, P=0.003). Understanding demographic and clinical risk factors for ER/IP care among patients on ICIs can help highlight disparities, prospectively identify high-risk patients, and inform preventive programs aimed at reducing such care.


Crystallization and preliminary x-ray analysis of complexes of porcine pancreatic elastase with two natural inhibitors.
Two different natural protease inhibitors, the squash inhibitor MCEI III and the third domain of turkey ovomucoid inhibitor OMTKY3, were crystallized in complexes with porcine pancreatic elastase (PPE). About 700 conditions were screened altogether. Crystals of the complex between MCEI III and PPE were grown in citrate buffer with and without ammonium acetate. X-ray diffraction data were collected to 1.9 angstroms resolution at room temperature using synchrotron radiation. The crystals belong to space group P2(1), with unit-cell parameters a = 49.17, b = 44.59, c = 67.08 angstroms, beta = 110.97 degrees. Crystals of the OMTKY3/PPE complex were obtained in the presence of ammonium sulfate, MES buffer and polyethylene glycol monomethylether (PEG). These crystals of this complex diffracted to 2.1 angstroms resolution and belongs to space group I222, with unit-cell parameters a = 84.58, b = 84.61, c = 89.92 angstroms and diffracted to 2.2 angstroms resolution. The diffraction data were collected using a conventional rotating anode X-ray generator at room temperature. In both cases the presence of inhibitor in the crystals was confirmed by crystallography.


Regional differences in endothelial cell cytoskeleton, junctional proteins and phosphorylated tyrosine labeling in the porcine vortex vein system.
We previously demonstrated endothelial phenotype heterogeneity in the vortex vein system. This study is to further determine whether regional differences are present in the cytoskeleton, junctional proteins and phosphorylated tyrosine labeling within the system. The vortex vein system of twenty porcine eyes was perfused with labels for f-actin, claudin-5, VE-Cadherin, phosphorylated tyrosine and nucleic acid. The endothelial cells of eight different regions (choroidal veins, pre-ampulla, anterior ampulla, mid-ampulla, posterior ampulla, post-ampulla, intra-scleral canal and the extra-ocular vortex vein) were studied using confocal microscopy. There were regional differences in the endothelial cell structures. Cytoskeleton labeling was relatively even in intensity throughout Regions 1 to 6. Overall VE-Cadherin had a non-uniform distribution and thicker width endothelial cell border staining than claudin-5. Progressing downstream there was an increased variation in thickness of VE-cadherin labeling. There was an overlap in phosphorylated tyrosine and VE-Cadherin labeling in the post-ampulla, intra-scleral canal and extra-ocular vortex vein. Intramural cells were observed that were immune-positive for VE-Cadherin and phosphorylated tyrosine. There were significant differences in the number of intramural cells in different regions. Significant regional differences with endothelial cell labeling of cytoskeleton, junction proteins, and phosphorylated tyrosine were found within the vortex vein system. These findings support existing data on endothelial cell phenotype heterogeneity, and may aid in the knowledge of venous pathologies by understanding regions of vulnerability to endothelial damage within the vortex vein system. It could be valuable to further investigate and characterize the VE-cadherin and phosphotyrosine immune-positive intramural cells.


The relationship between duration of physical therapy services in the acute care setting and change in functional status in patients with lower-extremity orthopedic problems.
This study examined the relationship between the duration of physical therapy and functional status at discharge. The subjects were 173 inpatients, with a mean age of 67.9 years (SD = 20.5, range = 18-101), referred to physical therapy with lower-extremity orthopedic problems. For this retrospective cohort study, medical and physical therapy quality assurance records were used. Functional status, at initiation of and discharge from physical therapy, was measured using the Acute Care Index of Function (ACIF). The ACIF scores, which ranged from 0 to 100, were obtained from quality assurance records. The duration of physical therapy was the number of minutes of physical therapy billed to each patient, as determined from billing records. Subjects received an average of 238.5 minutes of physical therapy (SD = 153.6, range = 15-1,110). Function improved an average of 15.4 points (SD = 17.0, range = -27.4 to 64.9), and the duration of physical therapy was an important predictor of functional status at discharge after controlling for age, length of hospitalization, number of diagnoses, and initial functional status. This study provides evidence that the amount of physical therapy that patients with some types of orthopedic problems receive is directly related to the functional improvement that occurs during hospitalization in an acute care setting.


Flexible Pressure Sensors in Human-Machine Interface Applications.
Flexible sensors are highly flexible, malleable, and capable of adapting todifferent shapes, surfaces, and environments, which opens a wide range ofpotential applications in the field of human-machine interface (HMI). Inparticular, flexible pressure sensors as a crucial member of the flexiblesensor family, are widely used in wearable devices, health monitoringinstruments, robots and other fields because they can achieve accuratemeasurement and convert the pressure into electrical signals. The mostintuitive feeling that flexible sensors bring to people is the change ofhuman-machine interface interaction, from the previous rigid interaction suchas keyboard and mouse to flexible interaction such as smart gloves, more inline with people's natural control habits. Many advanced flexible pressuresensors have emerged through extensive research and development, and to adaptto various fields of application. Researchers have been seeking to enhanceperformance of flexible pressure sensors through improving materials, sensingmechanisms, fabrication methods, and microstructures. This paper reviews the flexible pressure sensors in HMI in recent years, mainlyincluding the following aspects: current cutting-edge flexible pressuresensors; sensing mechanisms, substrate materials and active materials; sensorfabrication, performances, and their optimization methods; the flexiblepressure sensors for various HMI applications and their prospects.


Herpes ICP8 protein stimulates homologous recombination in human cells.
Recombineering has transformed functional genomic analysis. Genome modification by recombineering using the phage lambda Red homologous recombination protein Beta in Escherichia coli has approached 100% efficiency. While highly efficient in E. coli, recombineering using the Red Synaptase/Exonuclease pair (SynExo) in other organisms declines in efficiency roughly correlating with phylogenetic distance from E. coli. SynExo recombinases are common to double-stranded DNA viruses infecting a variety of organisms, including humans. Human Herpes virus 1 (HHV1) encodes a SynExo comprised of ICP8 synaptase and UL12 exonuclease. In a previous study, the Herpes SynExo was reconstituted in vitro and shown to catalyze a model recombination reaction. Here we describe stimulation of gene targeting to edit a novel fluorescent protein gene in the human genome using ICP8 and compared its efficiency to that of a "humanized" version of Beta protein from phage λ. ICP8 significantly enhanced gene targeting rates in HEK 293T cells while Beta was not only unable to catalyze recombineering but inhibited gene targeting using endogenous recombination functions, despite both synaptases being well-expressed and localized to the nucleus. This proof of concept encourages developing species-specific SynExo recombinases for genome engineering.


Effects of resisted sled towing on sprint kinematics in field-sport athletes.
Weighted sled towing is a common resisted sprint training technique even though relatively little is known about the effects that such practice has on sprint kinematics. The purpose of this study was to explore the effects of sled towing on acceleration sprint kinematics in field-sport athletes. Twenty men completed a series of sprints without resistance and with loads equating to 12.6 and 32.2% of body mass. Stride length was significantly reduced by approximately 10 and approximately 24% for each load, respectively. Stride frequency also decreased, but not to the extent of stride length. In addition, sled towing increased ground contact time, trunk lean, and hip flexion. Upper-body results showed an increase in shoulder range of motion with added resistance. The heavier load generally resulted in a greater disruption to normal acceleration kinematics compared with the lighter load. The lighter load is likely best for use in a training program.


The Association Between a Mediterranean Diet and Symptoms of Irritable Bowel Syndrome.
Low adherence to Mediterranean diet (MD) has been shown to be associated with a higher prevalence of irritable bowel syndrome (IBS), but its association with IBS symptoms is not established. We aim to assess the association between MD and IBS symptoms, identify components of MD associated with IBS symptoms, and determine if a symptom-modified MD is associated with changes in the gut microbiome. One hundred and six Rome +IBS and 108 health control participants completed diet history and gastrointestinal symptom questionnaires. Adherence to MD was measured using Alternate Mediterranean Diet and Mediterranean Diet Adherence Screener. Sparse partial least squares analysis identified MD food items associated with IBS symptoms. Stool samples were collected for 16S ribosomal RNA gene sequencing and microbial composition analysis in IBS subjects. Alternate Mediterranean Diet and Mediterranean Diet Adherence Screener scores were similar between IBS and health control subjects and did not correlate with Irritable Bowel Syndrome Severity Scoring System, abdominal pain, or bloating. Among IBS participants, a higher consumption of fruits, vegetables, sugar, and butter was associated with a greater severity of IBS symptoms. Multivariate analysis identified several MD foods to be associated with increased IBS symptoms. A higher adherence to symptom-modified MD was associated with a lower abundance of potentially harmful Faecalitalea, Streptococcus, and Intestinibacter, and higher abundance of potentially beneficial Holdemanella from the Firmicutes phylum. A standard MD was not associated with IBS symptom severity, although certain MD foods were associated with increased IBS symptoms. Our study suggests that standard MD may not be suitable for all patients with IBS and likely needs to be personalized in those with increased symptoms.


Correlating ligand-to-metal charge transfer with voltage hysteresis in a Li-rich rock-salt compound exhibiting anionic redox.
Anionic redox is a double-edged sword for Li-ion cathodes because it offers a transformational increase in energy density that is also negated by several detrimental drawbacks to its practical implementation. Among them, voltage hysteresis is the most troublesome because its origin is still unclear and under debate. Herein, we tackle this issue by designing a prototypical Li-rich cation-disordered rock-salt compound Li1.17Ti0.33Fe0.5O2 that shows anionic redox activity and exceptionally large voltage hysteresis while exhibiting a partially reversible Fe migration between octahedral and tetrahedral sites. Through combined in situ and ex situ spectroscopic techniques, we demonstrate the existence of a non-equilibrium (adiabatic) redox pathway enlisting Fe3+/Fe4+ and O redox as opposed to the equilibrium (non-adiabatic) redox pathway involving sole O redox. We further show that the charge transfer from O(2p) lone pair states to Fe(3d) states involving sluggish structural distortion is responsible for voltage hysteresis. This study provides a general understanding of various voltage hysteresis signatures in the large family of Li-rich rock-salt compounds.


Study on switched reluctance generator.
The linear and non-linear math models of the switched reluctance generator (SRG) in generator mode were established in this work. The phase current and energy conversion process during generator operation were simulated by the linear math model. The non-linear math model was used to analyze the characteristics of the SRG operation in self-excitation mode and in separately-excitation mode. Some important findings on how the SRG is operated and controlled were obtained in this study, which provides theoretical basis for further design and experimental study.


Parkinson's disease: 10 years of progress, 1997-2007.
Many people with Parkinson's disease (PD) and their family members ask their physicians "What is happening in research on Parkinson's disease? Is there anything new?" As the initial speaker at the symposium organized by the Parkinson's Disease Foundation in celebration of its 50th anniversary, I sought to address these questions, focusing on research published between the years 1997 and 2007. I cataloged the advances I considered most important in the field, recognizing my viewpoint is a subjective one and most likely differs from similar listings that others would put together. Space limitation allows me to discuss only a tiny fraction of the remarkable new findings that have been discovered during this 10-year span. Nevertheless, I expect the readers of this summation of advances in the field to be as impressed as I am on the wealth, breadth, and excitement stirring in the field of PD research. Included in this overview are highlights in both laboratory science and clinical science of PD research. In the former category are advances in knowledge on the genetics of PD; potential etiologic and pathogenic causes, especially the better understanding of endogenous factors within dopaminergic neurons; pathologic changes including deposition of alpha-synuclein aggregates; and the consequences of altered alpha-synuclein on the degradation of proteins by both the ubiquitin-proteasomal pathway and the lysosome. Clinical science has also been very active and impressively productive with important clinical advances. In this category are new information on the epidemiology of PD, including awareness of additional factors (besides smoking) that might slow the onset and worsening of PD, such as caffeine and urate; neuroimaging with positron emission tomography and single photon emission tomography; keener awareness of nonmotor features of PD and their impact on quality of life for the persons with PD and their family; recognition of behavioral complications of medications utilized to treat PD, such as impulse control problems; appreciation of the natural history of PD with the increasing impairments as the disease relentlessly worsens over time; the many controlled clinical trials attempting to slow the progression of the disease and to provide new symptomatic therapies; and surgical approaches to alleviate symptoms and progression, including cellular and gene therapy as well as deep brain stimulation.


Synthesis of a trans-acting inhibitor of DNA maturation by prohead mutants of phage lambda.
Bacteriophage lambda with mutations in genes that control prohead assembly and other head precursors cannot mature their DNA. In this paper we present evidence that the failure of these phage mutants to mature DNA is a reflection of a mechanism that modulates terminase nicking activity during normal phage development. We have constructed plasmids that contain the lambda-cohesive end site (cos) and the genes that code for DNA terminase, the enzyme that matures DNA by cutting at cos. The DNA terminase genes are under control of a thermosensitive cI repressor. These plasmids lack most of the genes involved in prohead morphogenesis and other head precursors. However, when repression is lifted by destruction of the thermosensitive repressor, the terminase synthesized is able to cut almost 100% of the plasmids. Therefore, these plasmids can mature in the absence of proheads and other head gene products. The plasmids are also able to complement mutants of lambda deficient in terminase and DNA maturation. However, in these complementation experiments, if the phage carry mutations in prohead genes E or B, not only is phage DNA maturation blocked, but the plasmid also fails to mature. These experiments show that, in the absence of proheads, phage lambda produces a trans-acting inhibitor of maturation. The genetic determinant of this inhibitor maps in a region extending from the middle of gene B to the end of gene C. A model is proposed in which the nicking activity of DNA-bound terminase is inhibited by the trans-acting inhibitor. Prohead (and other factors) binding to this complex would release the block to allow DNA cleavage and packaging.


Primary human leukocyte subsets differentially express vaccinia virus receptors enriched in lipid rafts.
Poxviruses, including vaccinia virus (VV) and canarypox virus (ALVAC), do not indiscriminately infect all cell types of the primary human leukocytes (PHLs) that they encounter but instead demonstrate an extremely strong bias toward infection of monocytes and monocyte lineage cells. We studied the specific molecular events that determine the VV tropism for major PHL subsets including monocytes, B cells, neutrophils, NK cells, and T cells. We found that VV exhibited an extremely strong bias of cell surface protein-dependent binding to monocytes, B cells, and activated T cells to a similar degree and to neutrophils to a much lesser extent. Resting T cells and resting NK cells exhibited only trace amounts of VV binding. Activated T cells, however, became permissive to VV binding, infection, and replication, while activated NK cells still resisted VV binding. VV binding strongly colocalized with lipid rafts on the surfaces of all VV binding-susceptible PHL subsets, even when lipid rafts were relocated to cell uropods upon cell polarization. Immunosera raised against detergent-resistant membranes (DRMs) from monocytes or activated T cells, but not resting T cells, effectively cross-blocked VV binding to and infection of PHL subsets. CD29 and CD98, two lipid raft-associated membrane proteins that had been found to be important for VV entry into HeLa cells, had no effect on VV binding to and infection of primary activated T cells. Our data indicate that PHL subsets express VV protein receptors enriched in lipid rafts and that receptors are cross-presented on all susceptible PHLs.


Covert orienting of attention in macaques. I. Effects of behavioral context.
1. A task was used by Posner (1980) to measure shifts of attention that occurred covertly, in the absence of an eye movement or other orienting response. This paradigm was used here to assess the nature of covert attentional orienting in monkeys to develop an animal model for neurophysiological studies. Shifts of attention were measurable in monkeys and were consistent across a variety of experimental conditions. 2. The paradigm required that monkeys fixate and release a bar at the appearance of a target, which was preceded by a cue. Reaction times to targets that followed peripheral cues at the same location (validly cued) were significantly faster than those that followed cues in the opposite visual field (invalidly cued). This difference was defined as the validity effect, which as in humans, is used as the measure of a covert attentional shift. 3. When the proportion of validly to invalidly cued targets was decreased, no change was seen in the validity effect of the monkeys. This is in contrast to humans, for whom the ratio of validly to invalidly cued targets affected the magnitude of the validity effect. When 80% of the targets were preceded by cues at the same location, the validity effect was greatest. The effect was reversed when the proportions were reversed. From this result, it is concluded that cognitive processes can affect covert orienting to peripheral cues in humans, whereas in trained monkeys, performance was automatic. 4. To test whether cognitive influences on attention could be demonstrated in the monkey, an animal was taught to use symbolic, foveal signals to covertly direct attention. The magnitude of this validity effect was greater than that obtained with peripheral cues. 5. The effects of motivational and perceptual processes were tested. Although overall reaction times could be modified, the facilitating effects of the cues persisted. This constancy across motivational and perceptual levels supports the notion that the monkeys were performing the task in an automatic way, under the exogenous control of peripheral cues. 6. Most visual cuing has been tested with visual landmarks at the locations of cues and targets. These monkeys were trained with such landmarks, and when tested without them, the attentional effect of the cues was nearly abolished. These data suggest that local visual features can be important for covert orienting. 7. To determine the spatial extent of the effect of the cue, monkeys and humans were tested with four cue-target distances (0-60 degrees).(ABSTRACT TRUNCATED AT 400 WORDS)


[40 years of blood gases and critical care analytes measurements].
Drawing on his professional experience of fourty years, the author retraces the history of the technological development of blood gases and other critical care analytes measurements from the end of the fifties until today. He reviews the various techniques now available and comments on the phases of their development from test bench to hospital acceptance and market availability. Pulse oximetry is noted as being of particular interest.


A data-driven epidemic model with human mobility and vaccination protection for COVID-19 prediction.
Epidemiological models allow for quantifying the dynamic characteristics of large-scale outbreaks. However, capturing detailed and accurate epidemiological information often requires consideration of multiple kinetic mechanisms and parameters. Due to the uncertainty of pandemic evolution, such as pathogen variation, host immune response and changes in mitigation strategies, the parameter evaluation and state prediction of complex epidemiological models are challenging. Here, we develop a data-driven epidemic model with a generalized SEIR mechanistic structure that includes new compartments, human mobility and vaccination protection. To address the issue of model complexity, we embed the epidemiological model dynamics into physics-informed neural networks (PINN), taking the observed series of time instances as direct input of the network to simultaneously infer unknown parameters and unobserved dynamics of the underlying model. Using actual data during the COVID-19 outbreak in Australia, Israel, and Switzerland, our model framework demonstrates satisfactory performance in multi-step ahead predictions compared to several benchmark models. Moreover, our model infers time-varying parameters such as transmission rates, hospitalization ratios, and effective reproduction numbers, as well as calculates the latent period and asymptomatic infection count, which are typically unreported in public data. Finally, we employ the proposed data-driven model to analyze the impact of different mitigation strategies on COVID-19.


Dynamic control of synaptic vesicle replenishment and short-term plasticity by Ca(2+)-calmodulin-Munc13-1 signaling.
Short-term synaptic plasticity, the dynamic alteration of synaptic strength during high-frequency activity, is a fundamental characteristic of all synapses. At the calyx of Held, repetitive activity eventually results in short-term synaptic depression, which is in part due to the gradual exhaustion of releasable synaptic vesicles. This is counterbalanced by Ca(2+)-dependent vesicle replenishment, but the molecular mechanisms of this replenishment are largely unknown. We studied calyces of Held in knockin mice that express a Ca(2+)-Calmodulin insensitive Munc13-1(W464R) variant of the synaptic vesicle priming protein Munc13-1. Calyces of these mice exhibit a slower rate of synaptic vesicle replenishment, aberrant short-term depression and reduced recovery from synaptic depression after high-frequency stimulation. Our data establish Munc13-1 as a major presynaptic target of Ca(2+)-Calmodulin signaling and show that the Ca(2+)-Calmodulin-Munc13-1 complex is a pivotal component of the molecular machinery that determines short-term synaptic plasticity characteristics.


Efficacy of home-based exercise for improving quality of life among elderly women with symptomatic osteoporosis-related vertebral fractures.
This randomized controlled trial was designed to investigate the effect of a 6-month home-based exercise program versus control (usual activities) on quality of life for postmenopausal women with osteoporosis who had at least one vertebral fracture. Twelve-month assessments of outcomes were completed to determine if women would continue exercising with minimal supervision and if benefit could be sustained. The home exercise program followed a "lifestyle exercise" approach where participants completed exercises 60 min per day, 3 days a week and could complete exercises in small periods of time throughout the day. Exercise activities included stretching, strength training and aerobics (i.e. walking). Participants were assessed at baseline, 6 months, and 12 months using the Osteoporosis Quality of Life Questionnaire (OQLQ), the Sickness Impact Profile (SIP), a balance test, and the Timed Up And Go test. Bone mineral density was assessed at baseline and 12 months for both the lumbar spine and femoral neck. Quality of life (OQLQ) improved over 6 months in the exercise group compared to the control group in the domains of symptoms (P=0.003), emotion (P=0.01) and leisure (P=0.03). Results from the balance test indicated a greater effect in the exercise group over 12 months (P<0.05). There were no significant differences between groups in measures of Timed Up and Go, SIP at 6 and 12 months, and femoral neck and lumbar spine bone mineral density at 12 months. Home-based exercise with minimal supervision improves quality of life in elderly women with vertebral fractures. Future research is needed to determine if home exercise programs reduce falls and fall-related injuries in the elderly.


Fas binding to calmodulin regulates apoptosis in osteoclasts.
Promotion of osteoclast apoptosis is one therapeutic approach to osteoporosis. Calmodulin, the major intracellular Ca(2+) receptor, modulates both osteoclastogenesis and bone resorption. The calmodulin antagonist, trifluoperazine, rescues bone loss in ovariectomized mice (Zhang, L., Feng, X., and McDonald, J. M. (2003) Endocrinology 144, 4536-4543). We show here that a 3-h treatment of mouse osteoclasts with either of the calmodulin antagonists, tamoxifen or trifluoperazine, induces osteoclast apoptosis dose-dependently. Tamoxifen, 10 microm, and trifluoperazine, 10 microm, induce 7.3 +/- 1.8-fold and 5.3 +/- 0.9-fold increases in osteoclast apoptosis, respectively. In Jurkat cells, calmodulin binds to Fas, the death receptor, and this binding is regulated during Fas-mediated apoptosis (Ahn, E. Y., Lim, S. T., Cook, W. J., and McDonald, J. M. (2004) J. Biol. Chem. 279, 5661-5666). In osteoclasts, calmodulin also binds Fas. When osteoclasts are treated with 10 microm trifluoperazine, the binding between Fas and calmodulin is dramatically decreased at 15 min and gradually recovers by 60 min. A point mutation of the Fas death domain in the Lpr(-cg) mouse renders Fas inactive. Using glutathione S-transferase fusion proteins, the human Fas cytoplasmic domain is shown to bind calmodulin, whereas a point mutation (V254N) comparable with the Lpr(-cg) mutation in mice has markedly reduced calmodulin binding. Osteoclasts derived from Lpr(-cg) mice have diminished calmodulin/Fas binding and are more sensitive to calmodulin antagonist-induced apoptosis than those from wild-type mice. Both tamoxifen- and trifluoperazine-induced apoptosis are increased 1.6 +/- 0.2-fold in Lpr(-cg)-derived osteoclasts compared with osteoclasts derived from wild-type mice. In summary, calmodulin antagonists induce apoptosis in osteoclasts by a mechanism involving interference with calmodulin binding to Fas. The effects of calmodulin/Fas binding on calmodulin antagonist-induced apoptosis may open a new avenue for therapy for osteoporosis.


Cannabinoid-free Cannabis sativa L. grown in the Po valley: evaluation of fatty acid profile, antioxidant capacity and metabolic content.
Within a project aimed to reintroduce non-drug hemp cultivars in the Italian Po valley, for fibre but also high added-value nutraceutical production, investigation on locally grown plants has been performed, in order to assess their oil and metabolic content. This study provides useful information regarding three different hemp cultivars, from two sites, in view of their potential industrial application. The oil was characterised by a high unsaturated/saturated fatty acid ratio and by an almost perfect balance of ω-3 and ω-6 fatty acids, as requested for healthy foods. The alcoholic extracts, for which a high content of amino acids and phenolic compounds has been highlighted, could provide dietary supplements to help in preventing oxidative stress. By investigating the Carmagnola cultivar, six known and four new lignanamides have been identified, confirming and assessing the general metabolic pattern in the seeds of these locally grown plants.


Chirality-Induced Noncollinear Magnetization and Asymmetric Domain-Wall Propagation in Hydrogenated CoPd Thin Films.
Array-patterned CoPd-based heterostructures are created through e-beam lithography and plasma pretreatment that induces oxidation with depth gradient in the CoPd alloy films, breaking the central symmetry of the structure. Effects on the magnetic properties of the follow-up hydrogenation of the thin film are observed via magneto-optic Kerr effect microscopy. The system exhibits a strong vertical and lateral antiferromagnetic coupling in the perpendicular component between the areas with and without plasma pretreatment, and asymmetric domain-wall propagation in the plasma-pretreated areas during magnetization reversal. These phenomena exhibit evident magnetic chirality and can be interpreted with the Ruderman-Kittel-Kasuya-Yosida coupling and the Dzyaloshinskii-Moriya interaction (DMI). The sample processing demonstrated in this study allows easy incorporation of lithography techniques that can define areas with or without DMI to create intricate magnetic patterns on the sample, which provides an avenue toward more sophisticated control of canted spin textures in future spintronic devices.


Lecture as a mode of instruction in undergraduate medical education.
This study was carried out to determine the place of lecture as a mode of instruction in undergraduate medical education by examining the views of the students about some selected aspects of the lecturing sessions and their ability to recall the varying percentages of the content of the delivered lecture after a specified period of time. An observational cross sectional study was carried out in which the final year students of Fatima Jinnah Medical College for Women, Lahore belonging to sessions 1995-1996 and 1996-1997 participated. The study comprised of two parts; first was administration of a questionnaire containing the questions regarding students' opinions about the lectures attended, duration of lecturing sessions and comparison between lecture and clinical classes. The second part consisted of two surprise tests examining the ability of the students to recall the subject taught in a particular lecture after one week and one month intervals. According to 74% students lecturing sessions were not beneficial. Only 12% students remained attentive throughout the lecture their reason being ineffective and boring presentations and 55% participants wanted the existing duration of the lecture period to be halved. Clinical sessions were considered to be superior by 79% respondents. About 34% to 35% students could recall more than 50% of the content of the delivered lecture after one week and 20% were able to do so after one month. Consideration should be given to the feedback received and follow up studies should be carried out so that appropriate changes in the curriculum could be induced in order to ensure the effectiveness of the lecture and to avoid wastage of resources and time and to justify the place of lecture as a mode of instruction in undergraduate medical education.


FLIBase: a comprehensive repository of full-length isoforms across human cancers and tissues.
Regulatory processes at the RNA transcript level play a crucial role in generating transcriptome diversity and proteome composition in human cells, impacting both physiological and pathological states. This study introduces FLIBase (www.FLIBase.org), a specialized database that focuses on annotating full-length isoforms using long-read sequencing techniques. We collected and integrated long-read (351 samples) and short-read (12 469 samples) RNA sequencing data from diverse normal and cancerous human tissues and cells. The current version of FLIBase comprises a total of 983 789 full-length spliced isoforms, identified through long-read sequences and verified using short-read exon-exon splice junctions. Of these, 188 248 isoforms have been annotated, while 795 541 isoforms remain unannotated. By overcoming the limitations of short-read RNA sequencing methods, FLIBase provides an accurate and comprehensive representation of full-length transcripts. These comprehensive annotations empower researchers to undertake various downstream analyses and investigations. Importantly, FLIBase exhibits a significant advantage in identifying a substantial number of previously unannotated isoforms and tumor-specific RNA transcripts. These tumor-specific RNA transcripts have the potential to serve as a source of immunogenic recurrent neoantigens. This remarkable discovery holds tremendous promise for advancing the development of tailored RNA-based diagnostic and therapeutic strategies for various types of human cancer.


Acetylcholinesterase-based organophosphate nerve agent sensing photonic crystal.
We developed a polymerized crystalline colloidal array (PCCA) photonic crystal sensing material that senses the organophosphorus compound parathion at ultratrace concentrations in aqueous solutions. A periodic array of colloidal particles is embedded in a hydrogel network with a lattice spacing such that it Bragg diffracts visible light. The molecular recognition agent for the sensor is the enzyme acetylcholinesterase (AChE), which binds organophosphorus compounds irreversibly, creating an anionic phosphonyl species. This charged species creates a Donnan potential, which swells the hydrogel network, which increases the embedded particle array lattice spacing and causes a red-shift in the wavelength of light diffracted. The magnitude of the diffraction red-shift is proportional to the amount of bound parathion. These AChE-PCCAs act as dosimeters for parathion since it irreversibly binds. Parathion concentrations as low as 4.26 fM are easily detected.


From maternity to parental leave policies: women's health, employment, and child and family well-being.
Pregnancy and maternity are increasingly viewed as social as well as individual risks that require health protection, employment protection and security, and protection against temporary loss of income. Begun more than a century ago in Germany, paid and job-protected maternity leaves from work were established in most countries initially out of concern for maternal and child physical health. Beginning in the 1960s, these policies have expanded to cover paternity and parental leaves following childbirth and adoption as well. Moreover, they have increasingly emerged as central to the emotional and psychological well-being of children as well as to the employment and economic security of their mothers and fathers. They are modest social policies, but are clearly an essential part of any country's child and family policy. No industrialized country today can be without such provision, and the United States is a distinct laggard in these developments.


Identifying qualitative effects of different grazing types on below-ground communities and function in a long-term field experiment.
Herbivory is an important modulator of plant biodiversity and productivity in grasslands, but our understanding of herbivore-induced changes on below-ground processes and communities is limited. Using a long-term (17 years) experimental site, we evaluated impacts of rabbit and invertebrate grazers on some soil functions involved in carbon cycling, microbial diversity, structure and functional composition. Both rabbit and invertebrate grazing impacted soil functions and microbial community structure. All functional community measures (functions, biogeochemical cycling genes, network association between different taxa) were more strongly affected by invertebrate grazers than rabbits. Furthermore, our results suggest that exclusion of invertebrate grazers decreases both microbial biomass and abundance of genes associated with key biogeochemical cycles, and could thus have long-term consequences for ecosystem functions. The mechanism behind these impacts are likely to be driven by both direct effects of grazing altering the pattern of nutrient inputs and by indirect effects through changes in plant species composition. However, we could not entirely discount that the pesticide used to exclude invertebrates may have affected some microbial community measures. Nevertheless, our work illustrates that human activity that affects grazing intensity may affect ecosystem functioning and sustainability, as regulated by multi-trophic interactions between above- and below-ground communities.


A quantitative autonomous bioluminescence reporter system with a wide dynamic range for Plant Synthetic Biology.
Plant Synthetic Biology aims to enhance the capacities of plants by designing and integrating synthetic gene circuits (SGCs). Quantitative reporting solutions that can produce quick, rich datasets affordably are necessary for SGC optimization. In this paper, we present a new, low-cost, and high-throughput reporter system for the quantitative measurement of gene expression in plants based on autonomous bioluminescence. This method eliminates the need for an exogenous supply of luciferase substrate by exploiting the entire Neonothopanus nambi fungal bioluminescence cyclic pathway to build a self-sustained reporter. The HispS gene, the pathway's limiting step, was set up as the reporter's transcriptional entry point as part of the new system's design, which significantly improved the output's dynamic range and brought it on par with that of the gold standard FLuc/RLuc reporter. Additionally, transient ratiometric measurements in N. benthamiana were made possible by the addition of an enhanced GFP as a normalizer. The performance of new NeoLuc/eGFP system was extensively validated with SGCs previously described, including phytohormone and optogenetic sensors. Furthermore, we employed NeoLuc/eGFP in the optimization of challenging SGCs, including new configurations for an agrochemical (copper) switch, a new blue optogenetic sensor, and a dual copper/red-light switch for tight regulation of metabolic pathways.


[Cardiovascular risk factors in systemic lupus erythematosus and in antiphospholipid syndrome].
Systemic Lupus Erythematosus (SLE) is an autoimmune disorder affecting multiple organ systems. Treatment of the disease has contributed dramatically in the long-term survival of the patients and now SLE has become a chronic inflammatory disorder. Present data suggest 5, 10 and 20-year survival rates of 93%, 85% and 68% respectively. Accelerated atherosclerosis and early coronary artery disease have become important causes of death and hospitalisation in SLE patients. Many cardiovascular risk factors can be considered: disease activity (particularly kidney involvement), sedentary life (in nearly 70% of the patients), hyperlipidemia, antiphospholipid antibodies, serum homocysteine and many others. Although traditional risk factors are operative in patients with SLE, the risk for myocardial infarction was increased 8.3 folds after controlling these factors in a study, suggesting that SLE itself was the strongest risk factor for cardiovascular disease. Lipid abnormalities may play a major role in increasing cardiovascular risk in SLE patients who are characterized by elevated triglycerides, very low-density lipoprotein cholesterol (VLDL-C), reduced levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (Apo) A-1. Anticardioli-pin antibodies may influence lipid levels in SLE; in particular SLE patients with IgG anticardiolipin antibodies had significantly lower HDL-C compared with patients with no anticardiolipin antibodies. Elevation of serum homocysteine is observed in 15% of SLE patients and is significantly associated with the development of stroke and arterial thrombotic events. The antiphospholipid syndrome (APS) is an acquired thrombotic disorder characterised by recurrent venous or arterial thrombosis or recurrent miscarriages, or both, associated with the presence in the serum of IgG or IgM anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LAC). APS may occur as a primary disorder (PAPS) or associated with connective tissue diseases, mainly systemic lupus erythematosus (secondary APS). Primary and secondary APS are both associated with a significant increase of cardiovascular risk.


Gut microbiota disturbance during antibiotic therapy: a multi-omic approach.
It is known that the gastrointestinal tract (GIT) microbiota responds to different antibiotics in different ways and that while some antibiotics do not induce disturbances of the community, others drastically influence the richness, diversity, and prevalence of bacterial taxa. However, the metabolic consequences thereof, independent of the degree of the community shifts, are not clearly understood. In a recent article, we used an integrative OMICS approach to provide new insights into the metabolic shifts caused by antibiotic disturbance. The study presented here further suggests that specific bacterial lineage blooms occurring at defined stages of antibiotic intervention are mostly associated with organisms that possess improved survival and colonization mechanisms, such as those of the Enterococcus, Blautia, Faecalibacterium, and Akkermansia genera. The study also provides an overview of the most variable metabolic functions affected as a consequence of a β-lactam antibiotic intervention. Thus, we observed that anabolic sugar metabolism, the production of acetyl donors and the synthesis and degradation of intestinal/colonic epithelium components were among the most variable functions during the intervention. We are aware that these results have been established with a single patient and will require further confirmation with a larger group of individuals and with other antibiotics. Future directions for exploration of the effects of antibiotic interventions are discussed.


Update on optimal treatment for metastatic colorectal cancer from the ACTG/AGITG expert meeting: ECCO 2015.
The treatment of metastatic CRC (mCRC) has evolved over the last 20 years, from fluoropyrimidines alone to combination chemotherapy and new biologic agents. Median overall survival is now over 24 months for RAS mutated (MT) patients and over 30 months for RAS wild-type (WT) patients. However, there are subgroups of patients with BRAF V600E MT CRC who have a significantly poorer outlook. Newer treatment options are also being explored in select subgroups of patients (anti-HER 2 in HER2 positive mCRC and immunotherapy in patients with defective mismatch repair (dMMR)). The best use of these systemic treatment options, as well as surgery in well-selected patients requires careful consideration of predictive biomarkers and importantly, the optimal sequence in which therapies should be given to derive maximal benefit. A group of colorectal subspecialty medical oncologists from Australia, USA, The Netherlands and Germany met during ECCO 2015 in Vienna to review current practice.


[Infective endocarditis in elderly patients].
Infective endocarditis (IE) is a rare disease, but it is still associated with high mortality and elderly represent a growing proportion of patients with this disease. At the moment, more than one third of the IE patients is over 70 years old in developed countries. Although mean age of patients with endocarditis is still between 40 and 50 years old in our country, it is a fact that more elderly patients with IE will be seen in the coming years because of the prolongation of the life span and the increase in the proportion of the elderly. According to the information obtained from the case series, the clinical presentation of elderly patients with IE was remarkable for a more indolent course, lower rates of embolism and smaller vegetation. Additionally IE was more frequently associated with health care and a prosthetic device among elderly patients. The leading causative organisms were either healthcare associated Staphylococci or Streptococcus gallolyticus and enterococci originated from the digestive or the urinary tract. In addition, antimicrobial therapy is also difficult for elderly patients because of the higher rate of the side effects and drug interactions. In order to be able to cope with all these difficulties, elderly patients with IE should be managed by a team consisting of geriatric, cardiology and infectious diseases specialists and cardiac surgeons.


Successful outpatient parenteral antibiotic therapy delivery via telemedicine.
Most outpatient parenteral antimicrobial therapy (OPAT) services use a hospital-based model of care in which patients remain in proximity to large hospitals facilitating clinical review. We aimed to evaluate clinical outcomes and complication rates for patients living in geographically isolated locations managed by telemedicine-supported OPAT. Methods: This was a retrospective cohort study. Between 2011 and 2015, we delivered 88 episodes of care involving 83 adult patients resulting in 2261 days of OPAT. The median age was 56 years, 8 of 83 (10%) were indigenous Australian and the median Charlson comorbidity index score was 2 (IQR 1-4). The median distance of patients' residence from our hospital was 288 km (IQR 201-715) and the median duration on the programme was 26 days (IQR 14-34). Bone and joint infections accounted for 75% of infections treated. Favourable clinical outcomes (improvement or cure) were achieved in 87% of patients and the unplanned, OPAT-related readmission rate was 8%. Nineteen percent and 10% of patients had drug-related and line-related adverse effects, respectively. Despite a complex case mix, our adverse event and readmission rates are similar to the published literature describing a non-telemedicine model to deliver OPAT. High rates of favourable clinical outcomes and likely cost benefits suggest that telemedicine-supported OPAT is an efficacious and safe substitute for inpatient care in our setting.


A new approach to estimate the in situ fractional degradation rate of organic matter and nitrogen in wheat yeast concentrates.
In the classic in situ method, small particles are removed during rinsing and hence their fractional degradation rate cannot be determined. A new approach was developed to estimate the fractional degradation rate of nutrients in small particles. This approach was based on an alternative rinsing method to reduce the particulate matter loss during rinsing and on quantifying the particulate matter loss that occurs during incubation in the rumen itself. To quantify particulate matter loss during incubation, loss of small particles during the in situ incubation was studied using undegradable silica with different particle sizes. Particulate matter loss during incubation was limited to particles smaller than ~40 μm with a mean fractional particulate matter loss rate of 0.035 h-1 (first experiment) and 0.073 h-1 (second experiment) and an undegradable fraction of 0.001 and 0.050, respectively. In the second experiment, the fractional particulate matter loss rate after rinsing in a water bath at 50 strokes per minute (s.p.m.) (0.215 h-1) and the undegradable fraction at 20 s.p.m. (0.461) were significantly larger than that upon incubation in the rumen, whereas the fractional particulate matter loss rate (0.140 and 0.087 h-1, respectively) and the undegradable fraction (0.330 and 0.075, respectively) after rinsing at 30 and 40 s.p.m. did not differ with that upon rumen incubation. This new approach was applied to estimate the in situ fractional degradation rate of insoluble organic matter (OM) and insoluble nitrogen (N) in three different wheat yeast concentrates (WYC). These WYC were characterised by a high fraction of small particles and estimating their fractional degradation rate was not possible using the traditional washing machine rinsing method. The new rinsing method increased the mean non-washout fraction of OM and N in these products from 0.113 and 0.084 (washing machine method) to 0.670 and 0.782, respectively. The mean effective degradation (ED) without correction for particulate matter loss of OM and of N was 0.714 and 0.601, respectively, and significant differences were observed between the WYC products. Applying the correction for particulate matter loss reduced the mean ED of OM to 0.676 (30 s.p.m.) and 0.477 (40 s.p.m.), and reduced the mean ED of N to 0.475 (30 s.p.m.) and 0.328 (40 s.p.m.). These marked reductions in fractional degradation rate upon correction for small particulate matter loss emphasised the pronounced effect of correction for undegraded particulate matter loss on the fractional disappearance rates of OM and N in WYC products.


Microcystis genotypes in a tropical freshwater lake: Discovery of novel MIB-producing Microcystis with potentially unique synthesis pathway.
Harmful algal blooms (HABs) are a threat to freshwater systems over the world due to the production of hepatotoxins like microcystin (MC), and nuisance taste and odour (T&O) compounds like 2-methylisoborneol (MIB). While MCs are known to cause detrimental effects to both water quality and human health, MIB is only reported to cause aesthetical problems. In this study, we investigated a tropical, urban lake that was experiencing persistent MC and MIB events. Although it was dominated by Microcystis blooms, analysis revealed that the toxigenic Microcystis were not the only species driving the MC concentrations. Additionally, there was also a lack of causative species for the MIB events. Through isolation, we have identified three toxigenic Microcystis found to produce four different variants of MCs, and two novel non-toxigenic Microcystis that were capable of producing MIB. The ability to produce MIB had never been previously reported for this species. Compared to other major producers such as Planktothricoides sp. and Streptomyces sp., the MIB synthase genes of our Microcystis sp. strains were partial, illustrating the possibility of unique synthesis pathways. The Microcystis sp. strains were found to produce about 2.77-5.22 fg MIB cell-1, with a majority of the contents (70-80 %) existing in the extracellular phase. Correlation analysis of field study indicated that phosphorus limitation may have an indirect effect on non-toxigenic Microcystis abundance and proportion by influencing the toxigenic genotype, suggesting that current measures to control HABs may favour the proliferation of the non-toxigenic Microcystis. The potential for Microcystis sp. to produce MIB through unique synthesis pathway, coupled with the potential dominance of non-toxigenic genotypes in Microcystis blooms, signals the possibility that non-toxigenic Microcystis should be monitored as well.


Metrics-Based Evaluation and Comparison of Visualization Notations.
A visualization notation is a recurring pattern of symbols used to author specifications of visualizations, from data transformation to visual mapping. Programmatic notations use symbols defined by grammars or domain-specific languages (e.g., ggplot2, dplyr, Vega-Lite) or libraries (e.g., Matplotlib, Pandas). Designers and prospective users of grammars and libraries often evaluate visualization notations by inspecting galleries of examples. While such collections demonstrate usage and expressiveness, their construction and evaluation are usually ad hoc, making comparisons of different notations difficult. More rarely, experts analyze notations via usability heuristics, such as the Cognitive Dimensions of Notations framework. These analyses, akin to structured close readings of text, can reveal design deficiencies, but place a burden on the expert to simultaneously consider many facets of often complex systems. To alleviate these issues, we introduce a metrics-based approach to usability evaluation and comparison of notations in which metrics are computed for a gallery of examples across a suite of notations. While applicable to any visualization domain, we explore the utility of our approach via a case study considering statistical graphics that explores 40 visualizations across 9 widely used notations. We facilitate the computation of appropriate metrics and analysis via a new tool called NotaScope. We gathered feedback via interviews with authors or maintainers of prominent charting libraries (n = 6). We find that this approach is a promising way to formalize, externalize, and extend evaluations and comparisons of visualization notations.


Comparison of microbial and physicochemical behavior of expanded granular sludge bed system during methylparaben and triclosan removal.
Methylparaben and triclosan are antimicrobial agents widely used as preservatives in a variety of personal care and pharmaceutical products. Wastewater is considered the main source of these compounds in the environment. Expanded granular sludge bed (EGSB) reactors are a high rate technology for wastewater treatment based on biological processes and have been shown to be efficient in removing different types of compounds; however, little is known about the effect of contaminants such as methylparaben and triclosan on their behavior and effectiveness. In this study, we evaluate and compare the microbial and physicochemical behavior of EGSB systems during methylparaben and triclosan removal. The presence of different concentrations of pollutants had an influence on the cluster organization of microbial communities, especially bacteria. However, this did not affect the stability and performance of the EGSB systems. The banding patterns of the denaturing gradient gel electrophoresis of archaea demonstrated the constant presence and abundance of Methanosaeta concilii throughout all stages of operation, showing that this microorganism played a fundamental role in the stability of the reactors for the production of methane. The type of compound and its concentration influenced the expression of the mcrA and ACAs genes; however, these changes did not alter the stability and performance of the EGSB systems.


Aggravated CNS depression with urinary retention secondary to baclofen administration.
A 74-year-old woman with a history of cerebrovascular disease developed profound central nervous system (CNS) and respiratory depression, generalized hypotonia, sinus bradycardia, and urinary retention following an increase in dose of baclofen, an antispasticity agent. Before receiving baclofen therapy the patient had had minor urinary dysfunction associated with a remote cerebrovascular accident but no urinary retention. Cessation of baclofen therapy and the relief of the urinary obstruction improved mental status and normalized motor function within 24 hours. A withdrawal syndrome of agitation, hallucinosis, and convulsive activity persisted for eight days following discontinuation of the baclofen. Our experience suggests that patients with various forms of CNS disease states may be at risk of serious CNS depression with even small therapeutic doses of baclofen.


Knowledge coproduction to improve assessments of nature's contributions to people.
Sustainability science needs new approaches to produce, share, and use knowledge because there are major barriers to translating research into policy and practice. Multiple actors hold relevant knowledge for sustainability including indigenous and local people who have developed over generations knowledge, methods, and practices that biodiversity and ecosystem assessments need to capture. Despite efforts to mainstream knowledge coproduction, less than 3% of the literature on nature's contributions to people (NCP) integrates indigenous and local knowledge (ILK). Approaches and tools to better integrate scientific and ILK knowledge systems in NCP assessments are urgently needed. To fill this gap, we conducted interviews with ILK experts from Abancay and Tamburco, Peru, and convened focus groups and workshops during which participatory mapping, a serious game, a Bayesian belief network based on ILK were introduced. We inventoried 60 medicinal plants used to treat different illnesses, and analyzed the spatial distribution of the 7 plants that contribute the most to a good quality of life, and delineated their nonmedicinal uses. Based on the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services conceptual framework, we defined dimensions of a good quality of life according to indigenous and local worldviews. Medicinal plants contributed strongly to health and household security, among other contributions. Climate change and overexploitation were the main perceived threats to medicinal plants, despite the existence of formal and customary institutions to regulate trade. Our approach was flexible enough to integrate diverse forms of knowledge, as well as qualitative and quantitative information from, for example, the Bayesian belief network.


Parallel Rap1>RalGEF>Ral and Ras signals sculpt the C. elegans nervous system.
Ras is the most commonly mutated oncogene in humans and uses three oncogenic effectors: Raf, PI3K, and RalGEF activation of Ral. Understanding the importance of RalGEF>Ral signaling in cancer is hampered by the paucity of knowledge about their function in animal development, particularly in cell movements. We found that mutations that disrupt function of RalGEF or Ral enhance migration phenotypes of mutants for genes with established roles in cell migration. We used as a model the migration of the canal associated neurons (CANs), and validated our results in HSN cell migration, neurite guidance, and general animal locomotion. These functions of RalGEF and Ral are specific to their control of Ral signaling output rather than other published functions of these proteins. In this capacity Ral functions cell autonomously as a permissive developmental signal. In contrast, we observed Ras, the canonical activator of RalGEF>Ral signaling in cancer, to function as an instructive signal. Furthermore, we unexpectedly identified a function for the close Ras relative, Rap1, consistent with activation of RalGEF>Ral. These studies define functions of RalGEF>Ral, Rap1 and Ras signaling in morphogenetic processes that fashion the nervous system. We have also defined a model for studying how small GTPases partner with downstream effectors. Taken together, this analysis defines novel molecules and relationships in signaling networks that control cell movements during development of the nervous system.


Tibial subchondral trabecular bone micromechanical and microarchitectural properties are affected by alignment and osteoarthritis stage.
At advanced knee osteoarthritis (OA) stages subchondral trabecular bone (STB) is altered. Lower limb alignment plays a role in OA progression and modify the macroscopic loading of the medial and lateral condyles of the tibial plateau. How the properties of the STB relate to alignment and OA stage is not well defined. OA stage (KL scores 2-4) and alignment (HKA from 17° Varus to 8° Valgus) of 30 patients were measured and their tibial plateau were collected after total knee arthroplasty. STB tissue elastic modulus, bone volume fraction (BV/TV) and trabecula thickness (Tb.Th) were evaluated with nanoindentation and µCT scans (8.1 µm voxel-size) of medial and lateral samples of each plateau. HKA and KL scores were statistically significantly associated with STB elastic modulus, BV/TV and Tb.Th. Medial to lateral BV/TV ratio correlated with HKA angle (R = -0.53, p = 0.016), revealing a higher ratio for varus than valgus subjects. STB properties showed lower values for KL stage 4 patients. Tissue elastic modulus ratios and BV.TV ratios were strongly correlated (R = 0.81, p < 0.001). Results showed that both micromechanical and microarchitectural properties of STB are affected by macroscopic loading at late stage knee OA. For the first time, a strong association between tissue stiffness and quantity of OA STB was demonstrated.


Adenosine triphosphate regulates NADPH oxidase activity leading to hydrogen peroxide production and COX-2/PGE2 expression in A549 cells.
Non-small cell lung carcinoma (NSCLC) accounts for most of all lung cancers, which is the leading cause of mortality in human beings. High level of cyclooxygenase-2 (COX-2) is one of the features of NSCLC and related to the low survival rate of NSCLC. However, whether extracellular nucleotides releasing from stressed resident tissues contributes to the expression of COX-2 remains unclear. Here, we showed that stimulation of A549 cells by adenosine 5'-O-(3-thiotriphosphate) (ATPγS) led to an increase in COX-2 gene expression and prostaglandin E(2) (PGE(2)) synthesis, revealed by Western blotting, RT-PCR, promoter assay, and enzyme-linked immunosorbent assay. In addition, ATPγS induced intracellular reactive oxygen species (ROS) generation through the activation of NADPH oxidase. The increase of ROS level resulted in activation of the c-Src/epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/nuclear factor (NF)-κB cascade. We also found that activated Akt was translocated into the nucleus and recruited with NF-κB and p300 to form a complex. Thus, activation of p300 modulated the acetylation of histone H4 via the NADPH oxidase/c-Src/EGFR/PI3K/Akt/NF-κB cascade stimulated by ATPγS. Our results are the first to show a novel role of NADPH oxidase-dependent Akt/p65/p300 complex formation that plays a key role in regulating COX-2/PGE(2) expression in ATPγS-treated A549 cells. Taken together, we demonstrated that ATPγS stimulated activation of NADPH oxidase, resulting in generation of ROS, which then activated the downstream c-Src/EGFR/PI3K/Akt/NF-κB/p300 cascade to regulate the expression of COX-2 and synthesis of PGE(2) in A549 cells. Understanding the regulation of COX-2 expression and PGE(2) release by ATPγS on A549 cells may provide potential therapeutic targets of NSCLC.


Non-consensual sex in Benin.
The objective of the study is to investigate the prevalence and risk factors of non-consensual sex/rape in Benin. We surveyed 580 females in the University Community of Benin, 414 questionnaires were sufficiently completed for analysis. Seventy-six (18.4%) respondents reported that they had been victims of non-consensual sex (NCS), 36 in their current relationship. The unmarried single respondents had the lowest mean age at NCS experience of 18 years, while the divorced victims had the highest mean age of 32.5 ( P = 0.000). There was a major exposure peak age at 19 years with a smaller peak at 25. The majority of sex offenders were their present partners and next the husbands (22.2%). The father was the perpetrator on one (2.78%) occasion, while armed robbers raped two of the victims. Eighteen of the seventy-six respondents made a formal report. Cumulatively, 95.4% of the respondents felt it was futile reporting, four (5.3%) felt it was not all a bad experience. The risk of being infected with the HIV/AIDS virus was the worst fear. Ninety-five of four hundred and fourteen respondents want the public and parents to be educated, 64 would like the penal code to be tougher and better implemented, while 64 (14.0%) crave for a dress code for the University community. The self-reported incidence of NCS is high, majority were not formally reported as most of the sex offenders were the (ex)partners of the victims. There was a major exposure peak age at 19 with a smaller peak at 25 years. There was a condoned sense of futility and frustration in reporting.


Lithium-associated hypothyroidism and thyroid papillary carcinoma: a case report.
Ionizing radiation, some hereditary factors, and chronic thyroid-stimulating hormone elevation increases the risk of differentiated thyroid carcinoma. Lithium salts are used in the treatment of affective (mood) disorders as well as a variety of other psychiatric conditions. There have been occasional reports of hematologic and solid neoplasms associated with lithium use. We report a patient who developed hypothyroidism and subsequently, thyroid papillary carcinoma while on lithium treatment for bipolar affective disorder.


Integration and disruption effects of shape and texture in haptic search.
In a search task, where one has to search for the presence of a target among distractors, the target is sometimes easily found, whereas in other searches it is much harder to find. The performance in a search task is influenced by the identity of the target, the identity of the distractors and the differences between the two. In this study, these factors were manipulated by varying the target and distractors in shape (cube or sphere) and roughness (rough or smooth) in a haptic search task. Participants had to grasp a bundle of items and determine as fast as possible whether a predefined target was present or not. It was found that roughness and edges were relatively salient features and the search for the presence of these features was faster than for their absence. If the task was easy, the addition of these features could also disrupt performance, even if they were irrelevant for the search task. Another important finding was that the search for a target that differed in two properties from the distractors was faster than a task with only a single property difference, although this was only found if the two target properties were non-salient. This means that shape and texture can be effectively integrated. Finally, it was found that edges are more beneficial to a search task than disrupting, whereas for roughness this was the other way round.


[Suggestions for increasing physical activity levels of Korean older adults: a public health perspective].
2010 is the year when the Korean baby boomer generation faces retirement. With the need for affective strategies to keep this population healthy, the government has placed much effort to increase the regular physical activity (PA) level of older adults. Yet the prevalence of active seniors is still relatively low. This paper reviews the recent government strategies and efforts to enhance the physical activity levels of older adults and the PA programs provided in the community settings by major organizations and institutions. In addition, the problems of the current approaches are shown, and based on a review, the author provides five suggestions for promoting the PA level of older adults as follows. First, specific physical activity goals and objectives for older adults should be included in the National Health Plan 2020. Second, the recommendations for PA for seniors, which include a proper intensity, duration and frequency of exercise, should be provided. Third, the role of organizations and institutions should be rearranged for the proper dissemination of government provided community-based exercise programs. Fourth, a standard quality-control system should be provided, and finally, an evidence-based exercise program, which should be specifically created for the older Korean population, should be developed. Physical activity offers opportunities for people to extend the years of their active independent life and reduce functional limitations. To maximize the effects of government efforts to promote PA for seniors, we feel the comments provided in this paper should be closely examined.


Bovine mastitis therapy and why it fails.
Treatment of bovine mastitis depends on the cause, the clinical manifestation and the antibiotic susceptibility of the agent. Mastitis therapy is commonly unsuccessful owing to pathological changes that occur in the udder parenchyma as a result of the inflammatory reaction to mastitogenic bacteria, pharmacokinetic properties of antimicrobial mastitis drugs, mastitogenic bacterial and related factors, and poor animal husbandry and veterinary interventions.


Quantification of quantum dot concentration using inductively coupled plasma-mass spectrometry (ICP-MS).
As quantum dot (QD) bioconjugates are increasingly being used for biomedical in vitro and in vivo studies, validated methods for the quantitative determination of QD concentration are of considerable potential value. In this work, we have assessed inductively coupled plasma mass spectrometry (ICP-MS) as a method for the quantitative detection of QDs and QD bioconjugates. We have established a linear relationship between the concentration of unconjugated QD and the mass of cadmium, selenium and zinc detected by ICP-MS. Furthermore, ICP-MS was used to quantitatively estimate the unknown concentration of a QD-antibody bioconjugate. Quantitative measurement of QD bioconjugate concentration was also attempted by optical methods, including fluorescence and absorbance, and compared to ICP-MS. Consistent with previous literature, the fluorescence of the nanoparticle construct was reduced after functionalization with a biomolecule (biotin or streptavidin). Optical absorbance of the QD is unaffected by chemical modifications in this study and is a reliable method to determine the concentration. Optical absorption in this application achieves nanomolar concentrations but is not suitable for most biomedical studies that require a nanoparticle detection limit in the sub-nanomolar region. Unlike optical absorbance and fluorescence, ICP-MS can reliably detect the concentration of QD bioconjugates in the nanomolar range, making ICP-MS a quantitative, sensitive method for QD concentration measurements even after surface conjugation and consequent changes in fluorescence characteristics.


The influence of metabolic rate on longevity in the nematode Caenorhabditis elegans.
Much of the recent interest in aging research is due to the discovery of genes in a variety of model organisms that appear to modulate aging. A large amount of research has focused on the use of such long-lived mutants to examine the fundamental causes of aging. While model organisms do offer many advantages for studying aging, it also critical to consider the limitations of these systems. In particular, ectothermic (poikilothermic) organisms can tolerate a much larger metabolic depression than humans. Thus, considering only chronological longevity when assaying for long-lived mutants provides a limited perspective on the mechanisms by which longevity is increased. In order to provide true insight into the aging process additional physiological processes, such as metabolic rate, must also be assayed. This is especially true in the nematode Caenorhabditis elegans, which can naturally enter into a metabolically reduced state in which it survives many times longer than its usual lifetime. Currently it is seen as controversial if long-lived C. elegans mutants retain normal metabolic function. Resolving this issue requires accurately measuring the metabolic rate of C. elegans under conditions that minimize environmental stress. Additionally, the relatively small size of C. elegans requires the use of sensitive methodologies when determining metabolic rates. Several studies indicating that long-lived C. elegans mutants have normal metabolic rates may be flawed due to the use of inappropriate measurement conditions and techniques. Comparisons of metabolic rate between long-lived and wild-type C. elegans under more optimized conditions indicate that the extended longevity of at least some long-lived C. elegans mutants may be due to a reduction in metabolic rate, rather than an alteration of a metabolically independent genetic mechanism specific to aging.


Signaling-sensitive amino acids surround the allosteric ligand binding site of the thyrotropin receptor.
The thyrotropin receptor [thyroid-stimulating hormone receptor (TSHR)], a G-protein-coupled receptor (GPCR), is endogenously activated by thyrotropin, which binds to the extracellular region of the receptor. We previously identified a low-molecular-weight (LMW) agonist of the TSHR and predicted its allosteric binding pocket within the receptor's transmembrane domain. Because binding of the LMW agonist probably disrupts interactions or leads to formation of new interactions among amino acid residues surrounding the pocket, we tested whether mutation of residues at these positions would lead to constitutive signaling activity. Guided by molecular modeling, we performed site-directed mutagenesis of 24 amino acids in this spatial region, followed by functional characterization of the mutant receptors in terms of expression and signaling, measured as cAMP accumulation. We found that mutations V421I, Y466A, T501A, L587V, M637C, M637W, S641A, Y643F, L645V, and Y667A located in several helices exhibit constitutive activity. Of note is mutation M637W at position 6.48 in transmembrane helix 6, which has a significant effect on the interaction of the receptor with the LMW agonist. In summary, we found that a high proportion of residues in several helices surrounding the allosteric binding site of LMW ligands in the TSHR when mutated lead to constitutively active receptors. Our findings of signaling-sensitive residues in this region of the transmembrane bundle may be of general importance as this domain appears to be evolutionarily retained among GPCRs.